Amikacin

J Pharm Biomed Anal, 2005 Jan 4, 36(5), 969 - 74
Chemiluminescence determination of amikacin based on the inhibition of the luminol reaction catalyzed by copper; Ramos Fernandez JM et al.; A simple and sensitive method has been proposed for the amikacin sulphate determination . It is based on the inhibition of the chemiluminescence (CL) emission generated from the oxidation of luminol in alkaline medium by H(2)O(2) catalyzed by Cu(II), due to the interaction caused by amikacin, which forms a robust complex with the catalyst . The optimization of the experimental and instrumental variables affecting this CL inhibition effect has been carried out using statistical models, based on the application of two-level full factorial and Box-Behnken designs . The performance characteristics of the proposed method have been established, showing that the method is efficient to determine amikacin sulphate in the linear range of 9.89-20mg/L with a detection limit of 2.97mg/L . It has been successfully applied to the amikacin sulphate determination in pharmaceutical formulations.

Eur J Clin Microbiol Infect Dis . 2004 Dec 15; {Epub ahead of print}
Pneumonia involving Aspergillus and Rhizopus spp . after a near-drowning incident with subsequent Nocardia cyriacigeorgici and N . farcinica coinfection as a late complication; van Dam AP et al.; Reported here is the case of a 22-year-old man who developed pneumonia with unusual pathogens after a near-drowning incident . On day 7 following admission, Rhizopus spp . and Aspergillus fumigatus were cultured from the patient's bronchoalveolar lavage fluid . One week later, sputum cultures revealed N . cyriacigeorgici as well as N . farcinica . The patient recovered fully after prolonged therapy with liposomal amphotericin B, amikacin, meropenem and cotrimoxazole.

Support Care Cancer . 2004 Dec 15; {Epub ahead of print}
A randomized clinical trial of ceftriaxone and amikacin versus piperacillin tazobactam and amikacin in febrile patients with hematological neoplasia and severe neutropenia; Rossini F et al.; GOAL OF WORK: We compared the efficacy of ceftriaxone (CA regimen) and piperacillin-tazobactam (PTA regimen) in association with amikacin in the treatment of febrile episodes in severely neutropenic hematological patients . PATIENTS AND METHODS: A total of 252 febrile episodes in 224 patients were randomized . MAIN RESULTS: The CA regimen was effective in 62/122 evaluable episodes (50.8%), and the PTA regimen was effective in 64/121 (52.9%; P>0.2) . Median time to failure was 4 and 5 days (P>0.1) . Further infections developed in 21/122 episodes (17.2%) with the CA regimen and in 12/121 (9.9%) with the PTA regimen (P=0.06) . The overall mortality at the end of the febrile episode was 11/243 (4.5%); seven deaths were considered to be related to infection . CONCLUSIONS: Patients treated with piperacillin-tazobactam and amikacin tended to become afebrile sooner and to suffer a lower rate of further infections, even though our data did not show any statistically significant differences between the two groups.

J Chromatogr A, 2004 Nov 26, 1058(1-2), 197 - 201
Hydrophilic interaction chromatography combined with tandem-mass spectrometry to determine six aminoglycosides in serum; Oertel R et al.; A specific and automated method was developed to quantitate the aminoglycosides amikacin, gentamicin, kanamycin, neomycin, paromomycin, and tobramycin simultaneously in human serum . Samples were prepared with an automated solid phase extraction (SPE) . The hydrophilic interaction chromatography (HILIC) was used for separation of analytes from endogenous compounds and baseline separation . The aminoglycosides were detected with electrospray ionisation tandem mass spectrometry (ESI-MS-MS) . Using a volume of 500 microl biological sample the lower limits of quantification were 100 ng/ml or better . The described HILIC-MS-MS method is suitable for therapeutic drug monitoring and for clinical and pharmcokinetical investigations of the aminoglycosides.

Int J Syst Evol Microbiol, 2004 Nov, 54(Pt 6), 2385 - 91
Mycobacterium cosmeticum sp . nov., a novel rapidly growing species isolated from a cosmetic infection and from a nail salon; Cooksey RC et al.; Four isolates of a rapidly growing Mycobacterium species had a mycolic acid pattern similar to that of Mycobacterium smegmatis, as determined by HPLC analyses . Three of the isolates were from footbath drains and a sink at a nail salon located in Atlanta, GA, USA; the fourth was obtained from a granulomatous subdermal lesion of a female patient in Venezuela who was undergoing mesotherapy . By random amplified polymorphic DNA electrophoresis and PFGE of large restriction fragments, the three isolates from the nail salon were shown to be the same strain but different from the strain from the patient in Venezuela . Polymorphisms in regions of the rpoB, hsp65 and 16S rRNA genes that were shown to be useful for species identification matched for the two strains but were different from those of other Mycobacterium species . The 16S rRNA gene sequence placed the strains in a taxonomic group along with Mycobacterium frederiksbergense, Mycobacterium hodleri, Mycobacterium diernhoferi and Mycobacterium neoaurum . The strains produced a pale-yellow pigment when grown in the dark at the optimal temperature of 35 degrees C . Biochemical testing showed that the strains were positive for iron uptake, nitrate reduction and utilization of d-mannitol, d-xylose, iso-myo-inositol, l-arabinose, citrate and d-trehalose . The strains were negative for d-sorbitol utilization and production of niacin and 3-day arylsulfatase, although arylsulfatase activity was observed after 14 days . The isolates grew on MacConkey agar without crystal violet but not on media containing 5 % (w/v) NaCl or at 45 degrees C . They were susceptible to ciprofloxacin, amikacin, tobramycin, cefoxitin, clarithromycin, doxycycline, sulfamethoxazole and imipenem . The name Mycobacterium cosmeticum sp . nov . is proposed for this novel species; two strains, LTA-388(T) (=ATCC BAA-878(T)=CIP 108170(T)) (the type strain) and 2003-11-06 (=ATCC BAA-879=CIP 108169) have been designated, respectively, for the strains of the patient in Venezuela and from the nail salon in Atlanta, GA, USA.

Vet Res Commun, 2004 Jul, 28(5), 429 - 35
Pharmacokinetics of amikacin in lactating sheep; Haritova A et al.; The pharmacokinetics of amikacin (AMK) were investigated after intravenous (i.v.) and intramuscular (i.m.) administration of 7.5 mg/kg bw in 6 healthy lactating sheep . After i.v . AMK injection (as a bolus), the elimination half-life (t1/2beta), the volume of distribution (Vd,area), the total body clearance (ClB) and the area under the concentration-time curve (AUC) were 1.64 +/- 0.06 h, 0.19 +/- 0.02 L/kg, 1.36 +/- 0.1 ml/min per kg and 94.09 +/- 6.95 (microg.h)/ml, respectively . The maximum milk concentration of AMK (Cmax), the area under the milk concentration-time curve (AUCmilk) and the ratio AUCmilk/AUCserum were 1.18 +/- 0.22 microg/ml, 22.45 +/- 3.21 (micro.h)/ml and 0.24 +/- 0.02, respectively . After i.m . administration of AMK the t1/2beta, Cmax, time of Cmax (tmax) and absolute bioavailability (Fabs) were 1.29 +/- 0.1 h, 16.97 +/- 1.54 microg/ml, 1.0 +/- 0 h and 64.88% +/- 6.16%, respectively . The Cmax, AUCmilk and the ratio AUCmilk/AUCserum were 0.33 microg/ml, 1.67 (microg.h)/ml and 0.036, respectively.

J Coll Physicians Surg Pak, 2004 Sep, 14(9), 522 - 6
Allogeneic peripheral blood stem cell transplantation in patients with haematological malignancies; Shamsi TS et al.; OBJECTIVE: To report the initial data on allogeneic peripheral blood stem cell transplantation for haematological malignancies in Pakistan . DESIGN: A single centre descriptive study . PLACE AND DURATION OF STUDY: Bismillah Taqee Institute of Health Sciences and Blood Diseases Centre from September 1999 to June 2004 . PATIENTS AND METHODS: Patients with haematological malignancies were included who had received allogeneic PBSC transplantation of Filgrastim (rhG-CSF) mobilized peripheral blood stem cells from HLA-identical siblings (except one 5/6 antigen sibling) with Busulphan and Cyclophosphamide standard conditioning therapy in all patients . No patient received antibiotics for gut decontamination . Empirical antibiotics included Ceftriaxone and Amikacin for febrile neutropenia, oral Itraconazole for antifungal prophylaxis while oral acyclovir was used for antiviral prophylaxis . All donors and recipients were CMV IgG positive Cyclosporin A / Methotrexate were given for graft versus host disease (GvHD) prophylaxis . Stem cells were harvested using Haemonetics MCS+ cell separator . All patients received G-CSF starting from day +4 until their neutrophil count rose to normal . RESULTS: There were 21 patients with age range of 8-38 years and male to female ratio of 2:1 . Engraftment was achieved in all patients; median time to absolute neutrophil count of > 0.5 x 10(9)/l was 10 days (range 8 - 12 days) and platelet count of > 20 x 10(9)/l was 14 days (12-17 days) . Acute graft versus host disease ( aGvHD) was seen in 7 patients; one patient had grade IV skin and hepatic GvHD; another patient had grade III gut GvHD, grade II GvHD was seen in 3 patients while grade I skin aGvHD was seen in 2 patients . Median hospital stay was 34 days . Treatment related mortality was seen in 3 patients (18%) . Chronic GvHD was seen in 5 patients . Four more patients died during the follow-up period . Malaria was seen in 2 while tuberculosis developed in one case . Relapse was seen in 2 patients . The estimated probability of survival at one hundred day, at one year and five years was 82, 47 and 40 percent respectively . CONCLUSION: Haematopoietic stem cell transplant programme can be developed in a developed country setting . Post transplant complications are similar to what have been reported in the developed countries . In endemic areas malaria could prove to be fatal if not recognised and treated early.

ANZ J Surg, 2004 Aug, 74(8), 662 - 6
Mycobacterium fortuitum: an iatrogenic cause of soft tissue infection in surgery; Muthusami JC et al.; BACKGROUND: Mycobacterium fortuitum is an uncommon cause of soft tissue infections . Treatment is often inadequate with persistence of infection unless the aetiological agent and its antibiotic sensitivity are accurately established . METHODS: Medical records of 23 patients with chronic soft tissue infection caused by M . fortuitum over a 12-year period from 1991 to 2002 were studied . RESULTS: In 20 patients the cause was iatrogenic, following intramuscular injections (12), laparoscopy (5) and other surgical procedures (3) and in three patients discharging sinuses developed spontaneously . Patients presented with recurrent abscesses or chronic discharging sinuses that did not respond to conventional surgical drainage . The diagnosis was established by isolating M . fortuitum from the tissues in all cases . The treatment consisted of a more aggressive surgical intervention in form of excision, debridement and extensive lay open with curettage and prolonged administration of appropriate antibiotics . The organism showed maximum sensitivity to amikacin and ciprofloxacin . Healing occurred in all cases . Three patients suffered recurrences: two responded to further debridement and antibiotics and are well at 2 and 5 years, respectively . CONCLUSION: A high index of suspicion based on clinical presentation is essential to diagnose M . fortuitum as a cause of soft tissue infection . Treatment involves aggressive surgical debridement and administration of combination antibiotics based on sensitivity, which should be continued for a period that will ensure complete healing and prevent recurrence.

J Comp Neurol, 2004 Sep 13, 477(2), 149 - 60
Calpain activity in the amikacin-damaged rat cochlea; Ladrech S et al.; The principal aim of this study was to investigate the involvement of calpain in the degeneration of hair cells and ganglion neurons in the amikacin-poisoned rat cochlea . An antibody designed against fodrin-breakdown products (FBDP), which result exclusively from cleavage by calpain, was used . In addition, the involvement of both caspases and protein kinase C (PKC) was studied using, respectively, antibodies against activated caspase 3 and PKCgamma . The results demonstrate the accumulation of FBDP in the degenerating hair cells, in some supporting cells such as Deiters cells, and, later, in the affected ganglion neurons that had been deprived of their sensory targets . Activated caspase 3 was evidenced in a few dying hair cells and ganglion neurons . PKCgamma was highly expressed in all ganglion neurons, sometimes after the loss of hair cells . We conclude that calpain plays a role in the degradation of both the sensory cells and neurons after amikacin ototoxicity . In the poisoned hair cells, calpain and caspase 3 may have synergistic effects in the process of apoptosis . In the ganglion neurons deprived of their sensory elements, calpain may have a prominent role in cell degradation . By contrast, in these ganglion neurons PKCgamma may be implicated in a survival process . Finally, we suggest that calpain is involved in the remodeling of Deiters cells during the scarring process that follows hair cell loss.

J Clin Pathol, 2004 Aug, 57(8), 807 - 12
Secular trends of nocardia infection over 15 years in a tertiary care hospital; Matulionyte R et al.; AIMS: To assess the incidence of nocardia infection over 15 years in a tertiary care hospital . METHODS: Over a 15 year period, Nocardia spp were isolated from 20 patients hospitalised at the Geneva University Hospitals, Switzerland . RESULTS: Sixteen patients had one or more underlying conditions . The median time between symptom onset and diagnosis was 30 days . The most common initial unconfirmed diagnosis was pulmonary tuberculosis (four) . The lung was involved in 16 cases, followed by the central nervous system (two) and skin (two); one patient had disseminated infection . The most common species identified was N asteroides . In vitro susceptibility testing was performed on 14 of 20 strains . All strains were susceptible to imipenem and amikacin . Initial treatment with trimethoprim/sulfamethoxazole (TMP/SMX) was started in 14 patients, although five patients had to be switched to another treatment because of side effects or lack of efficacy . A cure was observed in 15 patients, death in three, and relapse or complications in two . CONCLUSIONS: Nocardiosis can become a severe infection and mainly affects profoundly immunocompromised patients . Differential diagnosis often delays the time to diagnosis, which worsens the outcome . New diagnostic tools, such as the polymerase chain reaction, could provide more rapid and reliable results . TMT/SMX was the most commonly prescribed treatment, but needed to be changed for another treatment because of side effects or lack of efficacy in a considerable proportion of patients . Imipenem should be used as an alternative treatment for severely ill patients, and the sulfa combination for less severe infections.

Clin Infect Dis, 2004 Jul 15, 39 Suppl 1, S56 - 8
Monotherapy versus dual therapy based on risk categorization of febrile neutropenic patients; Ohyashiki K; Cefepime monotherapy was compared with cefepime-plus-amikacin dual therapy for treatment of febrile neutropenic patients . Response rates were significantly lower for patients receiving monotherapy who had neutrophil counts of <500 cells/mm3 but did not differ significantly between patients receiving dual therapy who had neutrophil counts of > or =500 cells/mm3 or <500 cells/mm3 . Dual therapy is recommended for the initial treatment of patients with neutropenia with <500 cells/mm3 . Dual therapy was significantly more effective in patients with neutropenia lasting <5 days . The response rates to monotherapy or dual therapy did not differ significantly when neutropenia persisted for > or =6 days, indicating that sustained neutropenia is a risk factor for failure of initial empirical therapy . The rate of response to monotherapy was lower in leukemic patients, whereas the rate of response to dual therapy did not differ between leukemic and nonleukemic groups . The rate of response to either monotherapy or dual therapy did not differ for patients with temperatures of > or =38 degrees C or 37.5 degrees C-38 degrees C . Overall, defervescence occurred in >80% of patients with mild infections, whereas only 32% of those with moderate to severe infection responded by day 3 and 69.8% by day 7.

Biol Neonate, 2004, 86(3), 207 - 11 Epub 2004 Jul 07.
Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life; Allegaert K et al.; The aim of this study was to assess the effects of intravenous co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin during the first days of life in preterm infants . The pharmacokinetics of amikacin were retrospectively calculated in a cohort of 73 neonates (gestational age <31 weeks) who received either ibuprofen-lysine or placebo following inclusion in the multicentre ibuprofen prophylaxis study . Assuming a one-compartment model with instantaneous input and first-order output, there was no significant difference in the median distribution volume (0.63 vs . 0.59 liters/kg), but the median serum half-life (16.4 vs . 12.4 h) of amikacin was significantly longer (p <0.02), and the clearance (0.36 vs . 0.6 ml/kg/min; p <0.005) of amikacin was significantly lower in infants who received ibuprofen-lysine . We conclude that the time interval between consecutive amikacin administrations should be prolonged, if ibuprofen-lysine is co-administered.

Zhonghua Jie He He Hu Xi Za Zhi, 2004 May, 27(5), 328 - 31
{Treatment and a follow-up study on wound infection by Mycobacterium chelonae: report of 168 cases}; Weng KR et al.; OBJECTIVE: To summarize the experience of treatment on wound infection by non-tuberculous Mycobacterium (NTM) after operations . METHODS: A hundred and sixty-eight patients with NTM incision infection were retrospectively reviewed in terms of diagnosis, treatment and follow-up in a period of 4.5 years . On the basis of the results of in vitro drug sensitivity test, the main antibiotics used were clarithromycin and amikacin . The course of therapy was 4 - 8 months . An extirpative excision was performed in 104 cases following one month treatment by antibiotics and then followed by antibiotic therapy for 3 - 5 months after excision . RESULTS: Primary closure was achieved in 98 of the 104 cases . Fifty patients were cured by the use of antibiotics with dressing change . Eight patients were cured by dressing change without antibiotics . Five children with wound infection by NTM after circumcision were cured by antibiotics with local laser therapy . One patient with infection after hernia operation was cured by amikacin blocking of the area surrounding the lesion . There was no relapse after follow-up for four and half years . CONCLUSION: The study demonstrates that sensitive antibiotics combined with surgery extirpative excision is effective for wound infection by NTM.

Eur Arch Otorhinolaryngol . 2004 May 28; {Epub ahead of print}
Dose-dependent dual effect of melatonin on ototoxicity induced by amikacin in adult rats; Erdem T et al.; ABTRACTThe aim of this animal study was to reveal the dose-dependent effects of melatonin on aminoglycoside ototoxicity by utilizing distortion product otoacoustic emissions (DPOAEs) . Forty-four adult (aged 12 months) rats were divided into five groups . Rats of the control group (group C) were injected with vehicle, while the melatonin group (group M) received melatonin (4 mg/kg per day); there were four rats in each of these groups . The study groups consisted of 12 rats per group, and they were treated as follows: 600 mg/kg per day amikacin (group A), amikacin plus a low dose (0.4 mg/kg per day) melatonin (group AML) and amikacin plus high dose (4 mg/kg per day) melatonin (group AMH) for 14 days . During the serial measurements on days 0, 5, 10 and 15, the DPOAE results of groups C,M and AML were not significantly changed . Amikacin ototoxicity findings for input/output (I/O) functions were detected on the 3rd measurement of the study in group A . High-dose melatonin clearly enhanced and accelerated amikacin-induced ototoxicity . The DP-gram amplitudes and I/O amplitudes were reduced, and I/O thresholds were increased in group AMH . Group AMH was the group that was affected the most and earliest by amikacin . Our study results showed that while low-dose melatonin protected the inner ear from ototoxicity, high dose melatonin facilitated amikacin-induced ototoxicity, possibly via the vasodilatory effect, leading to an increased accumulation of amikacin in the inner ear . Probably, the protective effect of the melatonin at a dose of 0.4 mg/kg per day is related to its antioxidant properties . Apparently, the vasodilatory effect of melatonin seems to be more prominent than its antioxidant effect in high doses.

J Infect Chemother, 2004 Apr, 10(2), 101 - 4
Subcutaneous tissue release of amikacin from a fibrin glue/polyurethane graft; Nishimoto K et al.; We investigated whether fibrin glue (FG) might be useful as a carrier of amikacin (AMK) for prevention of local graft infection . After AMK (4.0 mg)-treated FG (AMK-FG) polyurethane grafts were implanted subcutaneously in the anterior abdominal region of Sprague-Dawley rats, AMK concentrations in tissues surrounding the implantation sites were compared over time with concentrations at the same sites in rats given an intravenous injection of AMK (4.0 mg) . In the injection group, AMK concentrations in serum were detectable only for 4 h, whereas AMK released from AMK-FG grafts remained detectable over 24 h . Until 4 h after implantation, AMK concentrations in tissues near implantation sites were significantly higher in the AMK-FG graft group than in the injection group; peak local concentrations during that time were 210 times higher for the AMK-FG graft group than for the injection group . Areas under the tissue concentration-time curve (AUC) for AMK were 171 microg x h/g and 1.35 microg x h/g in the AMK-FG graft and injection groups, respectively . FG therefore was considered to control release of AMK and to maintain a high AMK concentration in tissues surrounding the implantation site . Thus, AMK-FG polyurethane graft delivery may be useful in preventing local infection by local delivery of AMK.

Clin Infect Dis, 2004 Jun 1, 38(11), 1538 - 44 Epub 2004 May 05.
Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases; Peloquin CA et al.; Aminoglycoside use is limited by ototoxicity and nephrotoxicity . This study compared the incidences of toxicities associated with 2 recommended dosing regimens . Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin . Doses were adjusted to achieve target serum concentrations . The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels) . Risk of ototoxicity (found in 32 {37%} of the patients) was associated with older age and with a larger cumulative dose received . Vestibular toxicity (found in 8 {9%} of the patients) usually resolved, and nephrotoxicity (found in 13 {15%} of the patients) was mild and reversible in all cases . Subjective changes in hearing or balance did not correlate with objective findings . Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Acta Paediatr, 2004 Mar, 93(3), 356 - 60
Evaluation of an amikacin loading dose for nosocomial infections in very low birthweight infants; Berger A et al.; AIM: To develop a simplified amikacin dosage regimen for nosocomial infections in preterm infants including a loading dose in order to achieve therapeutic Maximum Serum Concentrations early in the course of therapy . METHODS: Open, non-comparative study during November 2000 to April 2001 . The modified amikacin dosing and monitoring protocol included a loading dose of 10 mg/kg in the first week of life, followed by a maintenance regimen of 7.5 mg/kg every 24 h . After the first week of life the corresponding doses were 17 mg/kg (loading) and 15 mg/kg (maintenance) . A peak level was measured 30 min after the second dose, a trough level immediately before the third dose . RESULTS: Twenty-five very low birthweight infants (median birthweight 739 g, median gestational age 25 wk) who had 34 episodes of amikacin treatment were included in the analysis . Median amikacin peak and trough values were 37.1 micromol/l and 6.3 micromol/l, respectively . Twenty-nine of all peak levels (85%) and 30 of all trough levels (88%) were within the targeted range of >35 micromol/l and <8.5 micromol/l, respectively . All patients with elevated trough levels were of extremely low birthweight and were born in the 24th week of gestation . Hearing evaluations were performed in 17 of 19 surviving infants at discharge home, all of which gave normal results . CONCLUSION: The new amikacin dosing protocol yielded targeted peak and trough concentrations in a high percentage of very low birthweight infants with nosocomial infection after the first week of life . Our simplified dosage regimen achieved acceptable serum concentrations in all birthweight and gestational age groups, with the exception of extremely low birthweight infants weighing less than 700 g and/or with a gestational age of 24 wk or less . Only limited information can be gained from our data regarding the use of amikacin during the first week of life.

Mycoses, 2004 Apr, 47(3-4), 156 - 8
Protothecosis successfully treated with amikacin combined with tetracyclines; Zhao J et al.; Summary We report a case of protothecosis in an 18-year-old female student caused by Prototheca zopfii successfully treated with amikacin combined with tetracyclines . Zusammenfassung Es wird uber eine Protothecose, verursacht durch Prototheca zopfii, bei einer 18-jahrigen Studentin berichtet, die erfolgreich mit Amikacin in Kombination mit Tetracyclinen behandelt wurde.

Z Geburtshilfe Neonatol, 2004 Feb, 208(1), 32 - 5
{Complicating neonatal Escherichia coli meningitis}; Sonntag J et al.; Neonatal Escherichia coli meningitis is a serious disease with high mortality and poor outcome . Ventriculitis, brain abscess and subdural empyema are frequent, with no homogeneous recommendations available for these complications . The case of a newborn infant who developed sepsis and meningitis caused by E . coli is presented . During intravenous treatment with ampicillin, cefotaxime and gentamycin in recommended doses, the patient developed severe subdural abscesses detected on MRI . After consequent antibiotic therapy over 2 months with fosfomycin, amikacin and meropenem the patient improved clinically and the abscesses regressed and disappeared without neurosurgical intervention . At the age of 6.5 months the infant is healthy and well developed . The conservative treatment of subdural abscesses complicating neonatal Escherichia coli meningitis without neurosurgical intervention is possible . The treatment of the individual case should be discussed between pediatrician and neurosurgeon.

J Pharm Biomed Anal, 2004 Mar 10, 34(5), 1021 - 7
Selective kinetic determination of amikacin in serum using long-wavelength fluorimetry; Sanchez-Martinez ML et al.; A simple and rapid method for the determination of the antibiotic amikacin, involving the use of a long-wavelength fluorophor, namely indocyanine green, (ICG) is presented . The dye is oxidised by cerium(IV) in acidic medium, resulting in a sharp decrease of the fluorescence, but this fluorescence quenching is inhibited in the presence of amikacin, which can be ascribed to the formation of an ion pair between the fluorophor and the analyte . The initial rate of the system is monitored at lambda(ex): 765 nm and lambda(em): 812 nm as excitation and emission wavelengths, respectively, using the stopped-flow mixing technique, which makes the method applicable to automatic routine analysis . Each measurement is obtained in only 2-3s . The method presents a detection limit of 0.02 microg m1(-1) in standard solutions, which corresponds to 2.5 microg ml(-1) in serum samples . The precision is in the range 4.8-6% . The good selectivity of the method allows amikacin to be determined in the presence of other antibiotics, including other aminoglycoside antibiotics, in serum . The recoveries obtained from the analysis of different samples were in the range 89.4-104.7%.

Ann Neurol, 2004 Mar, 55(3), 422 - 6
Readthrough of dystrophin stop codon mutations induced by aminoglycosides; Howard MT et al.; We report the translational readthrough levels induced by the aminoglycosides gentamicin, amikacin, tobramycin, and paromomycin for eight premature stop codon mutations identified in Duchenne's and Becker's muscular dystrophy patients . In a transient transfection reporter assay, aminoglycoside treatment results show that one stop codon mutation is suppressed significantly better (up to 10% stop codon readthrough) than the others; five show lower but statistically significant suppression (< 2% stop codon readthrough); and two appear refractory to aminoglycoside treatment . Readthrough levels do not substantially vary between different sources of gentamicin, and, for this set of mutations, the efficiency of termination at the premature stop codon mutation does not appear to correlate with disease severity.

J Formos Med Assoc, 2003 Nov, 102(11), 805 - 7
Therapeutic keratectomy for Mycobacterium abscessus keratitis after LASIK; Sun YC et al.; We report successful treatment of a case of Mycobacterium abscessus keratitis after laser in situ keratomileusis (LASIK) with therapeutic lamellar keratectomy . A 34-year-old woman developed a 2 x 2 mm feathery infiltration within the interface inferior to the pupil margin with mild inflammation of the conjunctiva in her left eye 40 days after LASIK surgery . Bacterial culture from the infiltrates of the interface of the stromal bed revealed Mycobacterium abscessus . After combination antibiotic therapy including amikacin and ciprofoxacin was given for 6 weeks, infiltration persisted despite the development of necrosis in the flap tissue . Therapeutic lamellar keratectomy combined with flap removal was performed . No recurrence was found 1 year after the surgery . Therapeutic lamellar keratectomy with flap removal can provide an effective treatment modality for the management of post-LASIK Mycobacterium abscessus keratitis that is unresponsive to medical treatment.

J Dermatol, 2003 Oct, 30(10), 742 - 7
Pulse therapy with amikacin and dapsone for the treatment of actinomycotic foot: a case report; Sharma N et al.; Actinomycetoma is a chronic disease caused by aerobic actinomycetes and affecting the skin, subcutaneous tissue, and bones . It causes significant morbidity and clinically manifests as abscesses and sinus/fistulae with or without granules . Early diagnosis is based on the color, size, histopathology of the granules; culture and metabolic studies are used for further species differentiation . Although sulfamethoxazole-trimethoprim alone or in combination with dapsone for a variable period of time are used as first line agents for treatment, slow response to the therapy and high relapse rates have led to increasing usage of alternative agents like gentamycin, amikacin and cefotaxime . We report a case of actinomycetoma foot who had complete treatment failure with a sulfamethoxazole-trimethoprim-dapsone combination and was successfully treated with combination therapy of amikacin and dapsone without any side effects.

Arch Otolaryngol Head Neck Surg, 2003 Dec, 129(12), 1331 - 3
Reversible anosmia after amikacin therapy; Welge-Luessen A et al.; Olfactory disorders are among the rare adverse effects of antibiotic therapy . To date, olfactory losses or distortions have been reported after the use of doxycycline, amoxicillin, clarithromycin, roxithromycin, kanamycin sulfate, and streptomycin sulfate . We describe what we believe to be the first case of transient anosmia associated with the use of intravenous amikacin sulfate . The appearance of the disorder and its subsequent resolution were demonstrated by psychometric testing as well as by chemosensory evoked potentials . Based on the well-documented temporal course of the anosmia, there is a probable causal correlation between the administration of amikacin and the appearance of the olfactory disturbance . However, the exact pathogenesis of the anosmia is still a matter of conjecture.

Shanghai Kou Qiang Yi Xue, 2003 Apr, 12(2), 96 - 8
{Analysis of parotid sialography and intervention in 78 cases of chronic pyogenic parotitis}; Mu BQ et al.; OBJECTIVE: To study the value of parotid sialography and intervention in the diagnosis and treatment of chronic pyogenic parotitis . METHODS: Undertake the technique of parotid sialography with 48% Lipiodol ultra-fluide (France) under X-ray upon 78 patients who were given systemic anti-infections and supporting treatments only with non-obvious-results, and classify all the cases into chronic obstructive (21 cases) and nonobstructive parotitis (57 cases) according to the results of sialography through microcatheter, then go on with bacterial culture and drug sensitivity test . Filling treatments were carried out on obstructive parotitis cases through the duct with mixed liquor consisting of 2% lidocanine, 1% methylviolet . In the same way, alpha-chymotrypsin, amikacin, lidocaine was used in nonobstructive cases . RESULTS: The cure rate of chronic obstructive parotitis was 80.95%, the cure rate of chronic nonobstructive parotitis was 87.72% . CONCLUSION: The method of parotid sialography and intervention in the diagnosis and treatment of chronic pyogenic parotitis is an effective way to treat chronic pyogenic parotitis.

J Clin Pharm Ther, 2003 Oct, 28(5), 425 - 32
Application of artificial neural network modelling to identify severely ill patients whose aminoglycoside concentrations are likely to fall below therapeutic concentrations; Yamamura S et al.; OBJECTIVE: Identification of ICU patients whose concentrations are likely to fall below therapeutic concentrations using artificial neural network (ANN) modelling and individual patient physiologic data . METHOD: Data on indicators of disease severity and some physiologic data were collected from 89 ICU patients who received arbekacin (ABK) and 61 who received amikacin (AMK) . Three-layer ANN modelling and multivariate logistic regression analysis were used to predict the plasma concentrations of the aminoglycosides (ABK and AMK) in the severely ill patients . RESULTS: Predictive performance analysis showed that the sensitivity and specificity of ANN modelling was superior to multivariate logistic regression analysis . For accurate modelling, a predictable range should be inferred from the data structure before the analysis . Restriction of the predictable region, based on the data structure, increased predictive performance . CONCLUSION: ANN analysis was superior to multivariate logistic regression analysis in predicting which patients would have plasma concentrations lower than the minimum therapeutic concentration . To improve predictive performance, the predictable range should be inferred from the data structure before prediction . When applying ANN modelling in clinical settings, the predictive performance and predictable region should be investigated in detail to avoid the risk of harm to severely ill patients.

J Am Vet Med Assoc, 2003 Nov 15, 223(10), 1469 - 74
Injection of corticosteroids, hyaluronate, and amikacin into the navicular bursa in horses with signs of navicular area pain unresponsive to other treatments: 25 cases (1999-2002); Dabareiner RM et al.; OBJECTIVE: To determine history, clinical and radiographic abnormalities, and outcome in horses with signs of navicular area pain unresponsive to corrective shoeing and systemic nonsteroidal anti-inflammatory drug administration that were treated with an injection of corticosteroids, sodium hyaluronate, and amikacin into the navicular bursa . DESIGN: Retrospective study . ANIMALS: 25 horses . PROCEDURE: Data collected from the medical records included signalment, history, horse use, severity and duration of lameness, shoeing regimen, results of diagnostic anesthesia, radiographic abnormalities, and outcome . RESULTS: 17 horses had bilateral forelimb lameness, 7 had unilateral forelimb lameness, and 1 had unilateral hind limb lameness . Mean duration of lameness was 9.2 months . All horses had been treated with corrective shoeing and nonsteroidal anti-inflammatory drugs for at least 6 months; 18 had previously been treated by injection of corticosteroids and sodium hyaluronate into the distal interphalangeal joint . Fourteen horses had mismatched front feet, and 21 horses had signs of pain in response to application of pressure over the central aspect of the frog . Palmar digital nerve anesthesia resulted in substantial improvement in or resolution of the lameness in all horses . Twenty horses (80%) were sound and returned to intended activities 2 weeks after navicular bursa treatment; mean duration of soundness was 4.6 months . Two horses that received numerous navicular bursa injections had a rupture of the deep digital flexor tendon at the level of the pastern region . CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that navicular bursa treatment may provide temporary improvement in horses with signs of chronic navicular area pain that fail to respond to other treatments.

Indian J Ophthalmol, 2003 Sep, 51(3), 263 - 5
Interface keratitis due to Mycobacterium fortuitum following laser in situ keratomileusis; Fogla R et al.; A case of unilateral interface keratitis due to Mycobacterium fortuitum following simultaneous bilateral LASIK procedure for low myopia is reported . Excimer phototherapeutic keratectomy was performed to the stromal bed to reduce the infective load . Intensive topical therapy with topical amikacin and ciprofloxacin resulted in resolution of the keratitis.

Antimicrob Agents Chemother, 2003 Oct, 47(10), 3296 - 304
Inhibition of aminoglycoside 6'-N-acetyltransferase type Ib-mediated amikacin resistance by antisense oligodeoxynucleotides; Sarno R et al.; Amikacin has been very useful in the treatment of infections caused by multiresistant bacteria because it is refractory to the actions of most modifying enzymes . However, the spread of AAC(6')-I-type acetyltransferases, enzymes capable of catalyzing inactivation of amikacin, has rendered this antibiotic all but useless in some parts of the world . The aminoglycoside 6'-N-acetyltransferase type Ib, which is coded for by the aac(6')-Ib gene, mediates resistance to amikacin and other aminoglycosides . RNase H mapping and computer prediction of the secondary structure led to the identification of five regions accessible for interaction with antisense oligodeoxynucleotides in the aac(6')-Ib mRNA . Oligodeoxynucleotides targeting these regions could bind to native mRNA with different efficiencies and mediated RNase H digestion . Selected oligodeoxynucleotides inhibited AAC(6')-Ib synthesis in cell-free coupled transcription-translation assays . After their introduction into an Escherichia coli strain harboring aac(6')-Ib by electroporation, some of these oligodeoxynucleotides decreased the level of resistance to amikacin . Our results indicate that use of antisense compounds could be a viable strategy to preserve the efficacies of existing antibiotics to which bacteria are becoming increasingly resistant.

Eur J Drug Metab Pharmacokinet, 2003 Jan-Mar, 28(1), 1 - 6
Relative pharmacokinetics of three amikacin brands in onco-hemotologic pediatric patients experiencing febrile neutropeina; Jamshaid M et al.; Three commercially available brands of amikacin were investigated in a parallel study design for the assessment of comparative pharmacokinetics in pediatric oncology patients with chemotherapy-induced neutropenic febrile episode . Amikacin concentration in serum samples was determined by fluorescence polarization immunoassay method using Abbott TDx system . Computer software, PK II was used for computation of pharmacokinetic parameters of amikacin . The serum concentration of all brands nonsignificantly (p > 0.05) varied at all time points, except at 1 and 2 hrs post dosing . At 1 hr post dosing, the serum concentration of brand II varied from rest of two brands . Whereas at 2 hr following I/V infusion, brands II and I were statistically different . Highest serum concentration of 38.69 +/- 1.45 microg/ml was observed in case of brand III while brands I and II showed lower but not significantly different serum concentration values, i.e., 36.30 +/- 1.65 and 37.89 +/- 1.32 microg/ml, respectively when compared with brand I . The other pharmacokinetic parameters of 3 brands found to have non-significant difference (P < 0.05) except, t(1/2)alpha and Cl of brands I and II that deviated statistically significant (p < 0.01) . The relative bioavailability of brand II and III as compared with brand I, considered as standard 86.17 and 96.86%, respectively falls within the accepted limits of +/- 20% required for the bioequivalence of any two brands . Based upon findings of the present study, all these brands may be used interchangeably in oncology patients . Further studies, however are needed to determine whether the statistically elevated Cl value in brand II is of any clinical significance.

Braz J Infect Dis, 2003 Apr, 7(2), 111 - 20
Evaluation of ticarcillin/clavulanic acid versus ceftriaxone plus amikacin for fever and neutropenia in pediatric patients with leukemia and lymphoma; Petrilli AS et al.; BACKGROUND: The empirical use of antibiotic treatments is widely accepted as a means to treat cancer patients in chemotherapy who have fever and neutropenia . Intravenous monotherapy, with broad spectrum antibiotics, of patients with a high risk of complications is a possible alternative . METHODS: We conducted a prospective open-label, randomized study of patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy . Patients received either monotherapy with ticarcillin/clavulanic acid (T) or ceftriaxone plus amikacin (C+A) . RESULTS: Seventy patients who presented 136 episodes were evaluated, 68 in each arm of the study . The mean neutrophil counts at admission were 217cells/mm(3) (T) and 201cells/mm(3) (C+A) . The mean duration of neutropenia was 8.7 days (T) and 7.6 days (C+A) . Treatment was successful without the need for modifications in 71% of the episodes in the T group and 81% in the C+A group (p=0.23) . Treatment was considered to have failed because of death in two episodes (3%) in the T group and three episodes (4%) in the C+A group, and because of a change in the drug applied in one episode in the T group and two episodes in the C+A group . Overall success was 96% (T) and 93% (C+A) . Adverse events that occurred in group T were not related to the drugs used in this study . CONCLUSION: In pediatric and adolescent patients with leukemia or lymphoma, who presented with fever and neutropenia, during chemotherapy, ticarcillin/clavulanic acid was as successful as the combination of ceftriaxone plus amikacin . It should be considered an appropriate option for this group of patients at high risk for infections.

Adv Drug Deliv Rev, 2003 Sep 12, 55(9), 1233 - 51
Clinical application of artificial neural network (ANN) modeling to predict pharmacokinetic parameters of severely ill patients; Yamamura S; Artificial neural network (ANN) modeling was used to evaluate the pharmacokinetics of aminoglycosides (arbekacin sulfate and amikacin sulfate) in severely ill patients . The plasma level was predicted by ANN modeling using parameters related to the severity of the patient's condition and the predictive performance was shown to be better than could be achieved using multiple regression analysis . These results indicate that there is a non-linear relationship between the pharmacokinetics of aminoglycosides and the severity of the patient's condition, and this should be taken into account when determining the dose for severely ill patients . Patients whose plasma levels are likely to fall below the effective level can be identified by ANN modeling with a predictive sensitivity and specificity superior to multivariate logistic regression analysis . The predictable range should be inferred from the data structure before the modeling in order to improve the predictive performance . The volume of distribution (Vd) in the normal range was weakly predicted by ANN modeling from the patients' data . Prediction of clearance by ANN modeling was poorer than that obtained from serum creatinine concentration by linear regression analysis . These results suggest that the input-output relationship (linear or non-linear) should be taken into account in selecting the modeling method . Linear modeling can give better predictive performance for linear systems and non-linear modeling can give better predictive performance for non-linear systems . In general, the performance of ANN modeling was superior to linear modeling for PK/PD prediction . For accurate modeling, a predictable range should be inferred from the data structure before the analysis . Restriction of the predictable region, as determined from the data structure, produced an increase in prediction performance . When applying ANN modeling in clinical settings, the predictive performance and predictable region should be investigated in detail to avoid the risk of harm to severely ill patients.

J Pediatr Nurs, 2003 Aug, 18(4), 287 - 92
Life span of peripheral intravenous cannula in a neonatal intensive care unit of a developing country; Gupta P et al.; The use of peripheral intravenous cannulas (IVCs) in the care of sick newborns is a common practice . IVCs, priced five times higher than conventional steel needles, can be more cost effective if insight is available on the variables affecting their life span in situ . The present report summarizes the efforts made to ascertain these factors in a neonatal intensive care unit (NICU) of a developing country . A total of 186 peripheral IVCs (24-gauge teflon) were used in 78 newborns amounting to 7,583 hours of IV therapy (mean, 40.8 hr per cannula; range, 1-136 hr) . Of these, 25 cannulas were removed selectively and 84, 50, 17, and 10 were removed for swelling, dislodgement/leakage, blockage, and local erythema, respectively . The median survival time of IVC as expressed by Kaplan-Meir survival analysis was 40 hours (SE, 2.49; 95% confidence interval, 35.12-44.88) . Birth weight, gestation, application of splint, fluid and glucose infusion rate, site of cannulation, and administration of ampicillin, gentamicin, amikacin, vancomycin, phenobarbitone, blood products, or calcium gluconate did not influence the median life span of IVCs . Children receiving cefotaxime had a significantly lower median survival time as compared with those not receiving it (36 vs 47 hours, p =.007) . Median survival time of IVCs in our set-up was comparable with those in developed countries and was not governed by the cannula or patient variables . Cefotaxime use led to decreased survival of IVCs; though this effect appeared to be related to the mode of administration rather than to the drug per se.

Ophthalmologe, 2003 Jul, 100(7), 550 - 3 Epub 2003 Jun 26.
{Diagnosis and treatment of mycobacterial keratitis following LASIK . Case report and review of the literature}; Holzer MP et al.; BACKGROUND: Mycobacterial keratitis is a rare complication following LASIK but can lead to an extremely unfavourable outcome . The diagnosis and treatment is often delayed due to confusion with other entities including diffuse lamellar keratitis and poor clinical outcomes with flap amputation and/or keratoplasty are often the case . PATIENT AND METHODS: We report the results of LASIK in a 51-year-old woman with subsequent early-diagnosed mycobacterial keratitis and compared this case to treatments and outcomes reported in the literature . RESULTS: The patient presented 10 days following LASIK with a white focal infiltrate in the stromal interface . The flap was lifted and cultures from the stromal bed and the reverse of the flap were obtained and the interface irrigated . The patient was treated with topical antibiotics (ciprofloxacin 0.3%, amikacin 2.5%, clarithromycin 40 mg/ml and tobramycin 15 mg/ml) for 8 weeks and at the most recent follow-up she had a visual acuity of 1.25 . CONCLUSION: In a large number of published cases in the literature the flap had to be amputated and/or corneal transplants were necessary . Early diagnosis and treatment however, are essential to successfully treat post-LASIK keratitis . Therefore the patients should be followed up carefully in the early postoperative period.

Int J Pediatr Otorhinolaryngol, 2003 Sep, 67(9), 1019 - 21
Otogenic cerebral venous infarction: a rare complication of acute otitis media; Ozer E et al.; A case of cerebral venous infarction (CVI) as a complication of acute otitis media (AOM) was presented in a 16-month-old male patient . The patient admitted with AOM in the right ear, ipsilateral facial paralysis and contralateral hemiplegia . Computerized tomography of the brain showed low density areas involving both the cortex and subcortical white matter in the right frontoparietal region, and there were patchy and multifocal enhancing areas with intravenous contrast enhancement . These findings disclosed the diagnosis of venous infarctions involving the superficial cortical veins on the right side . Complete recovery was achieved with 2 weeks of sulbactam-ampicilline, amikacin and prednisolone treatment . Although it is rather rare, CVI should also be remembered among the otogenic intracranial complications.

J Pineal Res, 2003 Sep, 35(2), 85 - 90
Amikacin-induced acute renal injury in rats: protective role of melatonin; Parlakpinar H et al.; It is well established that some agents such as aminoglycosides generate free oxygen radicals, leading to an increased oxireductase production, which in turn increases tissue toxicity . The aim of this study is to test whether melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant and free radical scavenger, reduces the nephrotoxicity caused by amikacin (AK) . Herein, we investigated the physiologic and pharmacological role of melatonin in influencing AK-induced nephrotoxicity . For this, pinealectomized (Px) and sham operated (non-Px) rats were used . Both AK and melatonin were administered to all groups . We investigated the effects of melatonin on AK-induced changes in levels of malondialdehyde (MDA), a lipid peroxidation product, glutathione (GSH), an antioxidant whose levels are influenced by oxidative stress, and blood urea nitrogen (BUN) and serum creatine (Cr) levels . Morphologic changes in the kidney were also examined by using light microscopy . MDA levels were found to be higher in Px than in non-Px AK-treated animals . Melatonin administration to Px rats reduced MDA levels . In relative to non-Px rats, Px animals treated with AK had significantly lower GSH concentrations while melatonin administration elevated GSH levels in the kidney; however, this stimulatory effect of melatonin was not observed in non-Px AK-treated rats . Treatment with AK alone resulted in significantly higher plasma Cr and BUN levels . Repeated administration of melatonin prevented the AK-induced elevation of plasma Cr and BUN levels . Morphologic damage to renal tubules as a result of AK was more severe in the renal cortex than in the medulla . The damage to the kidney induced by AK was reversed by melatonin in the Px rats . In conclusion, these results show that physiologic melatonin concentrations are important in reducing AK-induced renal damage, while pharmacologic concentrations of melatonin did not add to the beneficial effect.

J Chemother, 2003 Jun, 15(3), 253 - 9
Ticarcillin-clavulanic acid plus amikacin versus ceftazidime plus amikacin in the empirical treatment of fever in acute leukemia: a prospective randomized trial; Fanci R et al.; We evaluated the efficacy of ticarcillin-clavulanic acid plus amikacin (TCA) with ceftazidime plus amikacin (CFA) as empiric therapy of fever in acute leukemia in a total of 127 episodes . The overall success rate of the therapy (survival) was 93% in TCA group and 92% in CFA group . Success without therapy modifications (afebrile at 72 hours) was 39% for TCA, 31% for CFA; success with modifications was 55% and 61% respectively . Failure (death due to documented or presumed infection) was 6% for TCA and 8% for CFA . Differences were not statistically significant . The success without modifications was higher in the group of patients with fever of unknown origin (FUO) than in documented infections (DI), mainly with CFA . No differences were documented in the resistance rate and in clinical outcome during severe neutropenia (ANC <100 microl) . In our experience TCA is as effective as CFA as first-line treatment in severe neutropenic patients with acute leukemia, although in both regimens patients with DI are likely to require modifications in treatment.

J Am Acad Audiol, 2003 Apr, 14(3), 134 - 43
Antioxidant enzyme levels inversely covary with hearing loss after amikacin treatment; Klemens JJ et al.; This study's purpose was to determine if a correlation exists between cochlear antioxidant activity changes and auditory function after induction of amino-glycoside (AG) ototoxicity . Two groups of five 250-350 g albino guinea pigs served as subjects . For 28 days, albino guinea pigs were administered either 200 mg/kg/day amikacin, or saline subcutaneously . Auditory brainstem response testing was performed prior to the first injection and again before sacrifice, 28 days later . Cochleae were harvested and superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase activities and malondialdehyde levels were measured . All antioxidant enzymes had significantly lower activity in the amikacin group (p < or = 0.05) than in the control group . The difference in cochlear antioxidant enzyme activity between groups inversely correlated significantly with the change in ABR thresholds . The greatest correlation was for the high frequencies, which are most affected by aminoglycosides . This study demonstrates that antioxidant enzyme activity and amikacin-induced hearing loss significantly covary.

J Indian Med Assoc, 2003 Jan, 101(1), 16 - 7, 23
Treating tuberculous lymphadenitis--ifs and buts; Mukherjee S et al.; Treatment of tuberculous (TB) lymphadenitis is virtually a specialist's job due to multiple aetiopathological factors . Diagnosis is difficult often requiring biopsy for several times . Treatment monitoring is more complex due to peculiar behaviour of TB lymph nodes . Situation has become worse due to sharp increase in the incidence of atypical mycobacteria . Due to profound improvement in antibiotic action, life-expectancy of immuno-compromised patients has also increased along with increased incidence of atypical mycobacteria in them . Clarithromycin, ethambutol, rifabutin and amikacin seem to act best on atypical mycobacteria-induced lymphadenitis . Along with rise of multi-drug resistance (MDR), drug-resistant TB lymphadenitis cases are also on the rise.

Yonsei Med J, 2003 Jun 30, 44(3), 517 - 22
Comparative vestibulotoxicity of different aminoglycosides in the Guinea pigs; Selimoglu E et al.; The histopathological alterations in the vestibule due to aminoglycosides are well defined . Although there are reports comparing the vestibulotoxic effects of the many aminoglycosides, this is the first study to compare the effects of the most commonly used aminoglycosides i.e., streptomycin, gentamicin, amikacin and netilmicin administered both transtympanically and systemically . The transtympanic and systemic administration of each aminoglycoside caused similar histopathological alterations in the vestibule . The most severe degeneration in the cristae ampullaris, utriculus and sacculus was observed after streptomycine administration . The severity of the vestibular damage in terms of magnitude was in the order of streptomycine, gentamicin, amikacin, and netilmicin.

J Perinat Med, 2003, 31(3), 237 - 41
Amikacin alters auditory brainstem conduction time in newborns; Poblano A et al.; The purpose of this paper was to describe whether there are some relationships between amikacin serum levels and central conduction time in brainstem auditory evoked potentials (BAEP) within therapeutic range levels in newborns as index of drug toxicity in brainstem auditory centers in neonatally exposed infants . We performed a cross-sectional study to compare BAEP from 35 infants under amikacin administration and 24 control infants; both examinations were blinded to investigators . Bivariate and partial correlations were calculated between amikacin and BAEP measurements in treated infants . Amikacin determinations were within therapeutic levels . No clinical alterations in BAEP were found and no differences between amikacin-treated and control infants were found . Significant positive Pearson correlation between latency of I-III interwaves interval and amikacin Cmin serum levels was found and was present when calculations were controlled by partial correlations for gestational age at birth and Apgar score at 5 min . The findings suggest that increased amikacin levels in newborns are related to increased latencies in I-III interwave interval in infants, which may be an early index of brainstem effects of subclinical neurotoxicity of amikacin.

J Antimicrob Chemother, 2003 Jul, 52(1), 78 - 82 Epub 2003 Jun 12.
Evaluation of commercial assays for vancomycin and aminoglycosides in serum: a comparison of accuracy and precision based on external quality assessment; Wilson JF et al.; OBJECTIVE: To compare the accuracy and precision of commercial assay techniques in the measurement of gentamicin, tobramycin, amikacin, netilmicin and vancomycin in serum . METHODS: Data from the measurement of 40 external quality assessment samples from 358 laboratories providing a therapeutic drug monitoring service were analysed . RESULTS: Significant differences between techniques in accuracy and precision were observed for all drugs . Coefficients of variation ranged from 4.1% to 9.8% for the aminoglycosides and from 6.7% to 11.7% for vancomycin . The percentage difference in measurements from the weighed-in drug concentration ranged from -10.1% to +4.0% for the aminoglycosides and from -3.5% to +5.7% for vancomycin . The Dade Behring Emit immunoassay was notable in producing significantly more outliers (>4 S.D . from the weighed-in concentration) than other techniques in the measurement of gentamicin, amikacin and vancomycin . CONCLUSIONS: All assays performed to a satisfactory standard for measurement in non-renal patients, but none met the more stringent standards desirable for monitoring patients with renal impairment.

Graefes Arch Clin Exp Ophthalmol, 2003 Jun, 241(6), 478 - 83 Epub 2003 May 14.
Pars plana vitrectomy with or without silicone oil endotamponade in post-traumatic endophthalmitis; Azad R et al.; BACKGROUND: Results of core vitrectomy in post-traumatic endophthalmitis are poor . Our initial results of complete vitrectomy with primary silicone oil endotamponade were promising . A comparative study of this procedure with conventional core vitrectomy was therefore carried out . METHODS: A prospective randomized controlled study of 24 consecutive cases of post-traumatic endophthalmitis was conducted . Patients were randomized into two groups in the absence of clinical improvement after primary tap and treatment with intravitreal vancomycin and amikacin: group 1 consisted of patients who underwent core vitrectomy alone, group 2 of patients who underwent complete vitrectomy with silicone oil endotamponade . All patients included in the study received intravenous antibiotics and underwent lensectomy . Patients were followed up 1, 2, 4 and 12 weeks postoperatively . In all patients of group 2, silicone oil was removed 6 weeks after primary surgery . The mean duration of follow-up was 112+/-55 days . RESULTS: Vision of 20/400 or better was obtained in 58.33% of cases (14/24) . Visual acuity of only one patient in group 1 was >or=20/200, compared with that of 58.3% of patients (7/12) in group 2 ( P=0.02) . Intra-operative retinal breaks were found in 50% (6/12) of the patients belonging to group 1, but did not affect the final visual outcome . In group 1, 33.33% (4/12) developed rhegmatogenous retinal detachment in the immediate post-operative period . Only one of these patients had useful final visual outcome after resurgery . CONCLUSION: Complete vitrectomy with primary silicone oil endotamponade is a useful treatment modality which improves the anatomical and functional results in post-traumatic endophthalmitis.

Clin Pharmacokinet, 2003, 42(5), 493 - 500
Aminoglycoside dosages and nephrotoxicity: quantitative relationships; Rougier F et al.; OBJECTIVE: To develop a model that relates the probability of occurrence of nephrotoxicity to the cumulative area under the curve (AUC) of amikacin serum concentration . DESIGN AND PATIENTS: This was a retrospective study of two groups of patients in whom nephrotoxicity was observed after administration of amikacin . The first group consisted of patients treated with once-daily administration (ODA) {n = 13} . The second group consisted of patients treated with twice-daily administration (TDA) {n = 22} . MAIN OUTCOME MEASURES: The probability of nephrotoxicity occurrence . RESULTS: The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity . The onset of nephrotoxicity is delayed in the ODA group (p = 0.01) for the same total daily dose among the two groups . The cumulative serum AUC values at onset of nephrotoxicity were greater for the ODA group (p = 0.029) . In addition, for the same probability of nephrotoxicity occurrence (50%), the cumulative AUC for the ODA dosage regimen is 2 613 mg . h/L versus only 1 521 mg . h/L for the TDA dosage regimen . The difference in nephrotoxicity between ODA and TDA is greatest for a cumulative AUC of 2 495 mg . h/L, which corresponds to standard therapy with amikacin 900 mg/day during a 7-day period, i.e . 15 mg/kg/day for a 60kg patient with normal renal function (initial creatinine clearance >80 mL/min) . For an AUC above 2 495 mg . h/L, the difference in nephrotoxicity decreases slowly to zero . This result means that ODA is especially justified when the treatment is administered over a short duration, i.e . less than 7 days . CONCLUSIONS: The utility of selecting ODA in order to obtain less nephrotoxicity in comparison with TDA is therefore not established when the treatment is prolonged . In clinical use, the choice of the dosage regimen is not clear-cut, and both expected efficacy and expected toxicity must be taken into account in order to obtain an overall optimisation of each patient's therapy.

Rev Lat Am Enfermagem, 2003 Jan-Feb, 11(1), 88 - 95
{Drug therapy orphans: the administration of intravenous drugs in hospitalized children}; Peterlini MA et al.; Descriptive study, developed at a general university hospital that aimed at verifying the number and types of i.v . drugs administered to children, the adequacy of their pharmacological presentation for pediatric use and the estimated costs of some drugs administration . In a period of 30 days, 8,245 drug doses were administered, with an average of 274.83 doses a day, and a yearly estimation of 98.940 . The most used drugs were methylprednisolone, vancomycin, furosemide, ranitidine, penicillin, amikacin, midazolam, fentanyl, ceftriaxone, cephalothin, oxacillin, ampicillin and metronidazole . None of the 41 different drugs had a pediatric presentation, what caused, in some cases, more manipulation during the preparation, increasing the contamination risks and the loss of stability . Authors observed that the lack of pediatric presentation generated an increase in care costs; as an example, considering the prescription of a child in the period after surgery, with an estimated time of hospitalization of 5 days, the daily therapy costs were of U$6.71, and U$39.52 of drugs were thrown away as they exceeded the children therapeutic needs.

Lupus, 2003, 12(4), 312 - 6
Mycobacterium avium complex-associated hemophagocytic syndrome in systemic lupus erythematosus patient: report of one case; Yang WK et al.; Hemophagocytic syndrome (HPS) in systemic lupus erythematosus(SLE) patients has not commonly been reported . In this case study, we report the first case of Mycobacterium avium complex (MAC)-associated hemophagocytic syndrome in a patient with systemic lupus erythematosus (SLE) . This SLE patient, a 15-year-old girl, had been on a high dose of prednisolone (> 0.5mg/kg/day) for more than 3 years . She presented with a spiking fever, hepatosplenomegaly, pancytopenia, hyperferritinemia and adult respiratory distress syndrome . Bone marrow examination revealed hemophagocytosis as well as non-caseating granulomatosis . There was no indication of SLE fare-up . She responded poorly to initial treatment with methyl-prednisolone, intravenous immumoglobulin, etoposide, and drugs for Mycobacterium tuberculosis including rifampin, ethambutol, isoniazid and pyramide . However, gastric lavage culture revealed MAC . Following treatment with clarithromycin, ciprofloxacin and amikacin, her condition gradually improved and she was discharged 3 months after admission . In SLE patients with pancytopenia and hyperferritinemia, MAC-associated HPS should be considered in the differential diagnosis.

Chemotherapy, 2003 May, 49(1-2), 24 - 6
In vitro activity of azithromycin in combination with amikacin, ceftazidime, ciprofloxacin or imipenem against clinical isolates of Acinobacter baumannii; Fernandez-Cuenca F et al.; The in vitro activity of the two-drug combinations of azithromycin with amikacin, ceftazidime, ciprofloxacin or imipenem against five clonally unrelated strains of Acinobacter baumannii were evaluated . Synergy studies were performed by the checkerboard microtiter method . The fractional inhibitory concentration (FIC) index was calculated for each drug combination . None of the four combinations tested was antagonistic . The combination of azithromycin and ceftazidime was synergistic (FIC index <or=0.5) for one strain and partially synergistic (FIC index 0.75) for another strain . An additive effect (FIC index = 1) was observed for the combinations of azithromycin with imipenem (two strains) or ceftazidime (one strain) . The activities of the other combinations were indifferent (FIC index range from 1.5 to 2.5) . It is concluded that azithromycin combined with ceftazidime has moderate synergistic activity against some multiresistant A . baumannii .

Infection, 2003 Mar, 31(2), 112 - 4
Disseminated Nocardia asteroides infection in an immunocompetent woman following an arm injury; Benes J et al.; A case of disseminated infection with Nocardia asteroides in a 55-year-old immunocompetent woman after mild trauma to the arm is reported . Secondary dissemination was identified in the skin, right kidney, liver, peritoneal cavity, lungs and thigh . The patient was successfully treated with surgical drainage and a 9-week course of antibiotics including cefotaxime, amikacin, chloramphenicol, trimethoprim/sulfamethoxazole (TMP/SMX) and doxycycline . The administration of TMP/SMX in combination with doxycycline was clinically beneficial despite in vitro resistance.

J Clin Microbiol, 2003 Apr, 41(4), 1705 - 9
Nocardia veterana, a new emerging pathogen; Pottumarthy S et al.; Nocardia veterana is a newly described species named after the veteran's hospital where it was first isolated . This initial type strain was not thought to be clinically significant . We describe three cases of pulmonary disease attributable to N . veterana: two cases in patients presenting with multiple pulmonary nodules in a setting of immunocompromise and one case of exacerbation of chronic pulmonary disease . The isolates were susceptible to ampicillin, imipenem, gentamicin, amikacin, and trimethoprim-sulfamethoxazole and had reduced susceptibilities to ceftriaxone, cefotaxime, minocycline, and ciprofloxacin . The MICs of amoxicillin-clavulanate were higher than that of ampicillin alone, and the bacteria produced a beta-lactamase detectable only after induction with clavulanic acid . Phenotypically, the isolates could not be characterized beyond the Nocardia genus level . All three isolates were definitively identified as N . veterana by PCR and sequencing of the 16S rRNA gene . On the basis of their susceptibility and restriction enzyme analysis profiles, our findings indicate that they could potentially be misidentified as N . nova . These cases illustrate the pathogenic potential of this newly described species and emphasize the importance of accurate identification of Nocardia isolates to the species level by integrated use of phenotypic and genotypic methods.

Klin Monatsbl Augenheilkd, 2003 Mar, 220(3), 204 - 6
Endogenous pneumococcal endophthalmitis followed by pneumococcal-induced uveitis; Nessi F et al.; BACKGROUND: We describe the case of a fulminant bilateral endophthalmitis occurring in a patient, who had 9 years earlier a splenectomy for an idiopathic thrombocytopenic purpura . HISTORY AND SIGNS: A 40-year-old woman, back from a trip to Morocco, presented with high fever, rapid decrease in visual acuity and loss of consciousness . Medical examination revealed a pneumococcal meningitis and bilateral endophthalmitis . THERAPY AND OUTCOME: Endophthalmitis was treated with local and intravitreal antibiotics injections (vancomycin and amikacin) . Repeated parabulbar betamethasone injections were performed . Intravenous (iv) methylprednisolone pulses were followed by oral steroid therapy while systemic antibiotics were given (ceftriaxone and vancomycin) . In spite of this therapy, fundus examination was impossible because the anterior chamber was filled with fibrin . A cataract developed with severe vitritis and we could observe a progressive narrowing of the anterior chamber . The patient underwent a bilateral vitrectomy and lensectomy . The retina had no lesion . No bacteria were found in the vitreous culture . Evolution was characterized by an increased ocular pressure due to anterior synechiae . Visual acuity remained under 1/10 . The severe ocular inflammation could be the result of a mixed mechanism including an infectious followed by a severe immune response against bacterial components . CONCLUSIONS: This case report is rare . To our knowledge, only 3 similar cases have been reported in the literature.

J Fr Ophtalmol, 2003 Feb, 26(2), 175 - 81
{Nontuberculous mycobacterial keratitis: report of two cases causing infectious crystalline keratopathy}; Labalette P et al.; We report two cases of nontuberculous mycobacterial keratitis, occurring after corneal trauma with superficial foreign body and after perforating keratoplasty for alkali burn, respectively . Patients initially presented with indolent white corneal infiltrates, which did not respond to topical treatment . Both secondarily developed infectious crystalline keratopathy with unequal intensity . In the first case, the excised flap of lamellar keratectomy was cultured, allowing identification of Mycobacterium abscessus . Mycobacterium chelonae was isolated from a corneal biopsy in the second case . The clinical course showed poor response to antibiotic therapy consisting of ciprofloxacin and amikacin drops in conjunction with a new-generation oral macrolide . Corneal infection recurred after lamellar keratectomy in the first patient . Topical corticosteroid interruption burst corneal inflammation and induced stromal necrosis in the other patient . These intractable mycobacterial infections were finally controlled with penetrating keratoplasty . Our data suggest that a rapidly growing mycobacteria culture is required when clinical presentation consists of chronic bacterial keratitis or infectious crystalline keratopathy.

J Antimicrob Chemother, 2003 Apr, 51(4), 803 - 11 Epub 2003 Mar 13.
Role of the acetyltransferase AAC(6')-Iz modifying enzyme in aminoglycoside resistance in Stenotrophomonas maltophilia; Li XZ et al.; Stenotrophomonas maltophilia is an emerging nosocomial pathogen that displays high-level intrinsic resistance to multiple antibiotics including aminoglycosides . A gene {aac(6')-Iz} encoding an aminoglycoside-modifying enzyme, AAC(6')-Iz acetyltransferase, was recently cloned and sequenced in S . maltophilia, but its importance with respect to aminoglycoside resistance in this organism was not determined . Using a homologous gene replacement approach, mutants carrying unmarked chromosomal deletions of the aac(6')-Iz gene were constructed in wild-type and in vitro-selected aminoglycoside-resistant S . maltophilia . AAC(6')-Iz-deficient mutants derived from both wild-type and aminoglycoside-resistant strains displayed an increase in susceptibility to amikacin, netilmicin, sisomicin and tobramycin (4- to 32-fold decrease in MICs), known substrates for AAC(6')-I enzymes . The cloned aac(6')-Iz gene restored the aminoglycoside resistance of the aac(6')-Iz mutants, and could also confer aminoglycoside resistance upon Escherichia coli . To assess the significance of the aac(6')-Iz gene with respect to the aminoglycoside resistance of clinical strains, its distribution was assessed in 65 clinical isolates from two hospitals . Using PCR, Southern hybridization, RT-PCR and/or nucleotide sequencing, the aac(6')-Iz gene was identified in 57% of the isolates . Susceptibility tests indicated a good correlation between the presence of the aac(6')-Iz gene and the resistance to tobramycin, netilmicin and sisomicin in these strains . These results indicate that the aac(6')-Iz gene is an important contributor to aminoglycoside resistance in clinical strains of S . maltophilia, particularly to tobramycin.

Ann Trop Paediatr, 2003 Mar, 23(1), 75 - 8
Disseminated nocardiosis in an immunocompetent child; Singh NP et al.; We report a 2-month-old child with a disseminated Nocardia farcinica infection that presented with suppurative lymphatic abscess . The child did not have any predisposing factors and responded to treatment with co-trimoxazole and amikacin . This is first case report of disseminated nocardiosis caused by Nocardia farcinica in an immunocompetent child.

Bioorg Med Chem Lett, 2003 Mar 24, 13(6), 993 - 6
Inhibition of bacterial IF2 binding to fMet-tRNA((fMet)) by aminoglycosides; Evans JM et al.; Screening for inhibitors of bacterial protein synthesis Initiation Factor 2 (IF2) binding to N-formyl-Methionyl-transfer RNA (fMet-tRNA((fMet))) identified a series of aminoglycosides, that included amikacin and kanamycin A1, as inhibitors of this interaction . Subsequent testing revealed that aminoglycosides displayed a wide range of inhibitory activity . However, the failure of these compounds to completely inhibit binding of IF2 to fMet-tRNA((fMet)), the known ability of aminoglycosides to bind RNA, and the ability of the aminoglycosides to displace PicoGreen bound to fMet-tRNA((fMet)) suggest these compounds act by binding fMet-tRNA((fMet)) . This hypothesis is further supported by isothermal denaturation experiments that failed to show any interaction between the IF2 protein and the aminoglycosides.

Fa Yi Xue Za Zhi, 2002 Aug, 18(3), 132 - 4, 136
{Tryptase and fatal anaphylaxic reaction}; Shen YW et al.; OBJECTIVE: To investigate the relationship between tryptase in serum and anaphylaxis . METHODS: The concentrations of tryptase in the sera of heart blood in three persons died from anaphylaxis shock were detected by ELISA . The first sample was obtained from a man, aged 38, died of injecting Amikacin . The second sample was obtained from a man, aged 42, died of injecting Cephradine . The third sample was from a woman, aged 39, died of injecting Lincomycin . All samples were stored in -20 degrees C . RESULTS: The concentrations of tryptase in sera were 52 ng/ml, 121 ng/ml and 0.73 ng/ml . It was unknown why the concentration of tryptase in the third sample was normal . CONCLUTION: In fetal anaphylaxia reaction tryptase measurement is a useful indicator, but the diagnosis is not to be based on the test alone.

Yan Ke Xue Bao, 1998 Sep, 14(3), 156 - 63
Mycobacterium chelonei keratitis: report of a case and review of the literature; Wong AK et al.; BACKGROUND: Mycobacterium (M) chelonei keratitis is a rare opportunistic eye infection that can cause significant morbidity when not being treated properly . The first case was documented by Gangadharam et al in 1978 and since then, a total of 49 cases were reported in the literature . One alarming fact is that more than 50% of cases were found in the Chinese population and mostly reported in recent years . The key to successful management of M . chelonei keratitis is early diagnosis by high index of suspicion . In order to alert ophthalmologists of this condition, we report a typical case of M . chelonei keratitis and review the literature of all the reported cases with special reference to its risk factors, treatments and outcome . METHODS: The cases reported in the literature and a case of our own were reviewed and analyzed . RESULTS: Our case was a 42-year-old gentleman who developed M . chelonei keratitis following pterygium surgery . He had typical clinical features of irregular infiltrates with radiating projections, indistinct fluffy lesion margins, satellite lesions and associated epithelial defect . Penetrating keratoplasty was performed after failed medical treatments . He recovered fully with a best corrected visual acuity (BCVA) of 20/30 at 24 months after the corneal transplant . A total of 49 cases were reported in the literature . The major risk factor was corneal injury, including surgical trauma . Corneal foreign bodies (24 cases, 48%) were found to be highly correlated, especially metallic foreign bodies (16 cases, 32%) . Diagnosis was usually delayed for weeks or months and medical treatment alone often failed . Amikacin is usually the treatment of choice but its efficacy is just sub-optimal . Multi-resistance to the commonly used board spectrum antibiotics is not uncommon . The drug sensitivity test against atypical mycobacterium is technically difficult to perform and in vitro results are well known to be poorly related to clinical response . Combined extirpative keratectomy and topical antibiotics had been tried and was shown to be effective . Penetrating keratoplasty appeared to be a good definitive treatment for drug-resistance and advanced cases . CONCLUSION: M . chelonei keratitis is a rare opportunistic infection . The major risk factor is eye injury, with foreign bodies or surgical trauma . Diagnosis is often missed and delayed as a result of its scarcity and variable presentations . High index of clinical suspicion with early diagnosis and prompt combined medical and surgical intervention seem to be the best measure to decrease ocular morbidity . Good alertness and knowledge of this condition would help our patients in the Far East as the literature review has shown a recent trend of increase in frequency and more than 50% of the reported cases come from the Chinese patients.

J Ocul Pharmacol Ther, 2002 Dec, 18(6), 549 - 58
In vivo transscleral iontophoresis of amikacin to rabbit eyes; Vollmer DL et al.; The objectives of these studies were to determine the amount and distribution of the aminoglycoside antibiotic amikacin delivered to rabbit eyes following transscleral iontophoresis and to determine the inter-study reproducibility of delivery over three identical studies . New Zealand White rabbits (N = 6 per dose group) were treated with a 200-mg/mL amikacin solution at 0, 2, 3 or 4 mA of (+) DC current for 20 minutes . Amikacin concentrations in eye tissues were highest with the 4-mA treatment . Concentrations for all three studies at this current were approximately 5.4, 40, 41, 343, and 92 mcg/g in the vitreous humor, anterior segment, non-treated hemisphere of the sclera, treated hemisphere of the sclera, and retina/choroid, respectively . These values were approximately 27, 50, 40, 10, and 13 fold greater than in the 0-mA control group and are well above the in vitro minimum inhibitory concentrations (MICs) for this drug . Inter-study reproducibility (measured as %CV) depended on the tissue type and treatment group and ranged from 8% for the retina/choroid to 51% for the anterior segment in the 4-mA group . Pretreatment with topical proparacaine hydrochloride local anesthetic did not affect amikacin delivery and total drug delivered was not affected by delivery time for the same total charge administered . Therapeutically relevant amounts of amikacin were delivered into eye tissues in a reproducible and controllable manner.

Infection, 2002 Dec, 30(6), 338 - 40
Infection with Nocardia species: clinical spectrum of disease and species distribution in Madrid, Spain, 1978-2001; Pintado V et al.; BACKGROUND: Clinical experience with nocardiosis is very limited in European countries . We describe 34 cases of nocardial infection seen at one Spanish teaching hospital . PATIENTS AND METHODS: A retrospective review of the clinical features and outcome of nocardial infections was conducted during a 24-year period (1978-2001) . All cases were confirmed by culture . RESULTS: Predisposing factors included immunosuppression and/or pulmonary disease in 85% of patients; eight cases were related to HIV infection . Most isolates were initially identified as Nocardia asteroides complex (97%) . The most common clinical form was pulmonary disease (41%), followed by disseminated (15%), cutaneous (12%), cerebral (9%) and articular disease (3%) . A high proportion of patients (20%) had pulmonary colonization . Therapy with sulfonamides, imipenem or amikacin was given to 26 patients and a clinical response was observed in 65%.Overall mortality among patients with nocardial disease was 48% (13/27) but only seven patients (26%) died from nocardiosis . CONCLUSION: Nocardiosis remains a rare opportunistic infection that appears in immunosuppressed patients . HIV infection has become a common predisposing condition . The species distribution and disease spectrum are similar to those described in other European countries . Although most patients develop active disease, pulmonary colonization might not be as rare as has generally been assumed.Treatment with sulfonamides is usually effective and many patients may remain free of nocardial disease for a prolonged period.

J Pediatr Hematol Oncol, 2002 Dec, 24(9), 714 - 6
Continuous infusion of ceftazidime in the empiric treatment of febrile neutropenic children with cancer; Dalle JH et al.; PURPOSE: Infection remains one of the most important complications in cancer therapy . The choice of antibiotics and the method of administration can affect results . Beta-lactam antibiotics can be administered by several short injections per day or by continuous infusion . The latter modality may provide superior pharmacokinetics . PATIENTS AND METHODS: The authors studied the pharmacokinetics of ceftazidime in children treated for malignancy and in febrile aplasia after chemotherapy . They received a continuous infusion of ceftazidime (200 mg/kg/day) after a loading dose (65 mg/kg/day) administered with amikacin (25 mg/kg/day) and vancomycin (50 mg/kg/day).RESULTS Twenty-three pharmacokinetic studies were performed . Mean ceftazidime serum levels were 31.1 +/- 11.9, 31.2 +/- 10, 32.4 +/- 11.6, 33 +/- 11.6, and 30.4 +/- 12.1 mg/L at 25, 27, 30, 36, and 43 hours, respectively . Treatment was tolerated well . There were no toxic or infectious deaths . CONCLUSIONS: Ceftazidime's time-dependent pharmacokinetics shows the advantage of continuous infusion . This study confirmed the feasibility and safety of this administration schedule in the empiric treatment of febrile neutropenic children with cancer.

J Zoo Wildl Med, 2002 Sep, 33(3), 193 - 203
Population pharmacokinetics of antituberculous drugs and treatment of Mycobacterium bovis infection in bongo antelope (Tragelaphus eurycerus isaaci); Auclair B et al.; After clinical illness, treatment, and death of a captive male bongo antelope (Tragelaphus eurycerus isaaci) caused by tuberculosis involving Mycobacterium bovis, four tuberculin test reactive captive bongos were treated for 6 mo with isoniazid (INH) and rifampin (RIF) and intermittent single doses of other medications before being euthanized . In all cases, postmortem examination indicated no evidence of active disease and cultures of multiple organs were negative . We present detailed pharmacokinetic (PK) data for amikacin (AMK), ethambutol (EMB), INH, pyrazinamide (PZA), RIF, and levofloxacin in four female bongos . Adequate absorption and serum levels were obtained after parenteral administration of AMK, EMB, and INH and after oral administration of INH and PZA . Parenterally administered drugs were well described by a one-compartment PK model with first-order absorption and elimination processes . Treatment with INH and RIF over a 6-mo period did not result in demonstrable adverse effects . Starting doses of 10-15 mg/kg, i.m., or 30 mg/kg, p.o., of INH, 50 mg/kg, p.o., of EMB, and 25 mg/kg, i.m., s.i.d., of AMK are recommended . The treatment is continued with at least two drugs to which the organism is susceptible for a total treatment length of 6-12 mo . Treatment may be an option to eradicate M . bovis from suspect animals, with carefully administered and monitored drug treatment.

Ther Drug Monit, 2002 Dec, 24(6), 696 - 700
Effect of analytical inaccuracy on dose adjustment for vancomycin, amikacin, and tobramycin using the Abbottbase Pharmacokinetic Systems; Zaera S et al.; The authors studied the inaccuracy effect in the determination of C(min) and C(1h) post-infusion serum concentrations of vancomycin, amikacin, and tobramycin on the recommended dose regimen (RDR) using the Abbottbase Pharmacokinetic Systems (PKS) program (Abbott; Abbott Park, IL) . According to previously established criteria, the clinically acceptable error (CAE) was defined as 1/8 of the therapeutic range . For a total of 647 simulations, in most cases (94.3%) an inaccuracy of up to three times the CAE did not lead to changes in the RDR . However, and particularly for amikacin and tobramycin, in some cases an inaccuracy in the order of the CAE in C(min) lead to important differences in the RDR, which could have important consequences in clinical practice . For therapeutic monitoring of these antibiotics, it is suggested that a serum concentration from a previous moment in time, which may be determined with greater precision and accuracy, could be used instead of C(min).

Ann Biol Clin (Paris), 2002 Nov-Dec, 60(6), 723 - 30
{Evaluation of Emit netilmicin and amikacin assays on Dimension RXL HM (Dade Behring) open channels}; Vetele F et al.; The aim of this study was to evaluate and to validate an enzyme immunoassay in homogeneous phase for netilmicin and amikacin, adapted on the Dimension RXL HM (Dade Behring) machine . The results were compared with those obtained with automated polarization of fluorescence immunoassay using TDx FLx (Abbott) . The protocol of the study and the analytical criteria were inspired by the protocol Valtec version 2002 recommended by the French Society of Clinical Biology (SFBC) . The validation of this technique as adapted to the Dimension RXL HM has allowed its use for routine dosage adjustment of amikacin and netilmicin . The practicability is however the weak point of the adaptation of these techniques, even limiting as for their implementation.

Eur J Biochem, 2002 Nov, 269(22), 5547 - 56
DNA and RNA damage by Cu(II)-amikacin complex; Jezowska-Bojczuk M et al.; The oxidation-promoting reactivity of copper(II) complex of aminoglycosidic antibiotic amikacin {Cu(II)-Ami} in the presence of hydrogen peroxide, was studied at pH 7.4, using 2'-deoxyguanosine (dG), pBR322 plasmid DNA and yeast tRNAPhe as target molecules . The mixtures of complex with H2O2 were found to be efficient oxidants, converting dG to its 8-oxo derivative, generating strand breaks in plasmid DNA and multiple cleavages in tRNAPhe . The complex underwent autooxidation as well, with amikacin hydroperoxides as likely major products . This reactivity pattern was found to be due to a combination of metal-bound and free hydroxyl radicals.

Ophthalmology, 2002 Nov, 109(11), 2144 - 8
Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis?
Zamir E, Hudson H, Ober RR, Kumar SK, Wang RC, Read RW, Rao NA.
PURPOSE: To describe the ocular presentation of disseminated mycobacterial disease occurring during immune-recovery in a patient with acquired immune deficiency syndrome (AIDS) . STUDY DESIGN: Case report and literature review . PARTICIPANTS: A 41-year-old AIDS patient with a prior diagnosis of cytomegalovirus retinitis . METHODS: The patient developed progressive, bilateral multifocal choroiditis with panuveitis 2 months after beginning and responding to highly active antiretroviral therapy . His left eye became blind and painful and was enucleated . Pathologic examination revealed massive choroiditis with well-formed, discrete granulomas and multiple intracellular and extracellular acid-fast organisms within the choroidal granulomas . Culture and polymerase chain reaction of vitreous specimens revealed Mycobacterium avium complex (MAC) . RESULTS: Empiric, and later sensitivity-guided, local and systemic antibiotic therapy was used to treat the remaining right eye, but it continued to deteriorate . Despite medical therapy, three vitrectomies and repeated intravitreal injections of amikacin, a total retinal detachment ensued . One week after the third vitrectomy, the patient died from mesenteric artery thrombosis in the setting of disseminated mycobacterial disease . CONCLUSIONS: This is the first report of ocular inflammation as the presenting finding in the recently recognized syndrome of immune-recovery MAC disease . Pathogenesis of this entity is related to an enhanced immune response to a prior, subclinical, disseminated infection . The formation of discrete granulomas, normally absent in MAC infections in AIDS, reflects this mechanism.

Pol J Pharmacol, 2002 May-Jun, 54(3), 275 - 80
Effects of some drugs on rat erythrocyte 6-phosphogluconate dehydrogenase: an in vitro and in vivo study; Ciftci M et al.; The in vitro and in vivo effects of some drugs on rat erythrocytes 6-phosphogluconate dehydrogenase were investigated in this study . Rat erythrocyte 6-phosphogluconate dehydrogenase was partially purified with ammonium sulfate precipitation . The enzyme activity was determined by Beutler's method . Some drugs such as ampicillin, amikacin sulfate, and netilmicin sulfate inhibited the enzyme activity in in vitro conditions, while metamizole activated it . The I50 values of the inhibiting drugs were 66.2, 5.836, and 0.963 mM, respectively . For the drugs having low I50 values (drug concentrations which produce 50% inhibition) (amikacin sulfate and netilmicin sulfate), in vivo studies were performed in rats (Sprague-Dawley) . Amikacin sulfate at 64 mg/kg inhibited the enzyme activity significantly (p < 0.05) 2 h after dosing . Netilmicin sulfate at 6.4 mg/kg also inhibited the enzyme significantly (p < 0.05) 4 h after dosing . Amikacin sulfate and netilmicin sulfate inhibited rat erythrocyte 6-phospogluconate dehydrogenase both in vivo and in vitro . The enzyme was inhibited in vitro by ampicillin and activated in vitro by metamizole.

CLAO J, 2002 Oct, 28(4), 228 - 30
Mycobacterium chelonae keratitis associated with soft contact lens wear; Malecha MA et al.; PURPOSE: To report a case of Mycobacterium chelonae keratitis associated with soft contact lens wear . METHODS: A 17-year-old boy who wore frequent replacement soft contact lenses developed keratitis in the right eye . There was no history of trauma to the right eye . The patient was treated initially with topical ciprofloxacin but without improvement . On presentation, visual acuity in his right eye was 20/40 . A Gram-stained scraping of the corneal infiltrate revealed beaded filamentous rods, and the organisms were acid-fast positive . The patient's right eye was treated with intensive topical amikacin, 20 mg/mL, and 10 % sulfacetamide . Eventually, Mycobacterium chelonae was cultured on Sabourard's agar, topical sulfacetamide was stopped, and amikacin was continued . RESULTS: The patient's keratitis responded well to amikacin and resolved over a period of 4 weeks . Visual acuity in the right eye improved to 20/25 . CONCLUSIONS: Mycobacterium chelonae is a rare cause of keratitis in soft contact lens wearers . We have identified fewer than five cases of Mycobacterium chelonae keratitis associated with soft contact lenses in the literature . Prompt and accurate diagnosis of the organism using comeal scraping can lead to appropriate therapy and resolution of the keratitis.

Asian J Androl, 2002 Sep, 4(3), 163 - 7
Treatment of chronic bacterial prostatitis with amikacin through anal submucosal injection; Hu WL et al.; AIM: To assess the efficacy and safety of anal submucosal injection (ASI) of amikacin in chronic bacterial prostatitis (CBP) . METHODS: Fifty male outpatients with CBP were randomly divided into two groups . Thirty cases of ASI group were given amikacin 400 mg daily by ASI for ten times and the other twenty cases of intramuscular injection (IM) group were given the same drug daily by IM . All patients were evaluated with NIH-Chronic prostatitis symptom index (NIH-CPSI), the bacteria culture of the expressed prostate secretion (EPS), proctoscopic examination, rectal biopsy and the clinical manifestation were checked at pretreatment and on day 7 and 90 after cessation of therapy . RESULTS: The cure rate, apparent effective rate and effective rate of ASI group and IM group were 33.3% vs 5% (P<0.05), 43.3% vs 10% (P<0.05) and 16.7% vs 20% (P>0.05), respectively . The score of NIH-CPSI in both of ASI group and IM group decreased significantly 7 days after cessation of therapy, both ASI and IM of amikacin could relieve symptoms within a short time . However, 3 months after cessation of therapy the score of NIH-CPSI in ASI group continued down in spite of no significant differences compared with 7 days after cessation of therapy, but the score of IM group was rebound nearly closed to level of pretreatment at 23.8 8.5 and significantly higher than that of ASI group . The amount of white blood cell (WBC) of EPS in ASI group increased slightly at 7 days after cessation of therapy without significant difference with pretreatment (P>0.05), but it significantly decreased at 3 months after cessation of therapy, the amount of WBC of EPS in ASI group was lower than that of IM group at 3 months after cessation of therapy (P<0.05) . Proctoscopic examination of anal canal were normal after ASI therapy and the rectum biopsy showed no obvious histopathologic abnormality at the site of injection except mild focal submucosal infiltration of lymphocytes and plasma cells at 7 days after cessation of therapy which disappeared on 3 months after cessation of therapy . All patients had no evident complications . CONCLUSION: ASI could be recommended as a new safe, effective, painless method of antibiotics administration in the treatment of CBP.

Infection, 2002 Aug, 30(4), 243 - 5
Pulmonary nocardiosis in a non-Hodgkin's lymphoma patient; Hizel K et al.; Nocardiosis is an opportunistic infection especially in immunocompromised patients . Lungs are the most common infection sites and therapy poses some difficulties . We describe a case of pulmonary infection with Nocardia asteroides in a non-Hodgkin's lymphoma patient . Although the mortality from pulmonary nocardiosis is high in immunocompromised patients, our patient was successfully treated with trimethoprim-sulfamethoxazole (TMP/SMZ) and amikacin . Maintenance therapy with TMP/SMZ was continued for 1 year . This case supports the importance of the long-term maintenance treatment after the initial combination therapy.

J Int Med Res, 2002 Jul-Aug, 30(4), 406 - 12
Comparative cochlear toxicities of streptomycin, gentamicin, amikacin and netilmicin in guinea-pigs; Kalkandelen S et al.; All the aminoglycoside antibiotics now in clinical use are ototoxic . This study was designed to compare the toxic effects of four aminoglycoside antibiotics, streptomycin, gentamicin, amikacin and netilmicin, administered to guinea-pigs systemically (at respective doses of 125 mg/kg, 50 mg/kg, 150 mg/kg or 37.5 mg/kg, twice daily for 1 week) or topically via the transtympanic route (0.25 ml/kg in 4% saline, twice daily for 1 week) . Chosen doses were 10-20 times higher than the recommended human dosage . Cochlear damage was observed in all animals that were given systemic and local aminoglycosides . The severity of the cochlear damage was in the order gentamicin, amikacin, streptomycin, netilmicin, with gentamicin being the most toxic . No statistically significant difference between the severity of cochlear damage resulting from the systemic and topical applications was detected.

J Clin Microbiol, 2002 Aug, 40(8), 2930 - 5
Clinical and laboratory features of Mycobacterium mageritense; Wallace RJ Jr et al.; Six clinical isolates of the nonpigmented, rapidly growing species Mycobacterium mageritense were recovered from sputum, bronchial wash, blood, sinus drainage, and two surgical wound infections from separate patients in Texas, New York, Louisiana, and Florida . The isolates matched the ATCC type strain by PCR restriction enzyme analysis of the 65-kDa hsp gene sequence of Telenti, high-performance liquid chromatography, biochemical reactions, and partial 16S rRNA gene sequencing . These are the first isolates of this species to be described in the United States and the first isolates to be associated with clinical disease . Susceptibility testing of all known isolates of the species revealed all isolates to be susceptible or intermediate to amikacin, cefoxitin, imipenem, and the fluoroquinolones and sulfonamides but resistant to clarithromycin . Because of their phenotypic and clinical similarity to isolates of the Mycobacterium fortuitum third biovariant complex (sorbitol positive), isolates of M . mageritense are likely to go undetected unless selected carbohydrate utilization or molecular identification methods are used.

Anesthesiology, 2002 Jul, 97(1), 199 - 206
Influence of lung aeration on pulmonary concentrations of nebulized and intravenous amikacin in ventilated piglets with severe bronchopneumonia; Elman M et al.; BACKGROUND: Pulmonary concentrations of aminoglycosides administered intravenously are usually low in the infected lung parenchyma . Nebulization represents an alternative to increase pulmonary concentrations, although the obstruction of bronchioles by purulent plugs may impair lung deposition by decreasing lung aeration . METHODS: An experimental bronchopneumonia was induced in anesthetized piglets by inoculating lower lobes with a suspension of 10(6) cfu/ml Escherichia coli . After 24 h of mechanical ventilation, 7 animals received two intravenous injections of 15 mg/kg amikacin, and 11 animals received two nebulizations of 40 mg/kg amikacin at 24-h intervals . One hour following the second administration, animals were killed, and multiple lung specimens were sampled for assessing amikacin pulmonary concentrations and quantifying lung aeration on histologic sections . RESULTS: Thirty-eight percent of the nebulized amikacin (15 mg/kg) reached the tracheobronchial tree . Amikacin pulmonary concentrations were always higher after nebulization than after intravenous administration, decreased with the extension of parenchymal infection, and were significantly influenced by lung aeration: 197 +/- 165 versus 6 +/- 5 microg/g in lung segments with focal bronchopneumonia (P = 0.03), 40 +/- 62 versus 5 +/- 3 microg/g in lung segments with confluent bronchopneumonia (P = 0.001), 18 +/- 7 versus 7 +/- 4 microg/g in lung segments with lung aeration of 30% or less, and 65 +/- 9 versus 2 +/- 3 microg/g in lung segments with lung aeration of 50% or more . CONCLUSIONS: In a porcine model of severe bronchopneumonia, the nebulization of amikacin provided 3-30 times higher pulmonary concentrations than the intravenous administration of an equivalent dose . The greater the lung aeration, the higher were the amikacin pulmonary concentrations found in the infected lung segments.

Hear Res, 2002 Jul, 169(1-2), 121 - 9
Amikacin ototoxicity enhanced by Ginkgo biloba extract (EGb 761); Miman MC et al.; An animal study was realized to investigate the possible beneficial effect of EGb 761 as an antioxidant agent on amikacin ototoxicity by measuring distortion product otoacoustic emissions (DPOAEs) . Twenty-eight adult rats were grouped equally as follows . GROUP AMIKACIN: rats received amikacin 600 mg/kg/day intramuscularly between postnatal days (PND) 30 and PND44 . Group amikacin/EGb 761: rats received amikacin 600 mg/kg/day intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50 . Group EGb 761: rats received equivolume saline intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50 . NO TREATMENT GROUP: rats received nothing . Group amikacin was found to be affected only on the last measurement day of study (PND57) . The frequencies greater than 2002 Hz were significantly reduced compared with the amplitudes of PND30 (P<0.05) . Group amikacin/EGb 761 was most and earliest affected by amikacin-induced ototoxicity . DPOAE amplitudes were found in this group to be decreased at 2-6 kHz starting on PND50 . The results of Group EGb 761 and No treatment group were not significantly changed . For the DPOAE input/output amplitude thresholds, Group amikacin (P<0.05) and Group amikacin/EGb 761 (P<0.01) had significantly elevated thresholds on PND57, except at 5 kHz for Group amikacin (P=0,06) . According to the results of the study, EGb 761 may be regarded as a facilitating drug for the development of amikacin ototoxicity . The results of the present study may warn against concomitant use of aminoglycosides, specifically amikacin, with EGb 761.

Hematol Oncol, 2002 Jun, 20(2), 51 - 62
Tuberculosis in blood and marrow transplant recipients; Yuen KY et al.; Although one third of the world's population is infected with tuberculosis (TB), TB in blood and marrow transplant (BMT) recipients is relatively less well studied, as the incidence of TB is relatively low in developed countries with BMT units . Since the report of the first two cases in 1983, 52 cases of TB complicating BMT have been reported in the English literature from BMT centers in ten different countries . Not unexpectedly, the two largest series were reported from areas with a high incidence of TB in the general population, with about 45 cases per 10(5) inhabitants per year in Spain and about 100 cases per 10(5) inhabitants per year in Hong Kong respectively . The overall frequency of occurrence of TB in BMT recipients was 0.4% (52 cases among 13 881 BMT recipients), with a male:female ratio of 11:9 and median age of 33 (range 7-57) . The incidence of TB in the general population is a major predictor of a higher frequency of occurrence in BMT recipients . Moreover, allogeneic transplantation, graft-versus-host disease, and total body irradiation were found to be risk factors associated with TB . Among the 48 cases in whom the time of manifestation were reported, only one case manifested during the neutropenic period (day 11) . On the other hand, 11 cases (23%) manifest after engraftment but before day 100, and 36 (75%) manifest after day 100 . The most important aspect towards making the diagnosis is a high index of suspicion, as TB occurred in relatively low frequencies especially in developed countries, and the clinical patterns usually mimic other more common infectious and non-infectious complications after BMT . As the incidence of drug resistant TB is increasing, we prefer to treat our patients for at least one year (as compared with six months in immunocompetent hosts) with four drugs in the first six months and two or three drugs for another six months . In those patients who could not tolerate oral medication, we used an intravenous regimen of rifampicin, ciprofloxacin, and amikacin until oral therapy could be instituted . The absence of relapse after termination of treatment in our patients suggested that secondary prophylaxis would not be necessary as long as immune function has been restored . With the rising incidence of TB in countries that previously enjoyed a very low prevalence of TB, attributed to the growing population of HIV-infected subjects with TB, and the changing patterns of population migration, it is important to bear a high index of suspicion of Mycobacterium tuberculosis as a pathogen in BMT recipients .

Antibiot Khimioter, 2001, 46(12), 42 - 52
{Efficacy of monotherapy by meropenem in ventilator-associated pneumonia}; Alvarez Lerma F; Serious Infections Study Group; We performed a prospective, open label, randomized study in intensive care unit patients with ventilator-associated pneumonia (VAP) to determine the efficacy and safety of empiric intravenous (i.v.) meropenem monotherapy compared with the combination of ceftazidime plus amikacin . A total of 140 patients receiving mechanical ventilation and diagnosed with pneumonia were included in the study . Patients were randomized to receive either 1 g meropenem i.v . every 8 hours or 2 g ceftazidime i.v . every 8 hours plus 15 mg/kg amikacin daily, administered to patients with normal renal function as two daily doses . Satisfactory clinical responses (cure or improvement) were achieved at the end of treatment in 68.1% of meropenem-treated patients and 54.9% in the ceftazidime/amikacin treated group (relative risk 1.25; 95% confidence interval > 1.00, 1.55) . When non-evaluable patients were excluded from the analysis, the satisfactory clinical response was 82.5% and 66.1% for the meropenem and ceftazidime/amikacin patients, respectively (p = 0.044) . Logistic regression demonstrated that treatment with meropenem and both the basic traumatic and medical pathologies were significantly associated with a satisfactory response . Adverse events judged to be possible or probably related to treatment were reported by seven (10.1%) patients in the meropenem group and by eight patients (11.3%) in the ceftazidime/amikacin group . The results of this study confirm that monotherapy with meropenem is well tolerated and provides superior efficacy to the conventional combination of ceftazidime and amikacin in combating VAP.

Int J Tuberc Lung Dis, 2002 Jul, 6(7), 622 - 7
Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis; de Jager P et al.; OBJECTIVE: To investigate the ototoxic and nephrotoxic effects of long-term use of aminoglycosides . DESIGN: Patients treated for tuberculosis with aminoglycosides were evaluated for hearing loss and nephrotoxicity for a minimum of 14 days . RESULTS: Hearing loss of 15 decibels (dB) at two or more frequencies, or at least 20 dB hearing loss at at least one frequency, was found in 18% of our total population treated with aminoglycosides (amikacin, kanamycin and/or streptomycin) . In the group treated with kanamycin this percentage was 15.6 . None of the factors sex, age, treatment duration, total aminoglycoside doses or first serum creatinine concentration, was found to be associated with hearing loss . Nephrotoxicity percentages at the end of treatment with aminoglycoside or kanamycin are 7.5% (1.9%) and 4.5% (2.3%) respectively, using the definition increase of serum creatinine > or = 27 micromol/l (> or = 44 micromol/l) . Patients developing nephrotoxicity had a longer duration of treatment and received larger total doses . CONCLUSIONS: Patients developing nephrotoxicity had a significantly longer duration of treatment with aminoglycosides, and received a larger total dose . We did not find any factor significantly associated with the development of hearing loss . In the long-term treatment of tuberculosis with aminoglycosides, ototoxicity seems to be a greater problem than nephrotoxicity.

Br J Dermatol, 2002 Jul, 147(1), 170 - 3
Cutaneous Mycobacterium fortuitum infection mimicking lupus vulgaris; Lin YC et al.; We report a woman with a lupus vulgaris-like skin eruption caused by Mycobacterium fortuitum . The presence of mycobacteria was confirmed with tissue culture and also the detection of mycobacterial heat shock protein 65 (hsp65) DNA in the biopsy specimen . The eruption resolved after treatment with amikacin and clarithromycin . Lupus vulgaris-like lesions might be included in the clinical spectrum of infections caused by rapidly growing mycobacteria.

Pathol Biol (Paris), 2002 May, 50(4), 227 - 32
{Efficacy and toxicity of aminoglycoside therapy in the elderly: combined effect of both once-daily regimen and therapeutic drug monitoring}; Foltz F et al.; This study was aimed to compare with previous results (Grillot et al., 1994), the efficacy of amikacin adaptive optimal control in a geriatric hospital . PATIENTS: During six months, 32 patients (aged of 82 +/- 8 years) were included versus 51 during two years (aged of 80 +/- 5) . The mean age was not different between the two populations (NS, Student test) . They received amikacin initial dosage of 17.7 +/- 5.1 mg/kg/d (vs 13.3 +/- 3.5 for the reference study) and maintenance dosage of 15.1 +/- 4.8 mg/kg/d (vs 11.8 +/- 5.1 for the reference study) . METHOD: Two efficacy outcomes (E1 and E2) and 1 toxicity outcome (T) were taken into account: E1 estimated the effect of adaptive control on maximal drug level, E2: overall recovery . Toxicity outcome was used: T the nephrotoxicity (increasing creatininemia over 44 mumol/l) . RESULTS: All the results are given versus the reference study . 57.6% versus 29.4% of adaptive strategy were once-a-day . E1: Chi square test show that initial dosage and maintenance dosage are greater our study than the previous one (p < 0.05: 78.8% versus 5.9% for initial dosage, 84.4% versus 13.8% for maintenance dosage) . E2: 73.6% overall of recovery versus 77% (NS, Chi square test) . T: 94% versus 85% (p < 0.05, Chi square test) of creatininemia variation are lower than 44 mumol/l . Duration of treatment is 9.8 +/- 4.8 versus 15 +/- 9 days (p < 0.5, Student test) . CONCLUSIONS: Once-a-day strategy in amikacin therapeutic regimen is no more efficient but decreases toxicity and duration treatment.

J Mol Med, 2002 Jun, 80(6), 367 - 76 Epub 2002 Jan 25.
Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system; Keeling KM et al.; Recent studies have suggested that the use of aminoglycosides to suppress disease-causing nonsense mutations may be a promising new therapy for a large number of genetic diseases . However, gentamicin is currently the only clinically relevant aminoglycoside shown to suppress premature stop mutations in a mammalian system . We compared the ability of the clinically approved aminoglycosides gentamicin, tobramycin, and amikacin to suppress premature stop mutations . Using readthrough reporter constructs as well as mammalian cDNAs containing naturally occurring premature stop mutations, we found that each of these aminoglycosides can suppress many premature stop mutations in a context-dependent manner in a mammalian translation system . Our results indicate that the tetranucleotide termination signal (the stop codon and the nucleotide 3' of the stop codon) is the primary determinant for aminoglycoside-mediated suppression . The levels of termination suppression achieved by tobramycin were substantially lower than those observed with gentamicin . In contrast, amikacin stimulated suppression in a manner that was generally similar to gentamicin . Amikacin produced higher levels of readthrough than gentamicin at some contexts, demonstrating a unique pattern of context dependence . Experiments with mammalian cDNAs confirmed these results and demonstrated that these aminoglycosides can also suppress disease-associated premature stop mutations previously identified in the IDUA gene (responsible for the lysosomal storage disease mucopolysaccharidosis I) and the P53 gene (associated with many forms of cancer) . Taken together, these results suggest that amikacin represents an alternative to gentamicin for suppression therapy in certain contexts, thus providing a means of optimizing the efficacy of aminoglycoside-mediated suppression of premature stop mutations.

Curr Pharm Des, 2002, 8(6), 475 - 82
Design of anti-bacterial drug and anti-mycobacterial drug for drug delivery system; Yanagihara K; Liposome-encapsulated drugs often exhibit reduced toxicity and have also been shown to enhance retention of drugs in the tissues . Thus, encapsulation of drugs in liposomes has often resulted in an improved overall therapeutic efficacy . The results of efficacy of liposome-encapsulated ciplofloxacin or azithromycin for therapy of intracellular M . avium infection show enhanced cellular delivery of liposome-encapsulated antibiotics and suggest that efficiency of intracellular targeting is sufficient to mediate enhanced antimycobacterial effects . The antitubercular drugs encapsulated in lung specific stealth liposomes have enhanced efficacies against tuberculosis infection in mice . These results from stealth liposome study indicate that antitubercular drugs encapsulated in liposome may provide therapeutic advantages over the existing chemotherapeutic regimen for tuberculosis . Liposomes with encapsulated amikacin are able to protect collagen almost completely from adherence of bacterial cells of all strains examined and prevent from invading of bacteria.

Clin Nephrol, 2002 May, 57(5), 392 - 7
Edema due to protein-losing enteropathy--a disorder rarely considered by nephrologists; Chang JM et al.; In the differential diagnosis, protein-losing enteropathy (PLE) is a rarely considered explanation of edema . Three such cases are reported in this article . Clinical presentations varied from severe generalized anasarca and respiratory distress to mild pitting edema on the pretibial surface . Hypoalbuminemia (< 35 g/l) was another common finding in addition to edema . The patients were carefully examined to exclude other causes of hypoalbuminemia . Two patients experienced diarrhea . Endoscopic studies (plus biopsies) for any mucosal lesion in the stomach and colon were also performed . PLE was confirmed by the positive radionuclide scanning results after infusing intravenous 99mTc human serum albumin (USA) . Investigation for the etiologies showed intestinal lymphangiectasia in 1 patient, Menetrier's disease in another, and no recognizable cause in the third . The severe anasarca of the patient with intestinal lymphangiectasia didn't respond to corticosteroids and albumin supplement plus large doses of furosemide . She died of overwhelming pulmonary infection despite the use of powerful antibiotics (ceftriaxone and amikacin) . We planned to treat the Menetrier's disease patient with somatostatin to decrease the exocrine activities of the intestinal tract . The patient with presumable idiopathic PLE had the least severe edema and was not treated with any medication . In addition to the above patients, another 3 patients with hypoalbuminemia and edema were also noted to have positive HSA scan results . However, 2 of these patients had systemic lupus erythromatosus and the third pulmonary tuberculosis and biopsy-proven membranous nephropathy . Treatment of their underlying diseases showed satisfactory remission of edema.

Hear Res, 2002 Mar, 165(1-2), 152 - 5
Click-evoked potentials on the neck of the guinea pig; Matsuzaki M et al.; Vestibulocollic reflex in humans is called vestibular evoked myogenic potential . To try to establish an animal model of the acoustically evoked vestibulocollic reflex, 18 guinea pigs were used in this study . Eight of the 18 guinea pigs received intramuscular injection of amikacin for 18 days (450 mg/kg/day) before recording to destroy the cochlea pharmacologically . Under general anesthesia with intraperitoneal injection of pentobarbital sodium (40 mg/kg body weight), auditory brainstem responses (ABRs) were recorded . Then potentials on the neck evoked by loud clicks were recorded on the pre-vertebral muscle or on the spinal cord at the level of third cervical vertebral bone using a silver-ball electrode . As a result, a negative peak (NP) with a latency of 6 approximately 8 ms was observed on the neck muscle or on the spinal cord in the control group . The thresholds of the NP were 90-100 dB above those of ABRs . The NP was also observed in the amikacin-administered group using clicks with the same intensity as that for the control group, while the ABR thresholds were highly elevated . These results are in agreement with a vestibular origin of the NP potential.

QJM, 2002 May, 95(5), 291 - 7
Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides; Raveh D et al.; BACKGROUND: There remain concerns about the safety of once-daily dosing of aminoglycosides (AGs) in the elderly . AIM: To assess the safety of once-daily AGs in elderly patients and evaluate possible risk factors for nephrotoxicity . DESIGN: Prospective, non-interventional surveillance study . METHODS: All patients receiving AGs were monitored over 4 months . Clinicians determined the AG dose for each patient after estimating patient weight and calculating creatinine clearance (CrCl) using the Cockcroft-Gault formula . Parallel figures were calculated by the investigators using measured weight . Clinicians obtained an AG trough level 24 h after initiation of treatment, and, if non-toxic, every 5-7 days thereafter . AG toxicity was defined as an increase in serum creatinine of > or =50% . RESULTS: In the study period, 249 consecutive patients received an AG: 116 (47%) males, mean+/-SD age 75+/-16 years . Forty-two (17%) received amikacin and 207 (83%) gentamicin . An increase of > or =50% in serum creatinine was detected in 31/249 (12.4%); maximal creatinine was < or =177 micromol/l in 16/249 (6.4%), 186-265 micromol/l in nine (3.6%), and >265 micromol/l in six (2.4%) . None developed oliguric renal failure . Renal damage correlated with a high AG trough level (>1.1 microg/ml) (p<0.001); haemoglobin level <10 g/dl (p<0.05); hospital admission >7 days prior to AG treatment (p<0.005); and AG treatment > or =11 days (p<0.05) . Mean CrCl based on estimated weight was 52+/-18 ml/min; that based on actual weight was 71+/-37 ml/min . Despite this, mean AG dose was 1.3+/-0.6 higher than optimal . CONCLUSIONS: Oliguric and/or lasting renal toxicity is rare in elderly patients receiving once-daily aminoglycosides for <11 days, if regular trough drug levels are monitored.

J Cataract Refract Surg, 2002 May, 28(5), 887 - 90
Bilateral Mycobacterium abscessus keratitis after laser in situ keratomileusis; Giaconi J et al.; A 35-year-old man was diagnosed with Mycobacterium abscessus keratitis in the left eye 3 weeks after bilateral laser in situ keratomileusis (LASIK) . Infection in the right eye developed 6 weeks after surgery . Despite aggressive treatment with topical amikacin and clarithromycin and oral clarithromycin, the infection progressed in both eyes . To improve antibiotic penetration, the LASIK flap was removed in both eyes . Culture positivity was prolonged; however, after 8 weeks of intensive topical antibiotics, the infection was eradicated . The final best corrected visual acuity was 20/30 in both eyes.

Clin Microbiol Infect, 2002 Feb, 8(2), 125 - 9
Mycobacterium fortuitum complex endocarditis-case report and literature review; Olalla J et al.; Endocarditis due to Mycobacterium fortuitum complex is a rare entity generally linked to the hospital environment . Only 18 cases have been published since 1966 . Here we present a case of a female who developed an endocarditis due to Mycobacterium chelonae after valve replacement as well as a review of the literature . The course of this kind of endocarditis is generally subacute and the outcome is usually fatal . Blood cultures were positive in 75% of cases of metallic valve endocarditis, versus 20% in bioprostheses . The treatment must include antibiotics that have shown activity against these mycobacteria, such as amikacin, imipenem, cefoxitin, fluorinated quinolones and macrolides (especially clarithromycin) . Surgical removal is recommended . Although the prognosis for the patient is poor, we should expect better outcomes with the use of new antibiotic regimens.

Nihon Kokyuki Gakkai Zasshi, 2002 Jan, 40(1), 61 - 5
{Mycobacterium abscessus infection complicated with diabetes mellitus}; Takemura Y et al.; We report a case of Mycobacterium abscessus infection complicated with diabetes mellitus . A 38-year-old man with diabetes mellitus as an underlying disease, was admitted to our hospital because of a productive cough . He had had pulmonary tuberculosis two years before . Chest radiography revealed infiltration in both lung apices and chest CT showed a cavitary lesion in the left upper lobe . Gaffky 2 was found on a sputum smear . However, in the examination of PCR on sputum, not only M . tuberculosis but M . avium complex was negative, and repeated cultures of sputum were positive for M . abscessus . On the basis of the diagnosis of an M . abscessus infection, the patient was initially treated with amikacin, imipenem/cilastatin and levofloxacin during hospitalization while receiving insulin for diabetes mellitus . The smear and culture of sputum became negative for Mycobacterium, and the findings of chest radiography and chest CT improved . After discharge, treatment was continued with clarithromycin and levofloxacin . It is considered that the choice of effective drugs and the additional treatment of an underlying disease are very important for the treatment of a Mycobacterium abscessus infection.

Am J Vet Res, 2002 Mar, 63(3), 374 - 80
Comparison of intraosseous or intravenous infusion for delivery of amikacin sulfate to the tibiotarsal joint of horses; Scheuch BC et al.; OBJECTIVE: To establish the route of infusion (IV or intraosseous) that results in the highest concentration of amikacin in the synovial fluid of the tibiotarsal joint and determine the duration of peak concentrations . ANIMALS: 21 horses . PROCEDURE: Regional perfusion of a limb on 15 horses was performed . Amikacin sulfate was infused into the saphenous vein or via intraosseous infusion into the distal portion of the tibia (1 g in 56 ml of lactated Ringer's solution) or proximal portion of the metatarsus (1 g of amikacin in 26 ml of lactated Ringer's solution) . Amikacin concentrations were measured in sequential samples from tibiotarsal joint synovial fluid and serum . Samples were obtained immediately prior to release of the tourniquet and 0.5, 1, 4, 8, 12, and 24 hours after the tourniquet was released . Radiographic contrast material was infused into the same locations as the antibiotic perfusate to evaluate distribution in 6 other horses . RESULTS: Infusion into the saphenous vein produced the highest concentration of amikacin in the tibiotarsal joint, compared with the distal portion of the tibia (mean +/- SE, 701.8 +/- 366.8 vs 203.8 +/- 64.5 microg/ml, respectively) . Use of a lower volume of diluent in the proximal portion of the metatarsus produced a peak value of 72.2 +/- 23.4 microg/ml . CONCLUSIONS AND CLINICAL RELEVANCE: For regional perfusion of the tarsus, IV infusion is preferred to intraosseous infusion, because higher concentrations are achieved in the synovial fluid, and the procedure is easier to perform.

No Shinkei Geka, 2002 Feb, 30(2), 165 - 9
{Cranioplasty using the patient's autogenous bone preserved by freezing--an examination of post-operative infection rates}; Nagayama K et al.; The current technique for cranioplasty using artificial bone requires further improvement with regard to infection, strength and comfort through good fitting . We have carried out cranioplasty using the patient's autogenous bone flap obtained during first surgery . It was immersed in 200 mg of Amikacin Sulphate, and frozen at -16 degrees C until its use in cranioplasty . From 1980 to 1998, cranioplasty has been carried out on 206 patients . They consisted of 118 males and 88 females, and their age ranged in our institute from 1 to 81; average age 51.1 . Ruptured aneurysm (48%), head injury (14%), intracranial hemorrhage (23%) and cerebral infarction (12%) were the major causes requiring decompression surgery . We analyse the bone preservation period and the time between cranioplasty and the onset of infection . The infection rates per bone preservation periods, the causes of decompression and age groups are studied . Of the 208 case studies, infection necessitating bone removal or debridement was noted in 8 cases (3.88%) . Average bone preservation period in the infected group was 31.1 days as compared with 54.9 days for the non-infected group (p < 0.05) . Not patient age but the type of head injury is also a significant factor in post cranioplasty infection.

Am J Ther, 1995 Feb, 2(2), 100 - 105
A Nonparametric Alternative to Modeling Population Pharmacokinetics in Patients with Spinal Cord Injury: Comparison with the Standard Two-Stage Method; Segal JL et al.; The estimation of population-specific pharmacokinetic parameters from sparse of fragmentary data obtained during routine patient care is a powerful analytical tool in drug development and therapeutic drug monitoring . The Nonparametric Expectation Maximization program (NPEM) performs this function and generates robust parameter estimates which are distribution-free and unconstrained by assumption-rich parametric, for example, Gaussian, analyses . We compared standard two-stage method (STS) estimates of amikacin pharmacokinetic parameters (V, CL) derived from a sampling rich strategy (11 patients with spinal cord injury, SCI; 7 able-bodied controls) to estimates of pharmacokinetic parameters obtained from an NPEM one-compartment analysis incorporating the 11 optimally sampled SCI patients and 8 sparse data sets (19 patients with SCI; 7 controls) . The STS (n = 11) and NPEM (n = 19) analyses provided similar V and CL parameter estimates in patients with SCI: 0.20 plus minus 0.04 L kg(minus sign1), 0.93 plus minus 0.24 ml min(minus sign1) kg(minus sign1) and 0.20 plus minus 0.06 L kg(minus sign1), 1.12 plus minus 0.26 ml min(minus sign1) kg(minus sign1), respectively . NPEM is a useful, user-friendly, distribution-free computational program for estimating the central tendency and interindividual variability of amikacin pharmacokinetic parameters in spinal cord injured humans.

Nippon Hinyokika Gakkai Zasshi, 2001 Nov, 92(7), 706 - 9
{A case of septic shock and disseminated intravascular coagulation following transrectal prostatic biopsy}; Kato K et al.; A 60-year-old man underwent transrectal six sextant ultrasound-guided prostatic biopsy because of gradual elevation of PSA . Despite postoperative use of amikacin, spiking fever developed the next day and after emergency admission (39 hours after the biopsy), his blood pressure decreased to 56/40 mmHg with WBC 800/mm3, platelets 6.9 x 10(4)/mm3 (decreased further to 0.4 x 10(4)/mm3 on the following day) and FDP 51 micrograms/dl . Intensive care including chemotherapy with broad-spectrum antibiotics and endotoxin removal therapy using a polymyxin B immobilized fiber column (PMX), was useful to recover the patient from septic shock and disseminated intravascular coagulation . As the number of systematic prostatic biopsy is increasing rapidly in Japan, more attention must be paid to potential hazards of this procedure.

Scand J Infect Dis, 2001, 33(11), 827 - 31
Comparison of cefepime and ceftazidime in combination with amikacin in the empirical treatment of high-risk patients with febrile neutropenia: a prospective, randomized, multicenter study; Erman M et al.; A total of 208 adult patients with cancer and febrile neutropenia from 5 medical institutions were randomized to receive either cefepime (2 g b.i.d.) or ceftazidime (2 g t.i.d.) in combination with amikacin (15 mg/kg/o.d.) . Ninety-seven patients in the ceftazidime (CEZ) group and 98 in the cefepime group (CEF) were evaluable for efficacy . In 68 patients (35%), infection could be documented . The average duration of antibiotic therapy was 11 and 12 d and response rates to the empirical regimen were 36 and 30% for the CEZ and CEF groups, respectively (p > 0.05) . The average time of defervescence in responders was 3 d for both groups . Modification of the initial regimen with antivirals and/or azole antifungals raised the number of responders to 44% and 35%, respectively (p > 0.05) . Vancomycin was additionally given to 29 patients in the CEZ group and to 27 patients in the CEF group . Twenty-six patients in each group received empirical amphotericin B . Mild, reversible study drug-related side-effects were observed in 12 patients (12%) in the CEZ group and 13 patients (13%) in the CEF group (p > 0.05) . Cefepime in combination with amikacin seems to be as effective, safe and tolerable as ceftazidime + amikacin in patients with high-risk neutropenia and fever.

Zhonghua Nei Ke Za Zhi, 2001 Sep, 40(9), 581 - 4
{Clinical analysis of nosocomial infection of extended spectrum beta-lactamase-producing bacteria}; Cao B et al.; OBJECTIVE: To investigate the clinical characteristics of nosocomial infection of extended spectrum beta-lactamase(ESBL)- producing bacteria . METHODS: The data of 50 cases of ESBL(+) E . coli and K . pneumonia from January to November 1999 in Peking Union Medical Hospital were analysed; 45 cases of ESBL (-) infection were randomly selected as controls . t-test and chi-square tests were used for statistical analysis . RESULTS: Long time hospitalization and use of the third generation cephalosporins were risk factors for ESBL(+) pathogen infection(P < 0.02); the prevalence of ESBL(+) bacteria infection in abdominal and pelvic cavity was higher than that of ESBL(-) bacteria(P < 0.02); the outcome of properly treated group(sensitive antibiotics were used within 72 hours) was much better than improperly treated group . All ESBL(+) bacteria were sensitive to imipenam, the resistance rate of ESBL(+) bacteria to cefmetazole, amikacin and piperacillin/tazobactam was low; the in vitro activity of ceftazidim to ESBL(+) bacteria was high but the in vivo activity is still under study . CONCLUSION: The mortality of ESBL(+) bacteria infection was high; the outcome would be improved if sensitive antibiotics were chosen as soon as the diagnosis was made.

Int J Lepr Other Mycobact Dis, 2001 Jun, 69(2), 104 - 7
Nocardia farcinica pleuritis in a lepromatous patient with severe necrotizing reaction: an unusual presentation; Arunthathi S et al.; A young, male, lepromatous leprosy patient with a severe necrotizing erythema nodosum leprosum reaction treated with prolonged oral steroids and thalidomide developed pleuritis that was caused by a rare opportunistic pathogen, Nocardia farcinica . This organism was resistant to most antibiotics but was susceptible to amikacin and minocycline . During the course of treatment the patient developed severe gastritis which necessitated the removal of clofazimine and the inclusion of an H2 receptor antagonist . Bilateral steroid-induced cataracts needed surgical correction . This case is being presented for its rare opportunistic bacterial infection and for the multiple complications which made treatment difficult.

J Comp Neurol, 2002 Jan 1, 442(1), 6 - 22
Transforming growth factor-alpha-induced cellular changes in organotypic cultures of juvenile, amikacin-treated rat organ of corti; Daudet N et al.; Hair cell losses in the mammalian cochlea following an ototoxic insult are irreversible . However, past studies have shown that amikacin treatment in rat cochleae resulted in the transient presence of atypical Deiters' cells (ACs) in the damaged organ of Corti . These ACs arise through a transformation of Deiters' cells, which produce, at their apical pole, densely packed microvilli reminiscent of early-differentiating stereociliary bundles . The ACs do not, however, express typical hair cell markers such as parvalbumin or calbindin . The present study was designed to determine whether specific growth factors could influence the survival and differentiation of these ACs and stimulate hair cell regeneration processes in vitro . Apical-medial segments of organ of Corti of juvenile amikacin-treated rats were established as organotypic cultures, and the effects of epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), transforming growth factor-alpha (TGFalpha), and retinoic acid were studied using morphological and molecular approaches . Our results indicate that TGFalpha supports the survival of the damaged organ of Corti and influences ACs differentiation in vitro, possibly acting through reorganization of the actin cytoskeleton . These effects could be directly mediated through activation of the EGF receptor, which is expressed by supporting cells in the mature organ of Corti . TGFalpha does not, however, allow the ACs to progress towards a hair cell phenotype .

Hear Res, 2001 Nov, 161(1-2), 72 - 80
Potentiation of noise-induced hearing loss by amikacin in guinea pigs; Tan CT et al.; Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs) . Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs . The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs . Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m . with either amikacin (100 mg/kg/day) or saline for 10 days . Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure . DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered . At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure . There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only . However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR . In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure . No gender difference in the responses to noise and/or amikacin could be demonstrated . The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

Clin Transplant, 2001 Dec, 15(6), 415 - 20
Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies; Tripodi MF et al.; Pulmonary nocardiosis is an infrequent but insidious disease in transplant patients . It has occurred in our centre in 3 out of 233 heart-transplant recipients since 1988 . Common clinical features were mild symptoms and a severe nodular lung involvement . Early diagnosis was based upon cultures of bronchoalveolar lavage or fine-needle aspirate specimens of the lung lesions . Susceptibility studies and tests of antibiotic synergism guided the therapy . Two patients were treated with a combination of piperacillin-tazobactam and ciprofloxacin, and one with imipenem and amikacin, for 3-4 wk followed by a 3-month course of trimethoprim-sulphamethoxazole . The nocardial disease was successfully treated in the 3 patients; however, one died of subsequent invasive pulmonary aspergillosis . In the absence of consensus on the length of therapy, this experience suggests that a synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of trimethoprim-sulphamethoxazole may be effective in eradicating nocardial disease and may reduce the need for long-term treatment.

Clin Pharmacokinet, 2001, 40(12), 947 - 53
Renal elimination of amikacin and the aging process; Ducher M et al.; OBJECTIVE: Although amikacin is primarily eliminated via glomerular filtration, drug concentrations are not consistently predicted in all patients . To better describe the relationship between amikacin clearance and both age and renal function, we used a new heuristic approach involving statistical analysis of dependence . DESIGN AND SETTING: Retrospective pharmacokinetic study using data from seven centres in France . PARTICIPANTS: 634 patients with sepsis aged between 18 and 98 years of age who received intravenous amikacin . METHODS: Clearance of amikacin was modelled using the NonParametric EM algorithm for a two-compartment model (NPEM2) with intravenous infusion . RESULTS: A total of 2499 serum amikacin determinations was available for analysis . The relationship between the clearance of amikacin and age was weak . Interestingly, the Z method, which filters data based on dependence criteria, selected data that were best fitted by a polynomial function (r = 0.90; p < 0.001) . This representation of the polynomial function was similar to a previously proposed theoretical model describing covariations between the clearance of amikacin and age . However, the polynomial function applied to only 33% of the patients that were selected by the Z method . The correlation between the clearance of amikacin and renal function was also relatively low (r = 0.39) . The Z method exhibited a continuous and strong dependence pattern between the clearance of amikacin and age for 49% of the patients . CONCLUSIONS: The Z methodology, which filters data using dependence criteria, confirms that age, renal function and amikacin clearance are strongly related, but only in less than half of a large sample of patients with sepsis without renal pathology . These results suggest that other variables should be taken into account in order to improve the description of the behaviour of amikacin . The Z methodology improved the classical description of relationships between variables, and should be applied to better select pertinent variables in pharmacokinetic studies.

Ophthalmology, 2001 Dec, 108(12), 2201 - 8
Mycobacterium interface keratitis after laser in situ keratomileusis; Solomon A et al.; PURPOSE: To report the clinical course, management, and outcome of infectious interface keratitis caused by mycobacterium species after laser in situ keratomileusis (LASIK) . DESIGN: A small noncomparative interventional case series . PARTICIPANTS: Five eyes in four patients who underwent LASIK in different locations around the world and had culture-positive mycobacterium keratitis develop . INTERVENTION: The LASIK flap was lifted or amputated, samples were submitted for Ziehl-Neelsen acid-fast stain and Lowenstein-Jensen's agar cultures for diagnosis; topical treatment with fortified clarithromycin and amikacin was administered until clinical resolution . MAIN OUTCOME MEASURES: Time periods from onset to diagnosis and from diagnosis to clinical resolution, and the final visual acuity . RESULTS: Onset of symptoms of infection occurred after a mean of 20 days (range, 11 days-6 weeks) after LASIK or an enhancement procedure . Definitive diagnosis was obtained after a mean period of 4.5 weeks (range, 12 days-8 weeks) from onset . Keratitis resolved within 8.4 weeks (range, 1-18 weeks) of treatment with fortified clarithromycin and amikacin . Corticosteroids were found to worsen and prolong the course of disease . In four of five eyes the LASIK flap was amputated . CONCLUSIONS: Mycobacterial keratitis is a potentially vision-threatening complication after LASIK, characterized by a long latent period, delayed diagnosis, and a protracted course even under intensive specific antibiotic therapy . Inclusion of specific culture media and staining protocols for mycobacteria, along with aggressive treatment on diagnosis, including lifting or amputating the LASIK flap, culturing, topical fortified clarithromycin and amikacin, while avoiding corticosteroids, may significantly improve resolution of the infection and potentially improve the visual outcome.

Antimicrob Agents Chemother, 2001 Dec, 45(12), 3287 - 92
Systematic analysis of a conserved region of the aminoglycoside 6'-N-acetyltransferase type Ib; Shmara A et al.; Alanine-scanning mutagenesis was applied to the aminoglycoside 6'-N-acetyltransferase type Ib conserved motif B, and the effects of the substitutions were analyzed by measuring the MICs of kanamycin (KAN) and its semisynthetic derivative, amikacin (AMK) . Several substitutions resulted in no major change in MICs . E167A and F171A resulted in derivatives that lost the ability to confer resistance to KAN and AMK . P155A, P157A, N159A, L160A, I163A, K168A, and G170A conferred intermediate levels of resistance . Y166A resulted in an enzyme derivative with a modified specificity; it conferred a high level of resistance to KAN but lost the ability to confer resistance to AMK . Although not as pronounced, the resistance profiles conferred by substitutions N159A and G170A were related to that conferred by Y166A . These phenotypes, taken together with previous results indicating that mutant F171L could not catalyze acetylation of AMK when the assays were carried out at 42 degrees C (D . Panaite and M . Tolmasky, Plasmid 39:123-133, 1998), suggest that some motif B amino acids play a direct or indirect role in acceptor substrate specificity . MICs of AMK and KAN for cells harboring the substitution C165A were high, suggesting that the active form of the enzyme may not be a dimer formed through a disulfide bond . Furthermore, this result indicated that the acetylation reaction occurs through a direct mechanism rather than a ping-pong mechanism that includes a transient transfer of the acetyl group to a cysteine residue . Deletion of fragments at the C terminus demonstrated that up to 10 amino acids could be deleted without a loss of activity.

Am J Med, 2001 Nov, 111(7), 528 - 34
The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy; Harbarth S et al.; PURPOSE: We sought to quantify the incidence of, define risk factors for, and examine the relation between renal functional impairment and treatment with conventional amphotericin B . SUBJECTS AND METHODS: We performed a 9-year retrospective analysis of amphotericin B-associated nephrotoxicity in 494 adult inpatients who received > or = 2 doses of amphotericin B . Nephrotoxicity was classified according to two nonmutually exclusive severity categories (50% increase or doubling in the baseline creatinine level) . RESULTS: The median cumulative dosage of amphotericin B was 240 mg (interquartile range, 113 to 500 mg), with the majority of patients (n = 361) receiving it for empiric treatment . Overall, 139 (28%) patients experienced renal toxicity, including 58 (12%) with moderate-to-severe nephrotoxicity . The rate of nephrotoxicity was relatively constant during amphotericin B treatment . For each 10-mg increase in the mean daily amphotericin B dose, the adjusted rate of renal toxicity increased by a factor of 1.13 (95% confidence interval: 1.02 to 1.25) . We defined 5 categorical risk factors: mean daily amphotericin B dose > or = 35 mg, male sex, weight > or = 90 kg, chronic renal disease, and use of amikacin or cyclosporine . The incidence of moderate-to-severe nephrotoxicity was 4% (6 of 137) in patients with none of these risk factors, 8% (14 of 181) in those with 1 risk factor, 18% (21 of 117) in those with 2 risk factors, and 29% (17 of 59) in patients with > or = 3 risk factors . Nephrotoxicity rarely led to hemodialysis (n = 3); however, at the time of discharge or death, 70% of patients with moderate-to-severe nephrotoxicity had a serum creatinine level that was > or = 0.5 mg/dL above baseline . CONCLUSION: Amphotericin B-related nephrotoxicity is an important dose-dependent and duration-dependent toxicity that is accentuated by certain nephrotoxic drugs and patient characteristics . Patients with more than two risk factors for nephrotoxicity are potential candidates for alternative antifungal therapy.

Eur J Clin Pharmacol, 2001 Sep, 57(6-7), 499 - 504
Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation; Bleyzac N et al.; OBJECTIVE: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates . This study evaluated the evolution of this variability with gestational age (GA) at birth in relation to renal maturation . METHODS: Population PK values of amikacin were studied in 131 newborns (postnatal age 1 day, GA 24-41 weeks) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per group) . PK variables were Kel/Vol, Ks/Vs, Cl/Vol . Cls/ where: Kel = Kslope x GA + Kintercept, Cl = Clslope x GA + Clintercept, and Vol = Vs x body weight . Ki and Cli were held as constants . The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group . RESULTS: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination . Amikacin volume of distribution increased with body weight up to a GA of about 38 weeks and then decreased for highest GA values . However, the PDF for the individual GA groups showed a multimodal PK distribution . Kel, Vol, Vs, Cl, and Cl, standard deviations increased linearly with GA, showing differential renal maturation . The higher the GA, the more interindividual PK variability increased . CONCLUSIONS: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability with high GA . Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA . Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.

Chem Res Toxicol, 2001 Oct, 14(10), 1353 - 62
Molecular mechanism of hydrogen peroxide conversion and activation by Cu(II)-amikacin complexes; Jezowska-Bojczuk M et al.; The interactions between Cu(II)-amikacin complexes {Cu(II)-Ami} and hydrogen peroxide were studied by spectroscopy (EPR, UV-vis, CD, XAS) and cyclic voltammetry . A monomer-dimer equilibrium was detected at complex concentrations above 5 mM (log K(dim) = 1.84 +/- 0.03) . The dimeric complex undergoes easy, although irreversible oxidation (ca . 0.5-0.6 V) to a Cu(III) species on platinum electrode . However, the monomeric complexes are able to catalyze hydrogen peroxide disproportionation reaction at pH 7.4 in a multistep process, mediated by hydroxyl radicals and involving both Cu(I)/Cu(II) and Cu(II)/Cu(III) redox pairs.

J Fr Ophtalmol, 2001 Sep, 24(7), 687 - 91
{Fifty-two cases of postoperative endophthalmitis treated with one protocol: anatomical and functional results}; Auclin F et al.; PURPOSE: To evaluate our management of postoperative endophthalmitis and compare our protocol to the Endophthalmitis Vitrectomy Study's (EVS) recommended protocol . PATIENTS AND METHODS: This study comprises 52 patients with postoperative endophthalmitis treated with the same protocol in 1996 and 1997 . Patients were given an intravitreal injection of antibiotics (vancomycin-amikacin) and steroids (dexamethasone), systemic antibiotics (pefloxacin-piperracillin), and systemic steroids in bolus . Vitrectomy was not systematic . So as not to delay the treatment, cultures were obtained only from an anterior chamber paracentesis . RESULTS: Visual acuity was measurable in 86.5% of the patients, with 20/100 in 63.4% and 20/40 in 44.2% . Our results are similar to those of the EVS even when initial visual acuity was Light Perception . CONCLUSION: Our protocol is simple and easy to perform in all ophthalmology centers . It is based on intravitreal injection, which must be performed as quickly as possible.

J Biol Chem, 2001 Dec 7, 276(49), 45876 - 81 Epub 2001 Oct 04.
Overexpression and mechanistic analysis of chromosomally encoded aminoglycoside 2'-N-acetyltransferase (AAC(2')-Ic) from Mycobacterium tuberculosis; Hegde SS et al.; The chromosomally encoded aminoglycoside N-acetyltransferase, AAC(2')-Ic, of Mycobacterium tuberculosis has a yet unidentified physiological function . The aac(2')-Ic gene was cloned and expressed in Escherichia coli, and AAC(2')-Ic was purified . Recombinant AAC(2')-Ic was a soluble protein of 20,000 Da and acetylated all aminoglycosides substrates tested in vitro, including therapeutically important antibiotics . Acetyl-CoA was the preferred acyl donor . The enzyme, in addition to acetylating aminoglycosides containing 2'-amino substituents, also acetylated kanamycin A and amikacin that contain a 2'-hydroxyl substituent, although with lower activity, indicating the capacity of the enzyme to perform both N-acetyl and O-acetyl transfer . The enzyme exhibited "substrate activation" with many aminoglycoside substrates while exhibiting Michaelis-Menten kinetics with others . Kinetic studies supported a random kinetic mechanism for AAC(2')-Ic . Comparison of the kinetic parameters of different aminoglycosides suggested that their hexopyranosyl residues and, to a lesser extent, the central aminocyclitol residue carry the major determinants of substrate affinity.

Chemotherapy, 2001 Sep-Oct, 47(5), 381 - 4
Comparison of cefepime versus ceftriaxone-amikacin as empirical regimens for the treatment of febrile neutropenia in acute leukemia patients; Borbolla JR et al.; BACKGROUND: High-intensity regimes of chemotherapy have led to longer and more severe episodes of neutropenia with a resulting increase in morbidity and mortality due to infections . Which empiric antibiotic regimen to use in these cases is still under debate . METHODS: We performed a randomized comparative study to evaluate the efficacy of cefepime versus ceftriaxone plus amikacin as the initial treatment in an escalating, empirical, antibiotic therapy regimen in febrile neutropenic patients . Both adults and children were included . All patients had less than 500 neutrophils/microl at the time of infection . Patients were randomized to receive either cefepime or ceftriaxone plus amikacin . If infection continued 72 h later, patients in both groups received vancomycin, and if infection had not disappeared 7 days after starting antibiotics, amphotericin B was started . RESULTS: Twenty patients were included in each group . Both treatment and control groups were comparable for age and sex, among other factors . There were 18 cures in the cefepime group and 17 in the ceftriaxone plus amikacin group (p = 0.9) . No patient discontinued therapy because of toxicity . CONCLUSIONS: Cefepime is a safe and very effective therapy for patients with acute leukemia and febrile neutropenia; in addition, it is a cheaper regimen in our country, and lacks the potential toxicity of the aminoglycosides .

J Assoc Res Otolaryngol, 2000 Dec, 1(4), 300 - 14
Consequences of outer hair cell damage for otoacoustic emissions and audio-vocal feedback in the mustached bat; Kossl M et al.; The cochlea of the mustached bat is adapted to process ultrasonic echolocation signals . To assess the involvement of active sound amplification by outer hair cells in high-frequency hearing and in audio-vocal interaction, selective hair cell damage was induced by the antibiotic Amikacin . Amikacin preferentially damaged the first row of outer hair cells in the basal cochlear turn . The cochlear regions coding for the second-harmonic constant-frequency component of the echolocation call (CF2) at 61 kHz and for frequencies between 75 and 100 kHz were the most affected . This was reflected in an increase of mechanical thresholds obtained by measuring distortion-product otoacoustic emissions . During initial periods of minor hair cell damage, when thresholds had deteriorated by less than 40 dB, a sharp, mechanical, cochlear resonance that is responsible for enhanced tuning to 61 kHz was still measurable as a stimulus-frequency otoacoustic emission and its frequency decreased by 350 Hz . The persistence of the resonance suggests that passive structures like the tectorial or basilar membrane are important for generation of the resonance . Behaviorally, the bats reacted to the change in cochlear micromechanics with a decrease of their CF2 frequency by 360 Hz . After larger hair cell damage, when the cochlear resonance had disappeared, the bats vocalized only sparsely and the CF2 frequency increased by up to 2 kHz, which may correspond to a state without audiovocal feedback . This indicates that audio-vocal feedback in the nondamaged animal works to lower the call frequency.

Anal Chem, 2001 Aug 15, 73(16), 4028 - 36
Basicity of the amino groups of the aminoglycoside amikacin using capillary electrophoresis and coupled CE-MS-MS techniques; Kane RS et al.; This paper describes the use of capillary electrophoresis (CE), and coupled CE and mass spectrometric techniques, to measure the values of the pKa of the amino groups of the aminoglycoside antibiotic amikacin and of its acetylated derivatives . These values of pKa (8.4, 6.7, 9.7, 8.4) were determined by measuring the electrophoretic mobilities of the molecules as a function of pH; they are within 0.7 unit of certain values reported in the literature (by 13C and 15N NMR spectroscopies) but resolved ambiguities left by these earlier studies . The range of values of pKa of amino groups also indicates the complex dependence of the acidity of a functional group (and thus the extent of ionization at a specified value of pH) on the molecular environment of that group.

J Antimicrob Chemother, 2001 Sep, 48(3), 333 - 44
Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies; Schiffelers R et al.; Liposome-encapsulated amikacin has recently entered clinical trials . The rationale for liposome encapsulation of aminoglycosides is the possibility to increase the therapeutic index of this class of antibiotics by increasing aminoglycoside concentrations at the site of infection and/or by reducing the toxicity of these drugs . Three approaches can be distinguished: the use of liposomes as a depot formulation for local drug administration; targeting of (relatively) short circulating conventional liposomes to the cells of the mononuclear phagocyte system (MPS) for treating intracellular bacterial infections; and targeting of long-circulating liposomes to infectious foci localized outside the MPS . This review discusses the pre-clinical and clinical data in connection with recent developments in liposome technology.

Indian J Med Res, 2001 Mar, 113, 83 - 4
Mycobacterium fortuitum wound infection following laparoscopy; Sethi S et al.; During a six week period in 1999, seven patients who underwent laparoscopic tubectomies at small town health centres near Chandigarh developed chronic discharging sinuses at the site of incision . Mycobacterium fortuitum was isolated from wound discharge of the five patients by standard methods and two patients were smear positive . Environmental samples e.g., tap water, and a variety of fluids did not yield any mycobacteria and swabs from different parts of the laparoscope were sterile . All patients responded to ciprofloxacin and amikacin therapy . Our observation demonstrates that M . fortuitum is a clinically important nosocomial pathogen in setting of surgical wound infection in our country.

Clin Neurophysiol, 2001 Jul, 112(7), 1357 - 63
Changes in electrovestibular brainstem responses after aminoglycoside intoxication in guinea pigs; Sugasawa K et al.; OBJECTIVE: To verify the usefulness of short-latency vestibular responses evoked by a combination of round window electrical stimulation and sinusoidal rotation (electrovestibular brainstem responses; EVBRs) as a new monitoring tool of the vestibular function in animal experiments . METHODS: EVBRs were obtained before, during, and after treatment with aminoglycosides, along with compound action potential (CAP) audiograms . The changes in EVBRs were compared with morphological changes observed by scanning electron microscopy . RESULTS: EVBR amplitudes did not change in the group of guinea pigs treated with amikacin, but markedly decreased in the streptomycin and gentamicin- treated groups . CAP audiograms indicated a significant threshold elevation in the amikacin group, a moderate elevation in the gentamicin group, and no change in the streptomycin group . Under scanning electron microscopy, the loss of the sensory hair cells observed in the cristae ampullares was slight to moderate in the amikacin group, moderate to severe in the streptomycin group, and severe in the gentamicin group . CONCLUSION: EVBRs reflect overall pathological changes undergone by vestibular hair cells, and support the vestibular specificity of EVBRs.

Biol Neonate, 2001 Aug, 80(2), 142 - 7
Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models; Labaune JM et al.; Amikacin is widely used in the treatment of suspected or confirmed neonatal infections . However, dosage regimens are not well defined in this group of patients because of a wide inter-individual pharmacokinetic variability . An individualized goal-oriented amikacin dosage design was applied using population pharmacokinetic data . A dosing chart was developed for neonates during the first 2 days of life, by using population pharmacokinetic parameter values and USCPACK software . This dosing chart based on gestational age (GA) and body weight gives a once-a-day amikacin dosage regimen involving an injection every 24 h . Validation was performed in 57 neonates less than 2 days old, divided into three GA groups and prospectively treated using the dosing chart . Target peak serum levels of amikacin were obtained in 62-80% of patients after the first dose and in 80-100% after the second dose, and trough concentrations were obtained in 100% . This study has confirmed the need for individualization of amikacin dosage regimens in neonates.

Acta Pharmacol Sin, 2000 Oct, 21(10), 954 - 60
Population pharmacokinetic analysis of amikacin and validation on neonates using Monte Carlo method; Wang J et al.; AIM: To make programs for population pharmacokinetic analysis and to assess the ability of this method in pharmacokinetic parameter estimation and in the prediction of serum concentrations . METHODS: Data of amikacin as a model drug were collected from 42 neonates with 142 serum samples . A one-compartment open model was used to describe the kinetics of amikacin after the intravenous infusion . Following Sheiner's idea of population pharmacokinetics, we made the programs to evaluate population parameter and individual parameter . The target function minimality was obtained from Monte Carlo algorithm . The validation of the population analysis was performed using classic pharmacokinetic program 3p87 for antithesis . The predictability of the developed method was evaluated by computing precision and accuracy of serum concentration predicted using the parameter estimates . RESULTS: The stability of our self-made program was good . The population parameters obtained from this approach were in conformity with those from 3p87, and the interindividual variability was relatively small . For the learning sample and the validation sample, predicted and observed concentrations were all close with correlation coefficient 0.995 and 0.990, respectively . Most of predicted errors were found < +/- 1 mg/L, and RMSD and BIAS were 0.58 and -0.07 for the validation sample, respectively . The choice of blood sampling time was an important factor for the predictive performance . An early sampling time after the infusion was observed to be the best sampling time . CONCLUSION: The estimation program of population parameter and individual parameter made by us ran stably, and allowed us to use sparse data to estimate population pharmacokinetic parameters . It provided accurate estimates of these parameters and satisfactory ability of serum concentration prediction . Therefore, it can be used for the population pharmacokinetic analysis and individualization of dosage regimen.

Clin Infect Dis, 2001 Sep 1, 33(5), 745 - 8 Epub 2001 Aug 06.
Failure of treatment for chronic Mycobacterium abscessus meningitis despite adequate clarithromycin levels in cerebrospinal fluid; Maniu CV et al.; We report a case of posttraumatic meningitis due to Mycobacterium abscessus, treated initially with oral clarithromycin and intravenous amikacin plus intrathecal amikacin . Despite cerebrospinal fluid (CSF) levels of clarithromycin and amikacin in excess of their in vitro minimum inhibitory concentrations for the organism, the CSF cultures remained continuously positive for M . abscessus . To our knowledge, this is the first documented case of M . abscessus meningitis and the first report of measured CSF levels of clarithromycin in a patient with meningitis, showing that even therapeutic CSF levels of clarithromycin and amikacin might not be successful in eradicating M . abscessus meningitis.

Cancer J, 2001 May-Jun, 7(3), 219 - 27
Clinical applications of a novel sustained-release injectable drug delivery system: DepoFoam technology; Howell SB; The therapeutic effectiveness of drugs is often limited by the inability to sustain therapeutic levels at the target site . Encapsulation of drugs in multivesicular lipid-based particles for sustained release is a novel approach to improving the pharmacokinetics of drug therapy . This paper reviews the preclinical and clinical literature on the applications and potential therapeutic benefits of DepoFoam technology, a novel sustained-release, injectable drug delivery system . DepoFoam formulations of drugs, including anticancer agents (cytarabine, methotrexate, bleomycin, recombinant interferon alfa, 5-fluorouridine-5'-monophosphate, and others), anti-infective agents (dideoxycytidine, 2'-norcyclic guanosine monophosphate, cidofovir, tobramycin, gentamicin, amikacin), analgesics (morphine, bupivacaine), and macromolecules (insulin, interleukin-2), delivered intrathecally, subcutaneously, intraperitoneally, or intralesionally, provide sustained therapeutic levels of drug at the intended target site and reduce systemic exposure and toxicity . Pharmacokinetic studies have demonstrated that DepoFoam particle encapsulation effectively extends the half-life of drugs, thus prolonging the duration of therapeutic drug concentrations in local tissues or in body spaces into which the encapsulated drug is injected . In the case of cell-cycle phase-specific chemotherapeutic agents, such formulations can improve efficacy and therapeutic ratio . DepoFoam is a promising drug delivery system for sustained release of hydrophilic injectable drugs that has a wide range of potential applications in oncology, infectious disease, analgesia, and other therapeutic areas.

Jpn J Antibiot, 2001 Feb, 54(2), 88 - 94
{Clinical effects of combination therapy with cefozopran and amikacin for infections in patients with hematological disorders}; Fukuda M et al.; Cefozopran (CZOP) and amikacin (AMK) were used concomitantly to treat infections complicated by hematological diseases . A total of 103 subjects were evaluated, and the all over efficacy rate was 69.9% . Acute leukemia was found in the largest number of patient, 57, followed by 29 cases of malignant lymphoma and 7 cases of myelodysplastic syndrome . By type of infection, patients having unknown origin were the largest in number, being 66, and the efficacy rate was 71.2% . The efficacy rates for sepsis, pneumonia and upper respiratory infection were 42.9% (7 cases), 71.4% (14 cases) and 90% (10 cases) respectively . The efficacy rates by neutrophil counts before administration of CZOP and AMK and at 1 week after administration were both 53.3% in the group of less than 100/microliter, both 60% in the group of less than 500/microliter . The efficacy rate by neutrophil counts at 1 week after administration was 58.6% in the group of less than 100/microliter . The efficacy rate was 75.4% in the group of granulocyte colony stimulating factor (G-CSF) concomitant usage, and 61.9% in the group of non-concomitant usage group . The efficacy rates by serum albumin levels before administration of CZOP and AMK and at 1 week after administration were both 92.9% in the group of over than 4 g/dl, both 50% in the group of less than 3 g/dl . Concomitant treatment with CZOP and AMK exhibited a high level of safety and efficacy rates in infections complicated by hematological diseases.

Otol Neurotol, 2001 Jan, 22(1), 70 - 5
Objective method for differentiating between drug-induced vestibulotoxicity and cochleotoxicity; Freeman S et al.; HYPOTHESIS: An objective direct method is proposed to differentiate between drug-induced functional vestibulotoxicity and cochleotoxicity . BACKGROUND: Many substances are ototoxic . Although there are objective methods to directly evaluate functional cochlear toxicity (auditory nerve brainstem responses {ABR}), it is more difficult to assess direct functional ototoxicity to the various vestibular end organs . METHODS: Short-latency vestibular evoked potentials (VsEP) from different vestibular end organs and ABR, were used to assess functional impairment of the vestibular and cochlear end organs caused by daily injections of the aminoglycoside amikacin (known to be preferentially cochleotoxic) in guinea pigs . RESULTS: There was no significant change in the various VsEPs . whereas ABR thresholds were elevated, confirming the selective functional cochleotoxicity previously reported, as evaluated by other (mainly nondirect) methods . CONCLUSION: This study demonstrates the feasibility in general of using short-latency evoked potentials to evaluate functional cochleotoxicity and vestibulotoxicity of ototoxic drugs and to differentiate between them.

Clin Neurol Neurosurg, 2001 Apr, 103(1), 59 - 62
Multiple nocardial abscesses of cerebrum, cerebellum and spinal cord, causing quadriplegia; Durmaz R et al.; In this paper we present a case of a diabetic patient with nocardial abscesses of cerebrum, cerebellum and the spinal cord . The present case is the first case in the literature of solitary intramedullary abscess in cervical spinal cord, causing tetraplegia . Nocardia asteroides grew in a culture of the abscess pus . After either surgical excision or drainage of lesions, a triple combination regimen of chemotherapy (amikacin, ceftriaxone and trimethoprim-sulfamethoxazole) was given, but the patient was lost in the postoperative period . This case gives suggestive evidence of an association between cervical spinal cord involvement and poor prognosis in CNS nocardiosis.

Dermatology, 2001, 202(2), 131 - 3
Cutaneous nocardiosis of the chest wall and pleura--10-year consequences of a hand actinomycetoma; Saarinen KA et al.; We report an unusual case of primary cutaneous nocardiosis due to Nocardia otitidiscaviarum presenting first as a mycetoma of the right hand and wrist . The patient refused treatment and was lost to follow-up until he showed up 10 years later with numerous discharging large sinuses and abscesses on the upper right quadrant of the chest wall and in the right armpit . Roentgenograms revealed pleural masses . Histology was in keeping with the diagnosis of mycetoma . Treatment with amikacin, rifampicin and co-trimaxole proved to be successful .

Cancer, 2001 Apr 15, 91(8), 1563 - 7
Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia; Paganini H et al.; BACKGROUND: Recent reports and a previous randomized trial conducted at the authors' institution suggested that a lower risk subset of children with febrile neutropenia under chemotherapy might benefit of an oral antibiotic outpatient approach . METHODS: The objective of this study was to test the efficacy of oral ciprofloxacin in the treatment of lower risk febrile neutropenia (LRFN) in children treated for malignant diseases . From November 1998 to December 1999, 93 episodes of LRFN in 87 children (median age, 5.5 years; range, 0.9-15.8 years) were included in a prospective randomized controlled single institution trial . Inclusion criteria included fever (> 38 degrees C), severe neutropenia (absolute neutrophil count, < 500/mm(3)), and lower risk features (e.g., absence of severe comorbidity factors, good clinical condition, negative blood cultures, control of local infection, prediction of a period of neutropenia less than 10 days after admission, and compliant parents) . After 24 hours of a single intravenous ceftriaxone (100 mg/kg) plus amikacin (15 mg/kg) and completed risk assessment workup, patients were discharged and randomly allocated to two groups . Group A (48 episodes) received ciprofloxacin 20 mg/kg/day orally (p.o.) every 12 hours for 6 days . Group B (45 episodes) received intravenous ceftriaxone plus amikacin for 2 days more followed by cefixime (8 mg/kg/day p.o.) every 24 hours for 4 additional days . Failure was defined as the need of a second hospitalization during the same episode . RESULTS: Most of the patients (59% in Group A and 52% in Group B) were treated for malignant solid tumors . Fifteen (31%) children in Group A and 15 (33%) in Group B presented with fever of unknown origin (P value was not significant) . No significant differences were found in sites of initial infection between both groups . Overall results in this study were excellent . Only one patient with respiratory failure was detected in Group B, who did well with secondary treatment . CONCLUSIONS: In febrile neutropenic children after anticancer therapy and lower risk features, oral ciprofloxacin for 6 days after 24 hours of intravenous ceftraxione plus amikacin appears to be as efficacious as intravenous ceftriaxone plus amikacin for 2 days more followed by cefixime for 4 additional days . These results contribute to strengthen the concept of LRFN .

Pathol Res Pract, 2001, 197(2), 123 - 6; discussion 127-8
Molecular diagnosis of a Mycobacterium chelonae infection; Schulz S et al.; A 23-year-old female presented with enlarged cervical lymph nodes, and a diagnosis of nonspecific lymphadenitis with formation of pyogranulomas was rendered . Despite an initial oral antibiosis and subsequent long-term intravenous and oral antibiosis under hospitalized conditions, the symptoms progressed . The lymph nodes became larger and then affected the cervical region bilaterally . Her general condition worsened, and an exanthema of the extremities accompanied by a reactive arthritis occurred . Serological assays of various viral and bacterial markers and blood cultures were negative . Application of a polymerase chain reaction (PCR) protocol allowing specific amplification of mycobacterial DNA revealed DNA of Mycobacterium chelonea in formalin-fixed, paraffin-embedded lymph node tissue . Sequencing of the PCR product showed a 97% homology with the known Mycobacterium chelonae sequence . Modification of the antibiotic therapy with clarithromycin, imipenem and amikacin resulted in a rapid regression of the symptoms . The clinical course, in combination with the difficulties in detecting the infectious agent, supports the usefulness of molecular pathological analyses specific for nontuberculous mycobacteria (NTM).

J Chemother, 2001 Feb, 13(1), 70 - 81
Efficacy of meropenem as monotherapy in the treatment of ventilator-associated pneumonia; Alvarez Lerma F; Serious Infection Study Group; We performed a prospective, open label, randomized study in intensive care unit patients with ventilator-associated pneumonia (VAP) to determine the efficacy and safety of empiric intravenous (i.v.) meropenem monotherapy compared with the combination of ceftazidime plus amikacin . A total of 140 patients receiving mechanical ventilation and diagnosed with pneumonia were included in the study . Patients were randomized to receive either 1 g meropenem i.v . every 8 hours or 2 g ceftazidime i.v . every 8 hours plus 15 mg/kg amikacin daily, administered to patients with normal renal function as two daily doses . Satisfactory clinical responses (cure or improvement) were achieved at the end of treatment in 68.1% of meropenem-treated patients and 54.9% in the ceftazidime/amikacin-treated group (relative risk 1.25; 95% confidence interval >1.00, 1.55) . When non-evaluable patients were excluded from the analysis, the satisfactory clinical response was 82.5% and 66.1% for the meropenem and ceftazidime/amikacin patients, respectively (p = 0.044) . Logistic regression demonstrated that treatment with meropenem and both the basic traumatic and medical pathologies were significantly associated with a satisfactory response . Adverse events judged to be possibly or probably related to treatment were reported by seven (10.1%) patients in the meropenem group and by eight patients (11.3%) in the ceftazidime/amikacin group . The results of this study confirm that monotherapy with meropenem is well tolerated and provides superior efficacy to the conventional combination of ceftazidime and amikacin in combating VAP.

Hear Res, 2001 Mar, 153(1-2), 181 - 95
Hair cell regeneration and recovery of auditory thresholds following aminoglycoside ototoxicity in Bengalese finches; Woolley SM et al.; Birds regenerate auditory hair cells when original hair cells are lost . Regenerated hair cells become innervated and restore hearing function . Functional recovery during hair cell regeneration is particularly interesting in animals that depend on hearing for vocal communication . Bengalese finches are songbirds that depend on auditory feedback for normal song learning and maintenance . We examined the structural and functional recovery of the Bengalese finch basilar papilla after aminoglycoside ototoxicity . Birds were treated with the ototoxic aminoglycoside, amikacin, daily for 1 week . Treatment resulted in hair cell loss across the basal half of the basilar papilla and corresponding high frequency hearing loss . Hair cell regeneration and recovery of auditory brainstem responses were compared in the same animals . Survival times following treatment were between 1 day and 12 weeks . Analysis of structural recovery at weekly intervals indicated that hair cells in the Bengalese finch papilla require a maximum of 1 week to regenerate and appear with immature morphology at the epithelial surface . An additional 6 days are required for adult-like morphology to develop . Repopulation of the damaged region was complete by 8 weeks . Recovery of auditory thresholds began 1 week after treatment and reached asymptote by 4 weeks . Slight residual threshold shifts at 2.0 kHz and above were observed up to 12 weeks after treatment . Direct comparison of structural and functional recovery indicates that auditory thresholds recover maximally before a full complement of hair cells has regenerated.

Med Mycol, 2000, 38 Suppl 1, 237 - 41
New aspects of some endemic mycoses; Poncio Mendes R et al.; The treatment of mycetomas varies according to their etiological agents and the clinical state of the patient . For the treatment of eumycetomas, the azole derivatives are the drugs of choice, with itraconazole rendering better results than ketoconazole and presenting better tolerance . Actinomycetomas are treated according to different therapeutic schemes: dapsone plus sulfamethoxazol-trimethoprim (SMT), and streptomycin or amikacin or amoxicillin plus clavulanic acid . The first therapeutic scheme is very useful in the treatment of Nocardia mycetoma, while the association of amikacin plus SMT is the best treatment for those cases produced by Actinomadura madurae . Ciprofloxacin is a very useful drug for the treatment of actinomycotic mycetomas with bone lesions . Although there are several criteria for evaluating clinical outcome there is no accepted criterion of cure . During the 1990s, there was a remarkable increase in the incidence of coccidioidomycosis in California, USA . An almost ten-fold increase in the number of cases was registered during 1992 and 1993 over the usual incidence . A gradual reduction in coccidioidomycosis cases was observed in the late 1990s . This particular coccidioidomycosis outbreak took place in areas of low endemicity, as well as in those of usual high endemicity . Among the factors believed to have influenced this phenomenon were a drought followed by abundant winter/spring rainfall, increased immigration of susceptible individuals, increase in excavation/construction work and a better diagnosis of the infection, particularly in the last part of the decade . The majority of patients presented the usual clinical manifestations of symptomatic primary infection but an unusual number of cases with acute respiratory failure were observed.

Diagn Microbiol Infect Dis, 2001 Jan, 39(1), 33 - 7
Disseminated Mycobacterium abscessus infection manifesting as fever of unknown origin and intra-abdominal lymphadenitis: case report and literature review; Mueller PS et al.; Mycobacterium abscessus is a rapidly growing mycobacterium found in soil and water throughout the world . Disease in immunocompetent patients usually consists of localized skin and soft tissue infections . In contrast, disseminated disease is uncommon, usually presents with rash, and almost always occurs in an immunocompromised host . We describe an unusual case of disseminated M . abscessus infection manifesting as fever of unknown origin and intra-abdominal lymphadenitis, but without rash . Our patient responded well to amikacin and clarithromycin therapy . We also review the literature related to the diagnosis and management of this uncommon disease.

Clin Microbiol Infect, 2000 Jul, 6(7), 368 - 75
Flow cytometric testing of susceptibilities of Mycobacterium avium to amikacin, ciprofloxacin, clarithromycin and rifabutin in 24 hours; Vena RM et al.; OBJECTIVE: To develop a biologically safe flow cytometric susceptibility test that depends on detection and enumeration of actively growing Mycobacterium avium organisms in drug-free and antimycobacterial agent-containing medium . METHODS: Prior to analysis by flow cytometry, all M . avium susceptibility test samples were inactivated by exposure to paraformaldehyde . The susceptibilities of 20 clinical isolates of M . avium to amikacin, ciprofloxacin, clarithromycin, and rifabutin were tested by the flow cytometric and BACTEC methods . RESULTS: Agreement was 97% between the results of the two methods . The results of flow cytometric susceptibility tests were available 24 h after inoculation of drug-containing medium, while the BACTEC method required 4-8 days to complete . CONCLUSIONS: The flow cytometric assay is safe, simple and reproducible.

Hear Res, 2000 Dec, 150(1-2), 12 - 26
Expression of NMDA, AMPA and GABA(A) receptor subunit mRNAs in the rat auditory brainstem . II . Influence of intracochlear electrical stimulation; Liao WH et al.; We investigated the effects of intracochlear electrical stimulation (ICES) on auditory pathways of neonatal rat deafened by daily amikacin injections . Expression of mRNAs encoding ionotropic glutamate receptor subunits such as alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid type A (GABA(A)) receptor subunits was assessed by in situ hybridization in the dorsal (DCN) and the ventral cochlear nucleus (VCN) and in the central nucleus of the inferior colliculus (CNIC) . After 15 days of daily unilateral ICES, the expressions of NR1, NR2b and NR2c subunits of NMDA receptor, that of GluRA, B, C, D flop isoforms of AMPA receptor and that of some GABA(A) subunits (alpha1, beta1, gamma1, gamma2) were increased bilaterally in the DCN, VCN and the CNIC . These changes last over a week after stimulation for only NR1 and NR2c . These modifications might be related to long lasting synaptic plasticity of brainstem auditory pathways . As far as analogy to deaf children can be made, early electrical stimulation might be of interest to maintain neuronal networks.

Hear Res, 2000 Dec, 150(1-2), 1 - 11
Expression of NMDA, AMPA and GABA(A) receptor subunit mRNAs in the rat auditory brainstem . I . Influence of early auditory deprivation; Marianowski R et al.; Impact of early post-natal deafening on auditory pathways was investigated in newborn rats deafened by daily amikacin injections from P7 to P16 inducing a complete destruction of the organ of Corti . The expression of mRNAs encoding N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and gamma-aminobutyric acid type A (GABA(A)) receptor subunits was then studied by in situ hybridization in the dorsal and ventral cochlear nucleus and in the central nucleus of the inferior colliculus (CNIC) . Early post-natal deafening decreased bilaterally the expression of mRNAs encoding NR1, NR2a, NR2b and flop isoforms of AMPA receptors . On the contrary, it increased the expression of mRNAs encoding some GABA(A) subunits (alpha1, beta1, gamma2) and flip isoforms of AMPA receptors . These changes were more pronounced in cochlear nuclei than in CNIC . They suggest that auditory sensation is essential in the normal development of central auditory pathways.

Ann Pharmacother, 2000 Oct, 34(10), 1109 - 16
Adequacy of a new chlorhexidine-bearing polyurethane central venous catheter for administration of 82 selected parenteral drugs; Xu QA et al.; OBJECTIVE: To screen 82 commonly used parenteral medications for compatibility with a new chlorhexidine-bearing central venous catheter, the ARROWg+ard Blue Plus . Evaluations were performed for completeness of drug delivery and impact, if any, of the drugs on the amount of chlorhexidine removed from the internal lumens . DESIGN: Drug solutions were prepared in dextrose 5% injection or NaCl 0.9% at common concentrations . Three 10-mL aliquots of each drug solution were delivered over 10 minutes, one aliquot through each lumen of the triple-lumen catheter . The initial drug concentrations of the admixtures and the effluent samples were analyzed by HPLC for chlorhexidine content and for the amount of drug delivered relative to its initial concentration . RESULTS: The delivery of the infusion solutions alone through sample catheters resulted in no more than trace amounts of chlorhexidine in the solution . Background amounts ranged from < 2.5 to 6.1 micrograms/mL in the first 10 mL of solution . Administration of none of the drugs tested resulted in a substantial increase in chlorhexidine delivery . Furthermore, delivery of most of the drugs was at least 95% and usually was in excess of 97% of the initial concentration . Concentrations of five drugs, amikacin sulfate, cefoperazone sodium, cefotaxime sodium, cefepime HCl, and netilmicin sulfate were somewhat lower than the initial concentration (range 91-95%), but were still considered acceptable . CONCLUSIONS: The ARROWg+ard Blue Plus central venous catheter can be recommended for use with all of the 82 parenteral drugs tested.

Neuropharmacology, 2000 Oct, 39(13), 2525 - 32
Block of the alpha9 nicotinic receptor by ototoxic aminoglycosides; Rothlin CV et al.; In the present study, we report that the alpha9 nicotinic acetylcholine receptor (nAChR) expressed in Xenopus laevis oocytes is reversibly blocked by aminoglycoside antibiotics . The aminoglycosides tested blocked the alpha9 nAChR in a concentration-dependent manner with the following rank order of potency: neomycin>gentamicin>streptomycin>amikacin>kanamycin . The antagonistic effect of gentamicin was not overcome by increasing the concentration of acetylcholine (ACh), indicative of a non-competitive type of block . Blockage of ACh-evoked currents by gentamicin was found to be voltage-dependent, being more potent at hyperpolarized than at depolarized holding potentials . Furthermore, gentamicin blockage was dependent upon the extracellular Ca(2+) concentration, shown by the fact that increments in extracellular Ca(2+) significantly reduced the potency of this aminoglycoside to block the alpha9 nAChR . Possible mechanisms of blockage by the aminoglycosides are discussed . The present results suggest that the initial reversible actions of aminoglycosides at the organ of Corti, such as the elimination of the olivocochlear efferent function, are due in part to the interaction with the native alpha9-containing cholinergic receptor of the outer hair cells.

Clin Lab, 2000, 46(9-10), 509 - 15
Therapeutic drug monitoring on COBAS INTEGRA 400--evaluation results; Domke I et al.; The COBAS INTEGRA 400 (Roche Diagnostics GmbH) is a random access analyzer with a consolidated test menue for routine clinical chemistry, specific proteins, drugs of abuse screening and therapeutic drug monitoring (TDM) and different measuring technologies . It was the aim of the present study to evaluate the suitability of this instrument as dedicated analyzer for TDM . Eight assays based on three different technologies were included: Acetaminophen (enzymatic method), Amikacin/ Phenytoin/ Free Phenytoin/ Lidocaine (fluorescence polarization immunoassays; FPIA), Digitoxin/Digoxin (kinetic interaction of microparticles in solution; KIMS) . The study comprised the determination of imprecision according to NCCLS EP-T protocol, method comparison and linearity studies . The assays were compared with the corresponding methods on AxSYM or TDx analyzers (Abbott Laboratories) . For Acetaminophen and Amikacin COBAS INTEGRA 700 was used as additional comparison instrument . The results are summarized in a table (table 6) . Precision results are well acceptable with within-run CVs < 5% and total CVs < 6% except for Digitoxin and Digoxin which show a somewhat higher imprecision at low concentrations . Results obtained for Acetaminophen and Amikacin on COBAS INTEGRA 400 and 700 show excellent agreement . A good comparability is also found between COBAS INTEGRA 400 and AxSYM or TDx methods with slight systematic deviations for Acetaminophen, Amikacin and Free Phenytoin . The lower correlation coefficient for the digoxin method comparison can be attributed to two discrepant samples . Linearity throughout the range studied which covered > 80% of the measuring range was confirmed for the five assays tested (Digitoxin, Digoxin, Lidocaine, Free Phenytoin, Phenytoin) based on the acceptance criteria of +/- 10% deviation of the measured values from the theoretical values . Based on the analytical performance of the TDM tests studied it can be concluded that the COBAS INTEGRA 400 is very well suited for routine TDM analysis.

J Comp Neurol, 2000 Oct 9, 426(1), 117 - 29
Projections from the medial geniculate body to primary auditory cortex in neonatally deafened cats; Stanton SG et al.; In the present study, anatomical projections from the medial geniculate body (MGB) to primary auditory cortex (AI) were investigated in normal adult cats and in animals that were neonatally deafened with the ototoxic drug amikacin . Cochleotopic/tonotopic maps in AI (based on neural response characteristic frequency) were obtained with microelectrode recording techniques, and single or multiple injections of retrograde tracers (horseradish peroxidase and fluorescent dyes) were introduced into AI . The AI maps of the amikacin-treated cats had an abnormal cochleotopic organization, such that deprived cortical areas exhibited an expanded representation of intact regions of the damaged cochlea . However, retrograde tracer injections into different regions of AI produced a normal pattern of labeling in the ventral division of the medial geniculate body (MGBv) . In both experimental and control animals, the main mass of labeled thalamic cells was found in the MGBv . Different isofrequency contours in AI receive input from different portions of the MGBv . Thus, cell arrays labeled by anterior AI injections were situated medially in MGBv, and injections into posterior AI labeled MGBv more laterally . Furthermore, the deafened cats did not develop a more divergent thalamocortical projection compared with normal control animals, indicating that an abnormal spread of the thalamocortical afferents across the frequency domain in AI (anterior-posterior axis) is not responsible for the altered cochleotopic map in these neonatally deafened animals . The relatively normal thalamocortical projection pattern suggests that, after neonatal cochlear lesions, the major reorganization of cochleotopic maps occurs at subthalamic levels .

Ophthalmic Surg Lasers, 2000 Jan-Feb, 31(1), 64 - 5
Nocardia endophthalmitis following uncomplicated phacoemulsification and implantation of a posterior chamber intraocular lens; Cacchillo PF et al.; A patient developed endophthalmitis 15 days after uncomplicated cataract extraction . Excised infectious material sequestered in the capsular bag revealed Nocardia on culture . She required multiple intravitreal injections of Amikacin and dexamethasone, pars plana vitrectomies with explantation of the lens, and chronic topical and oral sulfonamide antibiotics to control the infection . Clinicians should also consider Nocardia when the suspicion of fungal endophthalmitis is entertained, as Nocardia are resistant to antifungals, but respond to intravitreal amikacin and chronic topical and oral sulfonamides.

J Clin Pharm Ther, 2000 Aug, 25(4), 303 - 7
Aminoglycoside usage and monitoring in a Saudi Arabian teaching hospital: a ten-year laboratory audit; Adjepon-Yamoah KK et al.; BACKGROUND AND OBJECTIVE: In 1989, a therapeutic drug monitoring service was established in Assir Central Hospital, Abha, Saudi Arabia, by the Department of Clinical Pharmacology and Therapeutics of the College of Medicine, King Saud University Abha Branch (now King Khalid University) . We report a 10-year follow-up of the results of monitoring the commonly used aminoglycosides (amikacin, gentamycin and tobramycin) obtained from our adult patients on first monitoring . METHOD: Two educational seminars for doctors and nurses were conducted 6 months before the initiation of this study . Drug assay requests were made on specially designed forms . Drug dosages were determined by the attending physicians . Samples for peak and trough drug level determinations were drawn after the fourth dose . The results of first time monitoring were sent to the wards with appropriate comments for dosage modifications where indicated . RESULTS: The results for 2022 patients were analysed . Of these, 929, 899 and 194 were for amikacin, gentamycin and tobramycin, respectively . Therapeutic trough concentrations were 71.2%, 28.3% and 28.3% of patients on amikacin, gentamycin and tobramycin, respectively . A total of 8.8%, 17.6% and 11.9% had trough concentrations considered toxic for amikacin, gentamycin and tobramycin, respectively . Peak therapeutic concentrations were achieved in 31.6%, 42.3% and 39.7% of patients on amikacin, gentamycin and tobramycin . A total of 53.3% of patients on amikacin, 50.3% on gentamycin and 57.2% on tobramycin had peak serum drug concentrations in the subtherapeutic range . Toxic concentrations were noticed mainly in patients aged over 60 years and in the critically ill in the intensive care, coronary care and bums units of the hospital . CONCLUSION: To be cost-effective, intensive therapeutic monitoring of aminoglycosides in adults should continue to be monitored mainly for the old and sick patients in critical care units to optimize patient management.

Therapie, 2000 Mar-Apr, 55(2), 277 - 82
{Can we use a Bayesian method to build a pharmacokinetic population in two steps?}; Cabelguenne D et al.; The aim of this study is to evaluate the use of a pharmacokinetic population model built by the two-stage method and individual parameters determined by a Bayesian estimation instead of nonlinear regression . We performed a retrospective analysis on 32 patient files (mean age: 82 years) . First, we analysed prediction of amikacin serum levels for the Bayesian method (MAP) and nonlinear regression (MLS) . Second, we compared pharmacokinetic parameter values for each patient with MAP and MLS methods for a one- or two-compartment model . For the one-compartment model, no difference in prediction performance was found (correlation coefficient: rMLS = 0.911, rMAP = 0.903, p > 0.05; precision: pMLS = 134.3, pMAP = 147, p > 0.05) . A significant difference was observed only for systematic error (eMLS = -4.47, eMAP = -3.34, p < 0.05) . For a two-compartment model, the Bayesian method was better for long-term prediction: 4-8 days (rMLS = 0.877, rMAP = 0.886, p > 0.05; eMLS = 5.26, eMAP = 0.04, p < 0.01; pMLS = 441.7, pMAP = 149, p < 0.05) . The comparison of MAP and MLS estimated pharmacokinetic parameter values for a one-compartment model showed that the Bayesian method used to built a pharmacokinetic population in two stages does not influence pharmacokinetic parameter estimation (p > 0.05 for Vd, Kslope, Kel and t1/2) . We conclude that we can use a Bayesian method to build a pharmacokinetic population in two steps in order to perform adaptative control of a drug-dosage regimen.

Ther Drug Monit, 2000 Aug, 22(4), 427 - 31
Time-dependent absorption of therapeutic drugs by the gel of the Greiner Vacuette blood collection tube; Dasgupta A et al.; Stability of therapeutic drugs in sera collected in Becton-Dickinson VACUTAINER serum separator SST tubes has been well studied . Recently, the Greiner Vacuette serum separator tube has become available for blood collection . However, stability of therapeutic drugs in sera when the specimen is collected in the Greiner tube has not been reported . The authors studied the stability of 15 commonly monitored drugs in sera when stored on the gel of the Greiner serum separator tubes . The drugs studied were amikacin, gentamycin, tobramycin, vancomycin, digoxin, quinidine, theophylline, carbamazepine, phenobarbital, phenytoin, valproic acid, tricyclic antidepressants, salicylate, acetaminophen, and ethanol . The authors compared the concentrations of drugs in sera stored in plain tubes (no gel) and in sera stored in the Greiner tubes containing serum separator gel . They observed a significant decline in the concentrations of tricyclic antidepressants when stored in the Greiner tubes . Interestingly, concentrations of amitriptyline declined more than its metabolite nortriptyline and concentration of imipramine also decreased more than its metabolite desipramine . The concentration of carbamazepine also decreased slightly over time when serum was stored in the Greiner tube . Although declines in carbamazepine concentrations on prolonged storage in the Greiner tubes were statistically significant, the decreases may not be clinically significant . The concentrations of the other drugs studied did not decline when stored in the Greiner tubes . The authors conclude that the Greiner brand tube is not suitable for blood collection for analysis of tricyclic antidepressants.

Audiology, 2000 May-Jun, 39(3), 153 - 60
Tonotopic mapping in auditory cortex of the adult chinchilla with amikacin-induced cochlear lesions; Kakigi A et al.; We have found a reorganization of tonotopic maps (based on neuron response thresholds) in primary auditory cortex of the adult chinchilla after amikacin-induced basal cochlear lesions . We find an over-representation of a frequency that corresponds to the border area of the cochlear lesion . The reorganization observed is similar in extent to that previously seen in a developmental model . The properties of neurons within the over-represented area were investigated in order to determine whether their responses originated from a common input (an indication of true plasticity) or represented only the result of truncating the activity of the sensory epithelium ("pseudo-plasticity") . Some aspects of our data fit with a true plasticity model and indicate the potential for the deafferented cortex of the mature cortex to regain connections with the surviving sensory epithelium.

J Neurocytol, 1999 Oct-Nov, 28(10-11), 925 - 37
Morphological and molecular changes in the inner hair cell region of the rat cochlea after amikacin treatment; Lenoir M et al.; This study investigates the morphological and molecular changes that occur in the inner hair cell area of the rat cochlea following aminoglycoside treatment . Rats were injected daily with 500 mg/kg of amikacin between postnatal day 9 (PND9) and PND16 . Cochleae were examined at PND16 to PND120 using both scanning and transmission electron microscopy and molecular fluorescent labeling . The inner hair cells showed obvious signs of apoptosis in response to amikacin treatment and most of them were missing by one week after the end of the aminoglycoside exposure period . Concomitantly, the epithelium became scarred as the surrounding supporting cells expanded and filled the space vacated by the missing IHCs . The mid-basolateral region of these modified supporting cells was surrounded by many afferent and efferent terminals . However, these cells expressed neither calbindin nor SNAP25, proteins that are both expressed by IHCs in the normal, untreated organ of Corti in the rat . In addition, these supporting cells remained attached to the basal lamina by a thin cytoplasmic process . The supporting cells surrounding the inner hair cells therefore appear unable to convert directly into inner hair cells following aminoglycoside induced hair-cell loss but may be able to provide trophic support for the remaining afferent and efferent neurites.

Antimicrob Agents Chemother, 2000 Aug, 44(8), 2028 - 33
Monotherapy with a broad-spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial . The Severe Generalized Peritonitis Study Group; Dupont H et al.; In a randomized trial conducted in 35 centers, we compared the clinical efficacy and safety of piperacillin plus tazobactam (TAZ) alone (monotherapy {MT}) versus those of TAZ combined with amikacin (AMK) (combined therapy {CT}) for the treatment of severe generalized peritonitis (SGP) . Primary analysis consisted of blind assessment by an independent committee of the failure rate 30 days after the end of treatment in the modified intent-to-treat (ITT) analysis (mITT) population . Of the 241 patients with suspected SGP randomized into the study, 227 were eligible for ITT analysis, including 204 (99 in the MT group and 105 in the CT group) with confirmed SGP (mITT population) . A total of 159 patients were eligible for per-protocol (PP) analysis . The clinical failure rates were equivalent in the mITT and PP populations (MT versus CT): 56 versus 52%, (odds ratio {OR} 0.87, 90% confidence interval {CI} = 0 . 6 to 1.27) for mITT and 49 versus 49% (OR = 1.03, 90% CI = 0.67 to 1 . 59) for PP analysis . Mortality rates (ITT population, 19%; PP population, 21%) and overall adverse event rates (ITT population, 55%; PP population, 54%) were also similar . Six patients (three in MT group and three in the CT group) developed acute renal failure . In conclusion, the addition of AMK to TAZ does not seem to be necessary for the treatment of SGP, even after adjustment for the simplified acute physiology score (SAPS II) and type of SGP.

Cancer, 2000 Jun 15, 88(12), 2848 - 52
Oral administration of cefixime to lower risk febrile neutropenic children with cancer; Paganini HR et al.; BACKGROUND: Febrile neutropenia is a heterogeneous condition . Recently, several risk factors have been defined, permitting the definition of a lower risk group of patients who may benefit form less aggressive therapy . The use of an oral antibiotic approach was tested in the current trial . METHODS: From May 1997 to March 1998, 154 episodes of lower risk febrile neutropenia in 128 children with a mean age of 62 (range, 8-200) months were enrolled in this randomized, single-institution trial . Inclusion criteria were fever (> 38 degrees C), neutropenia (absolute neutrophil count < 500/mm(3)), lower risk features (i.e., absence of severe comorbidity factors, good clinical condition, negative blood cultures, control of local infection, no fever during the last 24 hours), and compliance of parents . After 3 days of ceftriaxone (100 mg/kg/day administered intravenously {i.v.}) every 12 hours plus amikacin (15 mg/kg/day i.v.) every 24 hours for 3 days, all patients were discharged and randomized to be allocated to 2 treatment arms . Group A (n = 74) received ceftriaxone cefixime (8 mg/kg/day administered orally) every 24 hours for 4 days, whereas Group B (n = 80) was treated with ceftriaxone plus amikacin for 7 days . Failure was defined as the need for second hospitalization during the same episode of neutropenia, or fever during the 7 days after discharge . RESULTS: Most of the patients (49% in Group A and 55% in Group B) had acute leukemia . Fifty-four (72%) children in Group A and 46 (56%) in Group B had fever of unknown origin (P = not significant {NS}) . No significant differences were found in the sites of initial infection between the two groups . Overall results were outstanding, with a favorable outcome in 73 of 78 cases (98.6%) in Group A and 78 of 80 cases (97.5%) in Group B (P = NS) . Three patients needed a second hospitalization due to failure of the initial therapy: one in Group A and two in Group B . All three did well with secondary treatment . CONCLUSIONS: In lower risk febrile neutropenic children receiving anticancer therapy, the efficacy of oral cefixime, given for 4 days after 72 hours of intravenous ceftriaxone plus amikacin, was similar to that of 7 days of parenteral ceftriaxone plus amikacin . The oral outpatient therapy approach to the treatment of lower risk febrile neutropenia after chemotherapy is safe and may be cost-saving . This strategy might be adopted as standard therapy in the future .

Lupus, 2000, 9(4), 304 - 6
Nocardia infection of a joint prosthesis complicating systemic lupus erythematosus; Arnal C et al.; The authors report the case of a 43-year-old woman suffering from severe systemic lupus erythematosus treated with long-term prednisone, who developed Nocardia nova infection on a hip prosthesis . Sepsis occurred about two years after an episode of pulmonary nocardiosis with the same Nocardia species, that was successfully treated by 12 months of antibiotics . A good outcome of the joint infection was observed in response to antibiotics and removal of the prosthesis . Nocardiosis is a rare infection, acting as an opportunistic infection, facilitated in the present case by systemic lupus erythematosus and chronic corticosteroid therapy . Nocardia infections mainly affect the lungs, skin and central nervous system; these last two sites are mostly due to haematogenous spread, a frequent event . Treatment is based on antibiotics, usually continued for 3-12 months, especially because of the risk of relapse . The imipenem-amikacin combination appears to be more effective than trimethoprim sulfamethoxazole . To our knowledge, this is the first case report of Nocardia nova joint prosthesis infection also presenting as late septic spread of pulmonary nocardiosis, complicating corticosteroid-treated systemic lupus erythematosus.

Proc Natl Acad Sci U S A, 2000 Jun 20, 97(13), 7597 - 602
Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity; Duan M et al.; Recent progress has been made regarding the prevention of hearing loss . However, the complete protection of both hair cells and spiral ganglion neurons, with restored function, has not yet been achieved . It has been shown that spiral ganglion neuronal loss can be prevented by neurotrophin 3 (NT3) and hair cell damage by N-methyl-D-aspartate (NMDA) receptor antagonists . Here we demonstrate that the combined treatment with MK801, a NMDA antagonist, and NT3 protect both cochlear morphology and physiology from injury . Pretreatment with MK801 prevented hearing loss and the dendrites of the spiral ganglion neurons from swelling after noise-induced damage . The acute phase of insult with the aminoglycoside antibiotic amikacin resulted in swollen afferent dendrites beneath the inner hair cells . The chronic phase resulted in complete hair cell loss and near-complete loss of spiral ganglion neurons . This damage caused a near-complete loss of hearing sensitivity as displayed by elevated (>90-dB sound pressure levels) auditory brainstem response thresholds . The treatment of amikacin-exposed animals with MK801 gave only a partial protection of hearing . However, the combined treatment with NT3 and MK801 in the amikacin-comprised ear resulted in improved mean hearing within 20 dB of normal . Furthermore, hair cell loss was prevented in these animals and spiral ganglion neurons were completely protected . These results suggest that the NMDA antagonist MK801 protects against noise-induced excitotoxicity in the cochlea whereas the combined treatment of NT3 and MK801 has a potent effect on preserving both auditory physiology and morphology against aminoglycoside toxicity.

Ther Drug Monit, 2000 Jun, 22(3), 307 - 12
Diurnal changes in the pharmacokinetic behavior of amikacin; Bleyzac N et al.; This retrospective study evaluated possible differences in the pharmacokinetic behavior of amikacin between the morning (AM) and evening (PM) . Of 634 patients receiving amikacin therapy, 17 received a dose every 12 hours (an i.v . infusion at 8:00 AM and 8:00 PM) with amikacin serum levels obtained after both the AM and PM infusions . Pharmacokinetic parameter values were estimated by the nonparametric EM algorithm (USC*PACK clinical software) for a one-compartment model . All patient data were analyzed in three ways . The parameter values were estimated by fitting the model first only to the serum levels drawn following the AM dose; second, only to the data following the PM dose; and third, to all serum levels (AM + PM) . Parameter values found were (mean, median, SD respectively): AM: Kel = 0.181114 h(-1), 0.224460 h(-1), 0.058820 h(-1); Vol = 23.657507 L; 23.376231 L; 1.353253 L; Cl = 4.326720 L x h(-1), 5.303726 L x h(-1), 1.447731 L x h(-1); PM: Kel = 0.110151 h(-1); 0.121295 h(-1); 0.016860 h(-1); Vol = 28.948043 L; 24.091703 L; 9.266628 L; Cl = 3.081761 L x h(-1), 2.810615 L x h(-1); 0.705874 L x h(-1); AM + PM: Kel = 0.165321 h(-1); 0.131796 h(-1); 0.075425 h(-1); Vol = 25.479043 L; 26.187970 L; 5.367054 L . These findings are in agreement with the known diurnal rhythm of glomerular filtration rate . Because pharmacokinetic parameter values are most often estimated using AM data, this may lead to an overevaluation of these values compared with PM or to values for the entire day . The resulting drug regimens may therefore be overestimated regarding the elimination rate constant and underestimated regarding the volume of distribution.

Mol Gen Genet, 2000 Apr, 263(3), 404 - 10
Tools for chloroplast transformation in Chlamydomonas: expression vectors and a new dominant selectable marker; Bateman JM et al.; Reverse-genetic studies of chloroplast genes in the green alga Chlamydomonas reinhardtii have been hampered by the paucity of suitable selectable markers for chloroplast transformation . We have constructed a series of vectors for the targeted insertion and expression of foreign genes in the Chlamydomonas chloroplast genome . Using these vectors we have developed a novel selectable marker based on the bacterial gene aphA-6, which encodes an aminoglycoside phosphotransferase . The aphA-6 marker allows direct selection for transformants on medium containing either kanamycin or amikacin . The marker can be used to inactivate or modify specific chloroplast genes, and can be used as a reporter of gene expression . The availability of this marker now makes possible the serial transformation of the chloroplast genome of Chlamydomonas.

Gac Med Mex, 2000 Mar-Apr, 136(2), 99 - 105
{Granulocyte colony-stimulating factor in the treatment of febrile neutropenia}; Lopez-Hernandez MA et al.; PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF) used in addition to antibiotic therapy, in patients with chemotherapy-induced febrile neutropenia shortens the period of fever, neutropenia and hospitalization . PATIENTS AND METHODS: The study was prospective . Patients with lymphoblastic acute leukemia (LAL) were included . They received intensive chemotherapy of induction, intensification, or consolidation . At random, a group received amikacin-ceftriaxone; if no had response after 3 days, we added vancomicin and, after 7 days, amphotericin . The other group received in addition these antibiotics, granulocyte colony-stimulating factor . RESULTS: The groups were comparable in the magnitude of the initial neutropenia (< 0.5 x 10(9)/L), site of the infection, chemotherapy received germs isolated, age, and sex . The patients of the group that received FEC-G were cured in the course of 3.1 days; in the group without FEC-G, this occurred in 7.2 days (p = 0.0001) . At the end of the infectious episode, the number of neutrophils, in the group with FEC-G, was of 1.9 x 10(9)/L versus 0.7 x 10(9)/L (p = 0.0009) . The mortality was of one and two cases (p = 0.46) . The global mortality was 7.5% . CONCLUSIONS: The addition of FEC-G to the treatment with antibiotics, in febrile neutropenia, decreases duration of days with fever, hospitalization and neutropenia . However, the frequency of cure is not augmented.

Acta Med Okayama, 2000 Apr, 54(2), 49 - 56
Possible postsynaptic action of aminoglycosides in the frog rectus abdominis; Karatas Y et al.; The present study was undertaken to investigate the postsynaptic effects of aminoglycosides on contractions evoked by acetylcholine (ACh), KCl, electrical field stimulation (EFS) and Na(+)- and Ca(2+)-free Ringer solution with 0.2 mM Na2 EDTA (NaFCaFR) in the isolated frog rectus abdominis . Neomycin inhibited contraction elicited by ACh, NaFCaFR, and EFS at the higher frequencies (8 and 10 Hz) but not those elicited by KCl and EFS at the lower frequencies (2, 3 and 5 Hz) . D-tubocurarine inhibited ACh-induced contractions in a concentration-dependent manner . In addition, drug reduced EFS-evoked contractions to a limited extent . Lower concentrations (10(-5), 5 x 10(-5), 10(-4), 2 x 10(-4) and 3 x 10(-4) M) but not higher concentrations (4 x 10(-4) and 5 x 10(-4) M) of methoxyverapamil exhibited a concentration-dependent inhibitory action on NaFCaFR-induced contractions . Similar inhibitions of the same type of contraction were displayed by aminoglycosides (neomycin, streptomycin, netilmycin, gentamycin and amikacin) . These results suggest that in addition to their antagonistic action on nicotinic receptors in the frog rectus abdominis, aminoglycosides may exert stabilizing effects on some functional components contributing to contractions at the membrane.

Jpn J Antibiot, 2000 Feb, 53(2), 61 - 74
{Efficacy and safety of cefozopran (CZOP) monotherapy and combination therapy with CZOP and amikacin (AMK) for infections accompanying hematological diseases}; Urabe A et al.; We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for infections in patients with hematological diseases . Efficacy was evaluated in 71 patients of monotherapy group and 70 patients of combination therapy group . Underlying diseases were mostly leukemia and lymphoma . Infections included sepsis, suspected sepsis, pneumonia and so on . Efficacy in CZOP monotherapy was excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients (7.5%) and the efficacy rate was 65.7% . On the other hand, in combination therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%) and the efficacy rate was 56.1% . Side effects such as eruption were noted in 2 patients . Abnormal laboratory findings were noted in 9 patients . All side effects as well as abnormal laboratory findings were minimal . It was concluded that CZOP monotherapy was effective in the treatment of various infections accompanying hematological diseases.

Haemophilia, 2000 Mar, 6(2), 116 - 7
HAART and Mycobacterium avium complex in an HIV infected patient with severe factor VII deficiency; Girmenia C et al.; A clinical syndrome represented by the association of Mycobacterium avium complex (MAC) infection with initiation of highly active antiretroviral therapy (HAART) has been recently described in patients with advanced HIV disease . HAART-associated improvement of the immune status might convert a clinically silent MAC infection into an active mycobacterial disease . A 40-year-old man with severe factor VII deficiency, advanced HIV-1 disease, a CD4 + lymphocyte count of 15 cells microL-1 (CDC stage A3) and 470,000 HIV-RNA copies mL-1 (measurement by NASBA system) underwent standard HAART (lamivudine, stavudine and ritonavir) . Two weeks after HAART onset, the patient developed enlargement of the lymph nodes throughout the mesentery and after seven weeks a rapidly enlarging mass on the left side of the neck . Culture from a needle aspirate specimen revealed MAC . His CD4 + count had increased to 97 cells microL-1 and viraemia dropped to undetectable HIV-RNA copies . While continuing antiviral therapy, multidrug therapy for MAC infection (clarithromycin, ciprofloxacin, ethambutol, amikacin) was started with progressive improvement and cure of the neck mycobacterial infection and disappearance of the abdominal lymph nodes . HAART has been shown to offer significant clinical and laboratory benefits in terms of HIV disease with limited side-effects in Haemophiliacs . However, the clinical manifestation of an opportunistic infection should be mentioned as a possible complication of HAART in these patients, as well as in other categories of HIV infected patients, and in patients with congenital coagulopathies.

J Assoc Physicians India, 1999 Oct, 47(10), 1022 - 3
Mycobacterium fortuitum endocarditis and meningitis after balloon mitral valvotomy; Kuruvila MT et al.; Mycobacteria rarely cause endocardial infections . We describe the clinical course of a patient who developed endocarditis, and meningitis with Mycobacterium fortuitum following balloon mitral valvotomy . The patient was treated with amikacin and clarithromycin but did not respond . She developed haemolytic anaemia as the terminal event.

J Refract Surg, 2000 Mar-Apr, 16(2), 191 - 5
Mycobacterium keratitis after laser in situ keratomileusis; Gelender H et al.; PURPOSE: The authors report two cases of Mycobacterium keratitis following LASIK . METHODS: The case reports are based on a retrospective review of clinical history and associated findings . RESULTS: Two patients developed infectious keratitis after undergoing laser in situ keratomileusis (LASIK) . In case #1, the infection developed after manipulation of the lamellar flap to remove epithelium from the stromal bed . In case #2, prior radial keratotomy may have been a contributing factor to development of the infection . Corneal infiltrates appeared as focal, white, stromal deposits . Cultures isolated Mycobacterium fortuitum from case #1 and Mycobacterium chelonae from case #2 . Topical fortified amikacin, clarithromycin, tobramycin, and ciprofloxacin eventually controlled the infection . Topical prednisolone acetate and bandage contact lenses were necessary to control inflammation and pain . Infiltrates were slow to resolve until focal necrosis eroded through the flaps leading to rapid clearing of the infiltrates; however, scarring of the cornea developed at the site of necrosis . Visual recovery was good in the first case but limited in the second . CONCLUSIONS: Mycobacterium keratitis complicating LASIK may be difficult to eradicate until the sequestered stromal infiltrate drains . Rapid recognition of the causative organism and aggressive medical and surgical management of the infection may improve the outcome.

Ann Acad Med Singapore, 2000 Jan, 29(1), 119 - 26
Case reports of nocardiosis in patients with human immunodeficiency virus (HIV) infection; Lee CC et al.; INTRODUCTION: We present 4 local cases of nocardiosis in HIV-infected patients and discuss the diagnosis, clinical syndromes and therapy of nocardiosis . CLINICAL PICTURE: Two cases presented with pulmonary nocardiosis, one had a cervical lymph node abscess and one had disseminated nocardiosis with pulmonary, cerebral and soft tissue involvement . TREATMENT: Combination therapy is often employed . Sulphonamides or co-trimoxazole, amikacin, imipenen, minocycline and ceftriaxone are some of the drugs that could be used . OUTCOME: Outcome hinges on the early recognition and optimal treatment of this infection . CONCLUSIONS: Clinical presentations vary and diagnosis is difficult and frequently delayed . Nocardiosis should be suspected in patients who present with pulmonary lesions with soft tissue and/or cerebral abscesses.

Am J Ophthalmol, 2000 Mar, 129(3), 382 - 4
Mycobacterium chelonae keratitis after laser in situ keratomileusis successfully treated with medical therapy and flap removal; Chung MS et al.; PURPOSE: To report a case of Mycobacterium chelonae keratitis after laser in situ keratomileusis successfully treated with medical therapy and flap removal . METHODS: Case report . A 36-year-old white woman in good health developed a paracentral keratitis in her right eye 1 month after bilateral laser in situ keratomileusis . Initial treatment included topical steroids and then intensive Ocuflox (ofloxacin ophthalmic solution; Allergan, Inc, Irvine, California) without success . Cultures were negative . The keratitis worsened, and she was referred to our institution . Interface infiltration was noted, and the flap was lifted to obtain adequate laboratory studies . Cultures were positive for M chelonae . RESULTS: The keratitis was treated with intensive topical amikacin sulfate 1%, topical clarithromycin 1%, and Ciloxan (ciprofloxacin HCL; Alcon Laboratories, Inc, Fort Worth, Texas) with minimal improvement in her clinical condition . She developed a toxic reaction to amikacin 1% . In order to improve antibiotic penetration, the hazy, ulcerated corneal flap was removed . The keratitis then resolved with intensive topical clarithromycin 1% and Ocuflox over 5 weeks . The patient now has visual acuity without correction of 20/50, despite superficial corneal haze . CONCLUSION: M chelonae is a rare and insidious cause of infection after laser in situ keratomileusis . Diagnosis can be difficult and is often delayed . Aggressive medical management, with flap removal, if needed, may lead to resolution of infection.

J Bacteriol, 2000 Mar, 182(6), 1754 - 6
AcrD of Escherichia coli is an aminoglycoside efflux pump; Rosenberg EY et al.; AcrD, a transporter belonging to the resistance-nodulation-division family, was shown to participate in the efflux of aminoglycosides . Deletion of the acrD gene decreased the MICs of amikacin, gentamicin, neomycin, kanamycin, and tobramycin by a factor of two to eight, and DeltaacrD cells accumulated higher levels of {(3)H}dihydrostreptomycin and {(3)H}gentamicin than did the parent strain.

Antimicrob Agents Chemother, 2000 Mar, 44(3), 665 - 75
Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides; El Mouedden M et al.; Kidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg . Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response ((3)H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with {(3)H}thymidine), and kidney dysfunction (blood urea nitrogen and creatinine) . Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells) . Comparative studies revealed a parallelism among the extents of phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin >> amikacin congruent with isepamicin) . By contrast, netilmicin induced a marked phospholipidosis but a moderate apoptosis and proliferative response . We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses . Netilmicin, and still more amikacin and isepamicin, appears safer in this respect . Whereas a relation between aminoglycoside-induced tubular apoptosis and cortical proliferative response seems to be established, no simple correlation with phospholipidosis can be drawn.

Pharmacol Res, 2000 Mar, 41(3), 355 - 60
Antinociceptive effect of amikacin and its interaction with morphine and naloxone; Atamer-Simsek S et al.; Amikacin sulphate (30 mg kg(-1)) administered either intraperitoneally (i.p.) or subcutaneously (s.c.) produced antinociceptive effect in BALB/c mice in the acetic acid writhing test which is employed as an inflammatory pain model . The lack of difference between two routes with regard to antinociceptive potency was taken as evidence for the absence of a local effect . Amikacin sulphate-induced antinociception seems unlikely to be due to non-specific behaviour alteration, since this drug, at a dose range of 15-100 mg kg(-1)did not affect motor coordination of mice in rot-a-rod test . Morphine (1 mg kg(-1)) also caused antinociception when administered i.p . or s.c . but the effect was greater with the latter route . At the i.p . site; the concurrent use of amikacin and morphine produced more remarkable antinociception compared to their individual usages . Besides, naloxone (2 mg kg(-1)) significantly decreased antinociceptive effect of amikacin but itself also exerted antinociception . At present, we have no plausible explanation for these findings at the i.p . site .

Aust N Z J Ophthalmol, 1999 Dec, 27(6), 435 - 6
Preretinal haemorrhages: an unusual manifestation of intravitreal amikacin toxicity; Kumar A et al.; PURPOSE: To report a case with multiple preretinal haemorrhages after intravitreal amikacin . METHOD: A 58-year-old patient developed postoperative endophthalmitis following a routine extracapsular cataract extraction in his left eye . He received two intravitreal injections of cephazoline (2.25 mg) and amikacin (0.4 mg), given 48 h apart . RESULTS: The patient presented to us with large preretinal haemorrhages at the posterior pole . Multiple large areas of blocked fluorescence were seen on fundus fluorescein angiography . CONCLUSION: Widespread posterior pole preretinal haemorrhages may be an unusual manifestation of intravitreal amikacin toxicity.

Gac Med Mex, 1999 Sep-Oct, 135(5), 517 - 21
{Combined cefotaxime and amikacin for immunomodulation in the treatment of actinomycetoma resistant to conventional treatment}; Mendez-Tovar LJ et al.; Actinomycetoma is a chronic disease that affects subcutaneous tissue . We present a case of a patient with abdominal actinomycetoma caused by Nocardia brasiliensis resistant to different treatments over several years, who also presented phagocyte immunodeficiency . He received two cycles (23 day cycles) of cefotaxime, 1 g every 8-h, and amikacin, 500 mg every 12 hours . Immunomodulation was carried out with levamisole 300 mg per week, during 4 weeks and bacterial antigen (at a concentration of 600,000,000 bacteria per mL), twice for a week during 20 months . The importance of susceptibility testing and immunological function investigation in this type of patients is discussed.

J Clin Pharmacol, 1999 Dec, 39(12), 1256 - 62
Pharmacokinetic changes of theophylline and amikacin through the menstrual cycle in healthy women; Matsuki S et al.; The objective of this open-label, single-dose study was to clarify the influence of the menstrual cycle on the pharmacokinetics of theophylline (n = 10) and amikacin (n = 8) in young healthy Japanese women with regular menstrual cycles . Each subject received an intravenous infusion of theophylline or amikacin sulfate at four different phases--mid-follicular (phase I), peri-ovulatory (phase II), mid-luteal (phase III), and premenstrual days (phase IV) . In the theophylline study, there were no significant differences in the pharmacokinetic parameters among the four phases studied . In the amikacin study, CLtot was 15% higher in phase III than in phase I (p < 0.01) . Vd beta was 35% higher in phase III than in phase I (p < 0.05) . The other pharmacokinetic parameters of amikacin were not significantly altered during the menstrual cycle . Evidence suggests that the phase of the menstrual cycle may be a factor in determining the pharmacokinetics of amikacin.

Int J Syst Bacteriol, 1999 Oct, 49 Pt 4, 1493 - 511
Mycobacterium wolinskyi sp . nov . and Mycobacterium goodii sp . nov., two new rapidly growing species related to Mycobacterium smegmatis and associated with human wound infections: a cooperative study from the International Working Group on Mycobacterial Taxonomy; Brown BA et al.; Previous investigations demonstrated three taxonomic groups among 22 clinical isolates of Mycobacterium smegmatis . These studies were expanded to 71 clinical isolates, of which 35 (49%) (group 1) were identical to five ATCC reference strains including the type strain ATCC 19420T . Twenty-eight isolates (39%) were group 2, and eight isolates (11%) were group 3 . Isolates of groups 2 and 3 were most often associated with post-traumatic or post-surgical wound infections including osteomyelitis, were susceptible to sulfamethoxazole, amikacin, imipenem and the tetracyclines, variably resistant to clarithromycin, and susceptible (group 1), intermediately resistant (group 2) or resistant (group 3) to tobramycin . The three groups were similar by routine biochemical and growth characteristics, but had different mycolic acid dimethoxy-4-coumarinylmethyl ester elution patterns by HPLC and different PCR-restriction enzyme patterns of a 439 bp fragment of the hsp-65 gene . Group 3 isolates differed from group 1 by 18 bp by 16S rRNA sequencing and exhibited < 25% homology by DNA-DNA hybridization, being most closely related to Mycobacterium mageritense . The 16S rRNA of group 1 and group 2 isolates differed by only 3 bp, but by DNA-DNA hybridization they exhibited only 40% homology . The following names are proposed: Mycobacterium goodii sp . nov . for group 2 isolates (type strain ATCC 700504T = MO69T), Mycobacterium wolinskyi sp . nov . for group 3 isolates (type strain ATCC 700010T = MO739T) and Mycobacterium smegmatis sensu stricto for group 1 isolates.

Antimicrob Agents Chemother, 1999 Oct, 43(10), 2366 - 71
Characterization of the chromosomal aac(6')-Iz gene of Stenotrophomonas maltophilia; Lambert T et al.; The aac(6')-Iz gene of Stenotrophomonas maltophilia BM2690 encoding an aminoglycoside 6'-N-acetyltransferase was characterized . The gene was identified as a coding sequence of 462 bp corresponding to a protein with a calculated mass of 16,506 Da, a value in good agreement with that of ca . 16,000 found by in vitro coupled transcription-translation . Analysis of the deduced amino acid sequence indicated that the protein was a member of the major subfamily of aminoglycoside 6'-N-acetyltransferases . The enzyme conferred resistance to amikacin but not to gentamicin, indicating that it was an AAC(6') of type I . The open reading frame upstream from the aac(6')-Iz gene was homologous to the fprA gene of Myxococcus xanthus (61% identity), which encodes a putative pyridoxine (pyridoxamine) 5'-phosphate oxidase . Pulsed-field gel electrophoresis of total DNA from BM2690 and S . maltophilia ATTC 13637 digested with XbaI, DraI, and SpeI followed by hybridization with rRNA and aac(6')-Iz-specific probes indicated that the gene was located in the chromosome . The aac(6')-Iz gene was detected by DNA-DNA hybridization in all 80 strains of S . maltophilia tested . The MICs of gentamicin against these strains of S . maltophilia were lower than those of amikacin, netilmicin, and tobramycin, indicating that production of AAC(6')-Iz contributes to aminoglycoside resistance in S . maltophilia.

J Antimicrob Chemother, 1999 Aug, 44(2), 235 - 42
Population pharmacokinetics of amikacin in patients with haematological malignancies; Romano S et al.; The aim of this study was to analyse the pharmacokinetic behaviour of amikacin in patients with haematological malignancies using a mixed-effect model and sparse data collected during routine clinical care . The patient population comprised 207 haematology patients divided into two groups: one for computing the population model (n = 134) and the other for validation (n = 73) . A one-compartment model was used and the following covariates were tested for their influence on clearance and volume of distribution: age, gender, weight, parenteral nutrition, creatinine clearance, stage of antineoplastic treatment (induction, consolidation, intensification), number of weeks postchemotherapy, clinical diagnosis, Eastern Cooperative Oncology Group score, neutropenia, hypoalbuminaemia, concomitant medication (vancomycin and/or amphotericin B), overhydration, and autologous or allogenic bone marrow transplant . The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in these patients . Apart from bodyweight and renal function, acute myeloblastic leukaemia and hypoalbuminaemia proved to be the most important covariates explaining the interindividual variability in amikacin pharmacokinetics in patients with haematological malignancies . The predictive performance of this population model for amikacin serum concentrations seems suitable for clinical purposes.

J Antimicrob Chemother, 1999 Jul, 44(1), 129 - 31
Efficacy and safety of an intravenous induction therapy for treatment of disseminated Mycobacterium avium complex infection in AIDS patients: a pilot study; Roger PM et al.; Monotherapy with macrolides for the treatment of disseminated Mycobacterium avium complex (MAC) bacteraemia leads to drug resistance and relapse of bacteraemia . Gastrointestinal intolerance is a common reason for treatment withdrawal of multidrug regimens . We have assessed the efficacy and safety of initial parenteral therapy together with a macrolide, for disseminated MAC infection, defined as two positive blood cultures, in AIDS patients . Patients received a daily infusion of amikacin 15 mg/kg + ethambutol 20 mg/kg + ciprofloxacin 400 mg/day, for 1 month, together with a macrolide by oral route . Fifteen patients were included and 13 (86%) achieved negative culture before the end of parenteral therapy.

Bone Marrow Transplant, 1999 Jul, 24(1), 57 - 61
Toxicity of single daily dose gentamicin in stem cell transplantation; Warkentin D et al.; To determine the safety of single daily dose (SDD) gentamicin in recipients of stem cell transplantation (SCT), we evaluated all adult patients at MD Anderson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia . Thirty-three patients received gentamicin 5 mg/kg i.v . every 24 h . Mean duration of therapy was 7 days (range 3-32 days) . All patients received vancomycin and 17 received cisplatinum . All patients had normal renal function prior to therapy . Serum gentamicin levels were monitored only when renal function deteriorated . The incidence of nephrotoxicity and clinically significant ototoxicity was 3% and 12%, respectively . All four patients who developed ototoxicity had normal renal function before and during therapy . The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity, 20 days vs 9 days (P = 0.001) . Patients treated with SDD gentamicin for >10 days were more likely to develop ototoxicity (P = 0.045) . Single daily dosing of gentamicin was associated with clinically significant ototoxicity in 12% of our patients . A larger randomized EORTC trial evaluating SDD vs MDD amikacin failed to detect a difference in ototoxicity . However, the median duration of therapy was only 8 days . The increased incidence of ototoxicity in our study may be due to prolonged therapy, type of aminoglycoside used, concomitant ototoxic agents, small sample size, or a combination of the above.

J Microencapsul, 1999 Jul-Aug, 16(4), 511 - 6
A novel method to prepare liposomes containing amikacin; Zhang JH et al.; This work describes a novel method to prepare liposomal amikacin composed of soyabean lecithin and cholesterol; these were also prepared using two other methods (cast film method and proliposome method) . Encapsulation efficiency was evaluated . Liposomes prepared by the new method, which combines the method of preparing proliposomes with freeze-drying, had the highest encapsulation efficiency . The influence of drug to lipid ratio on the encapsulation efficiency was investigated . The in vitro efflux of amikacin from liposomes with different lecithin: cholesterol ratios was also investigated.

J Paediatr Child Health, 1999 Jun, 35(3), 283 - 6
Once versus twice daily amikacin in neonates: prospective study on toxicity; Kotze A et al.; OBJECTIVE: To compare the potentially toxic effects in fullterm neonates of amikacin administered once daily, versus amikacin administered twice daily . METHODOLOGY: A controlled, randomized, prospective study in which one group of fullterm neonatal patients received amikacin 15 mg/kg per dose once daily (n = 20), and the other received amikacin 7.5 mg/kg per dose twice daily (n = 20) . Impairment of renal glomerular function was defined as a decline of less than 50% of the expected physiological drop in serum creatinine over time . Brainstem auditory evoked potentials were also evaluated and amikacin blood levels taken . RESULTS: Fifteen patients in the once-daily group and 12 patients in the twice-daily group demonstrated at least one period of renal function impairment while in hospital . This decreased to five of 16 and four of 16 patients during follow-up . These differences were not statistically significant . Brainstem auditory evoked potentials did not find signs of ototoxicity at any time . CONCLUSION: In fullterm neonatal patients, once daily dosing of amikacin is no more toxic than the twice daily regimen.

J Antimicrob Chemother, 1999 May, 43(5), 719 - 21
Difficulties in the assay of liposomal amikacin (MiKasome) in serum; Lovering AM et al.; Antibiotic-free human serum was spiked with known concentrations of liposomal amikacin and assayed on the Abbott TDx System, using polarization fluoroimmuno assay (PFIA) kits from Abbott Laboratories, Oxis and Sigma . Although all three kits gave a linear response, the Abbott and Oxis kits showed very low recovery (<21%) with only the Sigma kit giving near 100% recovery . Heating samples at 56 degrees C for 30 min improved recovery with the Abbott and Oxis kits (75-80% of target value), but decreased recovery with the Sigma kit (85% of target value) . The loss of amikacin from liposomal amikacin, as measured using the Sigma kit, was related to both temperature and duration of heating, reaching a maximal loss of 21% after 1 h at 60 degrees C.

Zhonghua Jie He He Hu Xi Za Zhi, 1997 Dec, 20(6), 354 - 7
{Bronchofiberscope and catheter intervention in treatment of multi-drug resistant pulmonary tuberculosis}; Zhang Y et al.; OBJECTIVE: To evaluate the clinical value of bronchofiberscope and catheter intervention in treatment of multi-drug resistant pulmonary tuberculosis . METHOD: Forty-eight patients with multi-drug resistant pulmonary tuberculosis were treated by injecting ofloxacin and amikacin through bronchofiberscope and catheter in addition to chemotherapy, while forty controls were treated by chemotherapy only . RESULT: At the end of the treatment, the sputum conversion rate was 92%, radiographic improvement rate 96% and cavity closing rate 27% in the treatment group, all of which were higher than the controls (63%, 58% and 10% respectively) (P < 0.01-0.05) . No complication and obvious adverse reaction were observed . CONCLUSION: The efficacy of bronchofiberscope and catheter intervention in addition to chemotherapy is better than only chemotherapy in treatment of multi-drug resistant pulmonary tuberculosis.

J Pharm Pharmacol, 1999 Mar, 51(3), 279 - 84
The presence of an Na+/spermine antiporter in the rat renal brush-border membrane; Kobayashi M et al.; This study was aimed at determining the driving force for spermine transport in rat renal proximal tubular brush-border membrane . The uptake of spermine and trientine, a spermine-like drug used for treating Wilson's disease, into rat renal brush-border membrane vesicles was significantly stimulated by an outwardly directed Na+ gradient . The Na+-dependent uptake was temperature dependent and saturable . A kinetic analysis of the initial uptake of spermine with an Na+ gradient gave a Km value of 1.44 microM and a Vmax value of 6.31 pmol (mg protein)(-1)/30s . The Na+ dependent uptake of {3H}spermine was inhibited by spermine, trientine and tetraethylene-pentamine . Substrates of the H+/organic cation transporter (cimetidine and tetraethyl-ammonium), physiological polyamines (putrescine and spermidine) with 2 or 3 amino groups and aminoglycosides (amikacin and tobramicin) with 4 or 5 cationic amines did not affect the uptake of spermine in the presence of an outwardly directed Na+ gradient . These results suggest that the renal tubular secretion of spermine is mediated by an Na+/spermine antiport system which is specific for a straight-chain polyamine compound with more than 4 amino groups.

Aten Primaria, 1999 Mar 15, 23(4), 222 - 6
{The use of antitubercular drugs in primary care}; Blazquez Perez A et al.; OBJECTIVES: To quantify the consumption of tuberculosis medication prescribed through the National Health Service in Spain during 1996 . To calculate the prevalence of tuberculosis from this consumption . To analyse possible inequalities between autonomous communities . To analyse the cost of these drugs . DESIGN: A crossover, retrospective and observational study . SETTING: Primary care . MEASUREMENTS AND RESULTS: 5533233 DDDs were taken in 1996 . 2215890 of these DDDs belonged to the rifinah association (rifampicin + isoniazid), followed by the active principle rifampicin with 973510 DDDs . Amikacin at 8,078 DDDs represented the lowest dose . DID (dose per inhabitant per day) in Spain was 0.37 . Dosage was greater in Galicia (0.66) and Ceuta (0.52) . The Canaries (0.19) and Balearics (0.27) were below the national average . Use was 40.05% for rifinah, followed by 17.59% for rifampicin . The least common active principles were amikacin (0.14%) and streptomycin (0.74%) . The number of cases of tubercular disease in Spain calculated was 11,211; its prevalence was 27.7 cases per 100,000 inhabitants . Total medication cost was 863275147 pesetas (0.1% of total pharmaceutical expenditure) . The attributable cost was rifinah, 40.26%, the rifater association, 21.68%, and rifampicin, 18.34% . CONCLUSIONS: The most often prescribed drug is the rifampicin + ilsoniazid association . Use varies between autonomous communities . We think that the prevalence calculated is high for a developed country.

J Clin Microbiol, 1999 Jun, 37(6), 1676 - 82
Multisite reproducibility of results obtained by the broth microdilution method for susceptibility testing of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum; Woods GL et al.; A multicenter study was conducted to assess the interlaboratory reproducibility of broth microdilution testing of the more common rapidly growing pathogenic mycobacteria . Ten isolates (four Mycobacterium fortuitum group, three Mycobacterium abscessus, and three Mycobacterium chelonae isolates) were tested against amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, sulfamethoxazole, and tobramycin (M . chelonae only) in four laboratories . At each site, isolates were tested three times on each of three separate days (nine testing events per isolate) with a common lot of microdilution trays . Agreement among MICs (i.e., mode +/- 1 twofold dilution) varied considerably for the different drug-isolate combinations and overall was best for cefoxitin (91.7 and 97.2% for one isolate each and 100% for all others), followed by doxycycline, amikacin, and ciprofloxacin . Agreement based on the interpretive category, using currently suggested breakpoints, also varied and overall was best for doxycycline (97.2% for one isolate and 100% for the rest), followed by ciprofloxacin and clarithromycin . Reproducibility among MICs and agreement by interpretive category was most variable for imipenem . Based on results reported from the individual sites, it appears that inexperience contributed significantly to the wide range of MICs of several drugs, especially clarithromycin, ciprofloxacin, and sulfamethoxazole . New interpretive guidelines are presented for the testing of M . fortuitum against clarithromycin; M . abscessus and M . chelonae against the aminoglycosides; and all three species against cefoxitin, doxycycline, and imipenem.

Acta Clin Belg Suppl, 1999, 1, 17 - 9
{"CAPCIL" . Posologic adjustment of aminoglycoside treatments}; Gougnard T et al.; The objectives of the therapeutic drug monitoring are to assume the efficacy and inocuity of a medical treatment and the patient's observance . The administration of a drug to a patient is not always performed in the same conditions and therefore treatment has to be adapted . When necessary, this one is very often based on empiric or very approximative notions and, more seldom, on results of plasmatic concentrations of the drug . The CAPCIL program allows the possibility to objectivate the medical decision and adapt the posology on the basis of two kinetic parameters: the biological half-life and the distribution volume . Indeed, most of pharmacokinetics modifications (drug interactions, diseases, ...) are affecting the two parameters . With basic informations so as height and weight, posology, treatment objectives and peak/trough plasmatic concentrations of the drug, the program is proposing several posology adaptation schemes . The example of a once-a-day administration of amikacin is discussed.

Haematologica, 1999 Mar, 84(3), 231 - 6
Randomized prospective study comparing cost-effectiveness of teicoplanin and vancomycin as second-line empiric therapy for infection in neutropenic patients; Vazquez L et al.; BACKGROUND AND OBJECTIVE: The current health-care philosophy dictates that new therapies should always be evaluated for their economic impact . Along with acquisition cost, the cost of delivery, monitoring, adverse effects and treatment failure must also be considered when determining the total cost of therapy . These auxiliary costs can be significant and greatly alter the overall cost of a drug treatment . We conducted a prospective randomized study to evaluate the efficacy, safety and cost of vancomycin and teicoplanin therapy in patients with neutropenia, after the failure of empirical treatment with a combination of piperacillin/tazobactam and amikacin . DESIGN AND METHODS: Seventy-six febrile episodes from 66 patients with hematologic malignancies under treatment, neutropenia (neutrophils <500/mm3) and fever (38 degrees C twice or 38.5 degrees C once) resistant to the combination piperacillin/tazobactam and amikacin were included in the study . RESULTS: Primary success of second-line therapy was obtained in 35 cases (46%) with no significant difference between vancomycin (17/38) and teicoplanin arms (18/38) . No difference in renal or hepatic toxicity related to the antibiotic therapy was observed . The average cost per patient according to glycopeptide used was $450+/-180 for the teicoplanin group and $473+/-347 for the vancomycin group . Interestingly, in the teicoplanin arm, drug acquisition accounted for 97% of the total cost, while in the vancomycin arm administration and monitoring play an important role in overall costs . INTERPRETATION AND CONCLUSIONS: In conclusion, our pharmacoeconomic analysis demonstrates that teicoplanin and vancomycin can be administered in neutropenic hematologic patients with similar efficacy and direct costs.

Hosp Formul, 1995 Feb, 30(2), 114 - 6
How a CQI program improved aminoglycoside use in a community hospital; Wade WE et al.; The P & T Committee of our institution, a 285-bed, non-tertiary care regional medical center, undertook a study to evaluate the use of the aminoglycoside amikacin sulfate (Amikin) . Results of an initial DUE, a follow-up to an educational effort, and the estimated annual cost savings that could be achieved with appropriate prescribing of aminoglycosides are presented.

Spectrochim Acta A Mol Biomol Spectrosc, 1999 Jan, 55A(1), 205 - 10
Delineation of conformational and structural features of the amikacin-Cu(II) complex in water solution by 13C-NMR spectroscopy; Gaggelli E et al.; The copper (II) complex of amikacin in water solution at pH 5.5 was investigated by 13C-NMR . The temperature dependence of spin-lattice relaxation rates was measured and fast exchange conditions were shown to apply . The motional correlation time of the complex was approximated by the pseudo-isotropic rotational correlation time of free amikacin in water solution (tau c = 0.17 ns at 300 K) . Formation of a pseudo-tetrahedral 1:1 complex was demonstrated by relaxation rates analysis and also by UV-Vis spectrophotometry . Two amino nitrogens of amikacin, together with the amide nitrogen and the hydroxyl in the hydroxyl-aminopropyl carbonyl side chain, were assigned as the copper-binding sites and a model of the complex was built by using copper-carbon distances obtained by NMR analysis as input parameters.

Brain Res, 1999 Mar 20, 822(1-2), 43 - 51
Sequential changes in anti-GAL-1 staining of the rat organ of Corti following amikacin exposure; Bartolome MV et al.; Hair cell loss and a non-functional epithelial reorganization appeared in the organ of Corti after acoustic or toxic damage . Moreover, in the drug damaged organ of Corti, transient atypical cells were recently described with characteristics of both immature hair cells and/or non-sensory epithelial cells . The phenotype of these atypical cells has been now investigated by using the galectine 1 (GAL-1) antibody . In the normal organ of Corti, this antibody recognizes all the epithelial cells except the sensory hair cells and their supporting cells . At PD 21, transient atypical cells were not stained by GAL-1 antibody, suggesting that they were originated from hair cells or their supporting cells . Later, the organ of Corti was substituted by an epithelial scare, GAL-1 stained . This study also emphasizes the particular resistance of the cochlear apex to degeneration after antibiotic intoxication .

Hear Res, 1999 Feb, 128(1-2), 40 - 4
Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid; Conlon BJ et al.; Free radical generation is increasingly implicated in a variety of pathological processes, including drug toxicity . Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of radical species both in vivo and in vitro, which suggests that this process plays an important role in aminoglycoside-induced ototoxicity . Free radical scavengers are compounds capable of inactivating free radicals, thereby attenuating their tissue damaging capacity . In this study we have determined the ability of the powerful free radical scavenger alpha-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by a highly ototoxic regimen of the aminoglycoside amikacin (450 mg/kg/day, i.m.) . Experiments were carried out on pigmented guinea pigs initially weighing 200-250 g . Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every 5 days, by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid . Results showed that animals receiving alpha-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone (P < 0.001; t-test) . These results provide further evidence of the recently reported intrinsic role of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of alpha-lipoic acid in the management of patients undergoing aminoglycoside treatment.

J Chemother, 1999 Feb, 11(1), 54 - 60
Strategies for cost-containment: once-daily ceftriaxone plus amikacin as empiric therapy for febrile granulocytopenic children with cancer; Castagnola E et al.; Administration of broad-spectrum antibiotics as empiric therapy to febrile granulocytopenic patients has become a widely accepted practice . In order to evaluate the cost-effectiveness of ceftriaxone plus amikacin in single daily doses as empiric treatment for febrile granulocytopenic children with cancer, a retrospective review (January-December 1996) of all febrile episodes at our institution was carried out . Overall, 101 febrile episodes in 89 granulocytopenic children with cancer were empirically treated with a once-daily ceftriaxone plus amikacin combination . 59/101 (59%) patients had absolute granulocyte count lower than 100/mm3 at entry; 46 (45%) were affected by solid tumors, 16 (15%) by Hodgkin's disease or lymphoma, and 30 (30%) patients underwent bone marrow transplantation . The ceftriaxone plus amikacin combination was effective in 72/101 (72%) patients with a median time to defervescence of 3 days (range, 1-4) . We also evaluated the economic advantages of the ceftriaxone plus amikacin once-daily regimen when compared with another treatment regimen such as ceftazidime plus amikacin requiring three daily doses . Compared with the multiple daily dose regimen of ceftazidime plus amikacin, there is a cost saving of US $11 (17,500 Italian liras) and US $66 (105,000 Italian liras) for both 1-day and 6-day treatments, respectively, by using the single daily dose regimen of ceftriaxone plus amikacin . The potential of ceftriaxone to lower costs in hospitalized patients depends upon its comparable efficacy with other extended-spectrum beta-lactams, in which case it can reduce overall treatment costs because of its once-daily administration schedule.

Zhongguo Yao Li Xue Bao, 1997 Jul, 18(4), 303 - 5
Effects of isolation housing and timing of drug administration on amikacin kinetics in mice; Zhou RH et al.; AIM: To study the influences of social condition and drug administration time on amikacin metabolism in mice . METHODS: Forty Male ICR mice were randomly assigned into 4 groups according to 1) housing condition: individual housing (I, one mouse in a cage) or aggregated housing (A, 10 mice in a cage) and 2) drug administration time: at midday (D) or at midnight (N), i.e . I-D, I-N, A-D, and A-N groups . Amikacin was injected s.c . 15 mg.kg-1 after 4 wk of raising at D or N . Blood samples were taken at 5, 10, 15, 20, 30, and 60 min after medication in each mouse . Plasma amikacin was measured by enzyme immunoassay . The concentration-time data were fitted with one-compartment open model in each mouse and data were analyzed with group t test . RESULTS: The clearance (Cl) of amikacin was larger and the half-life (T1/2) was shorter in A-N group than in A-D or I-N groups respectively . AUC(0-1) in A-N group was less than in I-N group . No differences of kinetic parameters between 2 isolated housing (I-D and I-N) groups were found . CONCLUSION: Aggregated housing and midnight drug administration increased the disposition of amikacin.

J Zoo Wildl Med, 1998 Dec, 29(4), 461 - 4
Infectious dermatitis in a ball python (Python regius) colony; Branch S et al.; Seven wild-caught ball pythons (Python regius), including six gravid females and one male, were obtained from Africa and were housed in a government animal facility in Research Triangle Park, North Carolina . Upon arrival, the snakes were found to be infested with ticks (Aponomma latus), which were manually removed . Four weeks following arrival, vesicular skin lesions began to appear on the snakes . Despite treatment of all affected female snakes with amikacin (5 mg/kg i.m., every 3 days) and cefotaxime (25 mg/kg i.m., every 3 days), the condition progressed and five of the female snakes died 7 wk after arrival . The remaining male and one female improved after an increase in environmental temperature, with ecdysis followed by healing . Physiologic stress, ectoparasites, and shipping may have predisposed the snakes to sepsis.

Presse Med, 1998 Dec, 27 Suppl 5, 7 - 8
{Liposomes: promising perspectives}; Bricaire F; NEW THERAPEUTIC VECTORS: Liposomes are nontoxic biodegradable lipid particles which can vehicle drug compounds to the site of action, thus limiting the risk of general toxicity . WITH AMINOGLYCOSIDES: Liposome vectors for aminoglycosides, particularly amikacin, have been developed . Oto- and hepatic toxicity can be limited allowing the use of higher doses for longer periods . WITH AMPHOTERICIN B: Liposomal amphotericin B is now available and appears to give interesting results both in terms of efficacy and tolerance . OTHER APPLICATIONS: Capsular forms of other antibiotics such as ciprofloxacin are being studied . An encapsulated anticytomegalovirus agent, foscamet, is also be explored . In cancerology, liposomes could be developed to deliver toxic agents such as doxorubicin for example . The high cost of these therapeutic vectors does however limit their current use.

Int J Cancer Suppl, 1998, 11, 35 - 9
Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition; Atkinson SA et al.; In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s . Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana-Farber Cancer Institute (DFCI) protocol 87-001 and 16 children receiving DFCI protocol 91-001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics . At diagnosis of ALL, > 70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover . During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels . During 24 months of chemotherapy-maintained remission, reduction in bone mineral content (BMC), as measured by Z-scores, occurred in 64% of children, most severely affecting those > 11 years of age . A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture . By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group . Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25-dihydroxyvitamin D remained abnormally low in 70% . Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia . Dietary intake and absorption of magnesium were normal . In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16-20 weeks, plasma magnesium normalized in only 50% of subjects.

J Neurosci, 1999 Jan 1, 19(1), 358 - 71
High-frequency auditory feedback is not required for adult song maintenance in Bengalese finches; Woolley SM et al.; Male Bengalese finches do not normally change their vocal patterns in adulthood; song is stereotyped and stable over time . Adult song maintenance requires auditory feedback . If adults are deafened, song will degrade within 1 week . We tested whether feedback of all sound frequencies is required for song maintenance . The avian basilar papilla is tonotopically organized; hair cells in the basal region encode high frequencies, and low frequencies are encoded in progressively apical regions . We restricted the spectral range of feedback available to a bird by killing either auditory hair cells encoding higher frequencies or those encoding both high and low frequencies and documented resultant changes in song . Birds were treated with either Amikacin alone to kill high-frequency hair cells or Amikacin and sound exposure to target hair cells across the entire papilla . During treatment, song was recorded from all birds weekly . After treatment and song recording, evoked-potential audiograms were evaluated on each bird, and papillas were evaluated by scanning electron microscopy . Results showed that hair cell damage over 46-63% of the basal papilla and the corresponding high-frequency hearing loss had no effect on song structure . In birds with hair cell damage extending further into the apical region of the papilla and corresponding low-frequency and high-frequency hearing loss, song degradation occurred within 1 week of beginning treatment and was comparable with degradation after surgical deafening . We conclude that either low-frequency spectral cues or temporal cues via feedback of the song amplitude envelope are sufficient for song maintenance in adult Bengalese finches.

Yao Xue Xue Bao, 1996, 31(12), 881 - 5
{Analysis of population pharmacokinetics with NONMEM in clinical patients treated with amikacin by intravenous infusion}; Chu XM et al.; Clinical data (n = 275) collected from 52 patients with respiratory tract infection receiving amikacin (AMK) by intravenous infusion were analysed with NONMEM, a computer program designed for estimating population pharmacokinetic parameters . Concentrations of AMK in serum were determined by fluorescence polarization immunoassay (FPIA) . A two compartment open model was used for analysing AMK population pharmacokinetics . The influence of body weight (BW), creatinine clearance (CC), administration history (HIS) and state of pathology (chronic obstructional pulmonary disease, COPD) on pharmacokinetics was investigated . The pharmacokinetic parameters of AMK were shown to be influenced by creatinine clearance (CC) and COPD.

Infection, 1998 Nov-Dec, 26(6), 396 - 8
Pharmacokinetic analysis of amikacin twice and single daily dosage in immunocompromised pediatric patients; Krivoy N et al.; Ten children received amikacin twice daily and 13 were treated using the single daily protocol . All had fever and neutropenia on admission, and received a total daily dose of 20 mg/kg when included in the study . Individual pharmacokinetic parameters were calculated using a one-compartment model for two blood amikacin samples . The mean (+/- SD) of elimination half-life (h), amikacin clearance (l/h/kg), volume of distribution (l/kg), peak concentration (microgram/ml) and trough concentration (microgram/ml) were: 2.51 (0.74) and 2.85 (0.32) h; 0.26 (0.16) and 0.115 (0.02) l/h/kg; 0.74 (0.44) and 0.47 (0.11) l/kg; 19.1 (12.3) and 42.6 (12.6) micrograms/ml; 0.85 (0.74) and 0.18 (0.24) microgram/ml with twice and single daily dosage schedules, respectively . A single daily dose of amikacin had a significantly longer elimination half-life, lower clearance, higher peak concentration and lower trough concentration in comparison to the twice-daily schedule . The use of amikacin 20 mg/kg daily delivered in a single daily dose is recommended for immunocompromised pediatric patients with fever and neutropenia, in spite of the measured pharmacokinetic differences.

Proc West Pharmacol Soc, 1998, 41, 61 - 3
Renal and hepatic interactions of acetaminophen and amikacin in the infant rat; Melendez Camargo ME et al.; Results suggest that amikacin at the highest dose induces more changes on the renal function while the effect of APAP is more marked on the hepatic function . It might suggest that simultaneous administration of amikacin-APAP produces less changes that when the drugs are administered alone.

Pharmacol Toxicol, 1998 Nov, 83(5), 220 - 4
Effects of chronic lithium on ototoxicity induced by gentamicin and amikacin in guinea-pigs; Sharifzadeh M et al.; The effects of chronic lithium co-therapy on the expression of gentamicin and amikacin ototoxicity were tested in guinea-pigs . Intramuscular injection of different doses of gentamicin (5, 10 mg/kg/day) and amikacin (150, 300 mg/kg/day) for three weeks, induced hearing loss consistent with the established pattern of aminoglycoside ototoxicity . Lithium salts remains one of the most widely used treatment for depressive illness . Administration of lithium chloride (600 mg/l, 35 days) in drinking water changed auditory brainstem response in a time-dependent manner . Pretreatment of animals with lithium chloride after seven days induced significant alterations in wave latency and interval . The present study assesses the protective effects of chronic lithium on gentamicin-induced ototoxicity in guinea pig . The results suggest that duration of lithium administration may be involved in auditory brainstem response changes and the observations could be accounted for, at least partially, by lithium- and aminoglycosides-induced perturbations of the phosphoinositide cascade within the inner ear.

Int J Syst Bacteriol, 1998 Oct, 48 Pt 4, 1349 - 55
Mycobacterium bohemicum sp . nov., a new slow-growing scotochromogenic mycobacterium; Reischl U et al.; A new, slow-growing, scotochromogenic mycobacterium was isolated from sputum of a 53-year-old patient with Down's syndrome suffering from tuberculosis . Growth occurred at temperatures between 25 and 40 degrees C with an optimum at 37 degrees C . This strain had surprisingly few enzymic activities (only positive for 68 degrees C heat-stable catalase and weakly positive for urease) and was sensitive to prothionamide, cycloserine, clarithromycin, gentamicin and amikacin but showed resistance to isoniazid, streptomycin, ethambutol, rifampin and ciprofloxacin . These characteristics assign this organism to a novel mycobacterial species characterized by a unique 16S rDNA nucleotide sequence . The name Mycobacterium bohemicum sp . nov . is proposed for this new, slow-growing, scotochromogenic mycobacterium . The type strain is DSM 44277T.

Drugs Exp Clin Res, 1998, 24(3), 153 - 7
Amikacin gel administration in the treatment of peristomal dermatitis; La Torre F et al.; Ten colostomized patients (six males, four females) and six ileostomized patients (three males, three females), presenting moderate (10 cases) or severe (6 cases) peristomal dermatitis, were treated for up to 28 days with a local daily application of amikacin sulphate 5% gel . All cases with moderate dermatitis and two patients with severe dermatitis recovered within 7 days of treatment . Two cases of severe dermatitis recovered in 14 days and the last two cases recovered in 28 days . No signs of intolerance to amikacin gel were shown by the patients . We conclude that amikacin sulphate 5% gel is a useful tool in the topical care of peristomal dermatitis in ostomate patients.

Brain Res, 1998 Nov 30, 813(1), 57 - 66
Attempt at hair cell neodifferentiation in developing and adult amikacin intoxicated rat cochleae; Parietti C et al.; Recent studies have shown that an attempt at auditory hair cell neodifferentiation occurs in vivo in the rat organ of Corti after amikacin intoxication during the last stages of cochlear maturation . Atypical cells, with morphological characteristics reminiscent of very immature sensory hair cells, were transiently observed after outer hair cell losses . The aim of the present study was to assess (i) if this attempt at hair cell neodifferentiation was related to the degree of maturity of the organ of Corti and (ii) to characterise morphological and molecular changes in the scarring epithelium . We therefore investigated, using electron and confocal microscopy, morphological and molecular changes in cochleae from rats treated with amikacin at two different periods: from post natal day (PND) 1 to PND 8, when the organ of Corti is very immature; and from PND 30 to 37, when the organ of Corti is morphologically and functionally mature . In both groups, transient atypical cells were observed, attesting that the attempt at hair cell neodifferentiation is not strictly related to the immaturity of the cochlea . The results also suggest that Deiters cells are involved in the appearance of atypical cells, possibly through a transdifferentiation process . Finally, it appears that non-sensory epithelial cells from the outer spiral sulcus progressively colonize the region of pre-existing outer hair cells .

J Comp Neurol, 1998 Nov 16, 401(2), 145 - 62
Characterization of atypical cells in the juvenile rat organ of corti after aminoglycoside ototoxicity; Daudet N et al.; Hair cell regeneration is well documented in the inner ear sensory epithelia of lower vertebrates and birds and may occur in the vestibular organs of mammals . By contrast, hair cell loss in the mature mammalian cochlea is considered irreversible . However, recent reports have suggested that an attempt at hair cell regeneration could occur in vivo in aminoglycoside-lesioned cochleas from neonatal rats . After amikacin treatment, atypical cells with apical specialization reminiscent of early differentiating stereocilia are transiently present at the apex of the intoxicated cochleas but fail to differentiate as hair cells in later stages . In the present study, we used electronic microscopy, histochemistry, and confocal microscopy to investigate the cellular rearrangements in the amikacin-lesioned organ of Corti of rat pups . In addition, we used 5-bromo-2'-deoxyuridine immunocytochemistry to determine whether mitotic processes are involved in the formation of the atypical cells . The morphologic and molecular data suggest that atypical cells are not recovering hair cells, but share characteristics of immature hair cells and supporting cells . Proliferative cells were absent from the region occupied by atypical cells, suggesting that the latter did not arise through mitotic processes . Altogether, the present results support the hypothesis that atypical cells arise through direct transformation of some of the supporting cells that reorganize during hair cell degeneration.

J Antimicrob Chemother, 1998 Oct, 42(4), 483 - 7
Treatment of disseminated Mycobacterium genavense infection in a murine model with ciprofloxacin, amikacin, ethambutol, clarithromycin and rifabutin; Vrioni G et al.; Mycobacterium genavense is a recently described agent which can induce disseminated infections in patients with AIDS . Up to now, no standard approach to treatment has been defined and patients have been treated empirically with antibiotics used for treating infections caused by other nontuberculous mycobacteria . In this study, we compared the effectiveness of ciprofloxacin, amikacin, ethambutol, clarithromycin and rifabutin in the treatment of an animal model of M . genavense infection in C57BL/6 mice . Antimycobacterial treatment was started 4 weeks after an intravenous bacterial challenge and was continued for 30 days . Treated and control mice were killed at days 15 and 30 of treatment and the number of viable bacteria in their spleens was counted . Treatment with clarithromycin (50 mg/kg/day sc) and rifabutin (20 mg/kg/day po) was found to decrease the bacterial counts in the spleens significantly as early as 15 days after the onset of treatment (P < 0.01) . The effect of treatment was more pronounced after 30 days of treatment (P < 0.001) . Amikacin (25 mg/kg/day sc) and ethambutol (50 mg/kg/day sc) were found to decrease significantly the cfu in the spleens only after 30 days of treatment (P < 0.01) . Ciprofloxacin (25 mg/kg/day sc) was ineffective in the experimental conditions used here.

Rev Cubana Med Trop, 1995, 47(1), 54 - 8
{A susceptibility study of Mycobacterium avium-intracellulare strains using the broth macrodilution method}; Mederos Cuervo LM et al.; The macrobroth dilution method was used for determining the resistance and/or sensitivity of 10 nontuberculous mycobacteria strains from Mycobacterium avium-intracellulare (MAI) complex isolated from patients presenting with respiratory symptoms . Drugs employed were as follows: isoniazid, ethambutol, rifampicin, streptomycin, gentamicin and amikacin . With respect to susceptibility of the strains studied, the greater sensitivity was found to be against ethambutol, amikacin, and gentamicin . The possibility of replacing the Middlebrook 7H9 liquid culture medium by the UIT-L liquid culture medium was analyzed . Normalization of the method was attained and a shortening of the reading time when using the UIT-L culture medium was also obtained.

Auris Nasus Larynx, 1998 Sep, 25(3), 223 - 32
Comparison of distortion-product and transient evoked otoacoustic emissions with ABR threshold shift in chinchillas with ototoxic damage; Kakigi A et al.; In this study we compare distortion product otoacoustic emissions (DPOAEs), transient evoked otoacoustic emissions (TEOAEs) and ABR threshold shifts in an animal model (chinchilla) of cochlear hearing loss . Subjects were treated with an aminoglycoside (amikacin) to produce basal cochlear lesions of various degree . DPOAE and TEOAE were measured throughout the treatment period and until hearing thresholds stabilized . ABR thresholds to tone pip stimuli were determined . Cytocochleograms of cochleas were prepared using scanning microscopy . DPOAEs (2f1-f2) were compared to fast Fourier transform (FFT)-analyzed TEOAEs components in the 1-, 2-, and 4-kHz frequency regions . Both types of emission were compared with corresponding ABR thresholds . There was no significant linear correlation between these different measures of cochlear function . Moreover, the amplitudes of DPOAEs reflected smaller regions of cochlear outer hair cell (OHC) damage better than TEOAEs . These results suggest that DPOAEs can be used to more accurately monitor hair cell function at specific hearing locations than TEOAEs.

Antimicrob Agents Chemother, 1998 Nov, 42(11), 3006 - 8
Pulsed-exposure and postantibiotic leukocyte enhancement effects of amikacin, clarithromycin, clofazimine, and rifampin against intracellular Mycobacterium avium; Horgen L et al.; We investigated the postantibiotic effects (PAEs) of four agents against Mycobacterium avium in a human macrophage model under two different experimental conditions . For postantibiotic leukocyte enhancement (PALE), bacteria were exposed to antibiotics prior to their phagocytosis, whereas for pulsed exposure (PE), antibiotics were added after phagocytosis . In both cases, the drugs were used at their peak concentrations in serum (Cmax) for 2 h . The results showed two different patterns: one for the drug for which results under PE and PALE test conditions did not significantly differ (amikacin) and one for drugs for which PAE values were significantly higher under PE test conditions (clarithromycin, clofazimine, and rifampin) . These data suggest that even a brief exposure of M . avium to peak concentrations of certain drugs in serum may result in prolonged and persistent suppression of bacterial growth inside human macrophages.

J Chromatogr A, 1998 Sep 11, 819(1-2), 93 - 7
Analysis of amikacin by liquid chromatography with pulsed electrochemical detection; Adams E et al.; The analysis of amikacin by liquid chromatography using a column packed with poly(styrene-divinylbenzene) and pulsed electrochemical detection on a gold electrode is described . A two-step gradient was necessary to obtain a good separation together with a reasonable analysis time of 60 min . The mobile phases consisted of an aqueous solution of 1 g/l or 60 g/l sodium sulfate, 1.8 g/l sodium octanesulfonate and 50 ml/l 0.2 M phosphate buffer, pH 3.0 . Sodium hydroxide was added postcolumn . The influence of the different chromatographic parameters on the separation was investigated . When a number of commercial samples of amikacin was analyzed using this method, ten different components were separated.

J Antibiot (Tokyo), 1998 Aug, 51(8), 735 - 42
The novel enzymatic 3''-N-acetylation of arbekacin by an aminoglycoside 3-N-acetyltransferase of Streptomyces origin and the resulting activity; Hotta K et al.; Kanamycin group antibiotics were subjected to enzymatic acetylation by a cell free extract containing an aminoglycoside 3-N-acetyltransferase, AAC(3)-X, derived from Streptomyces griseus SS-1198PR . Characterization of the incubated reaction mixtures by TLC and antibiotic assay revealed that a product retaining activity was specifically formed from arbekacin, an anti-MRSA semisynthetic aminoglycoside . The structural determination demonstrated that acetylation occurred at the 3"-amino group in arbekacin and amikacin, and at the 3-amino group in dibekacin as in the case of kanamycin . These results should reflected the effect of the (S)-4-amino-2-hydroxybutyryl side chain which is present in arbekacin and amikacin, but absent in dibekacin and kanamycin . The 3"-N-acetylation is the first finding in the enzymatic modifications of aminoglycoside antibiotics . 3"-N-Acetylarbekacin showed antibiotic activity as high as that of 2'-N-acetylarbekacin reported previously, whereas 3"-N-acetylamikacin showed no substantial activity . Thus, our results illuminated a novel aspect of arbekacin distinct from the other aminoglycosides.

Chemotherapy, 1998 Nov-Dec, 44(6), 397 - 404
Effects of a new topic amikacin formulation on chemotaxis and release of profibrotic factors by human monocytes; Baroni A et al.; Aminoglycosides, widely used because of their large-spectrum antibiotic effects, should not interfere with the healing process of an ulcer or an infected wound . We evaluated the effects of amikacin or the excipients present in the topic formulation BG 90, powder 2 . 5% (Boniscontro e Gazzone S.r.l., Rome, Italy), on human monocyte chemotaxis and the release of profibrotic factors by resting or lipopolysaccharide (LPS)-activated monocytes . The chemotactic response of monocytes to zymosan-activated serum is not modified in vitro by pre-incubation of the cells with amikacin (2 and 10 microg/ml/10(6) cells) or excipients . Unstimulated monocytes did not secrete appreciable amounts of cytokines . Vice versa, amikacin-stimulated cells released platelet-derived growth factor AB (PDGF-AB) (about 340 pg/ml), transforming growth factor (TGF)-beta1 (about 10 pg/ml), and tumour necrosis factor (TNF)-alpha (over 1,100 pg/ml); among excipients, ZnO and vitamin E induced PDGF-AB release (about 320 and, respectively, 200 pg/ml), while stimulation of monocyte monolayers by the other excipients did not lead to appreciable cytokine release . As expected, LPS-activated human monocytes produced PDGF-AB, TGF-beta1, and TNF-alpha . When monocytes were co-stimulated with LPS and amikacin, the PDGF-AB and TGF-beta1 values almost overlapped with those from the stimulation of cells with LPS alone, while TNF-alpha production was slowly reduced . The results show a stimulating effect of aminoglycoside on the production of profibrotic factors and, therefore, on the healing process of wounds in addition to a modulating effect on the production of pro-inflammatory cytokines like TNF-alpha . Moreover, ZnO and tocopherol (free-radical scavengers), used as excipients in the topic formulation, induce the release of growth factors with profibrotic activity (PDGF-AB) . Further research is warranted to explore the effects of this formulation in vivo, verifying whether the association of the antibiotic with scavengers has a double advantage in topical amikacin: on the one hand, it could limit the damage from free radicals, and on the other it could favour tissue healing.

Infect Immun, 1998 Oct, 66(10), 4676 - 89
Filament tip-associated antigens involved in adherence to and invasion of murine pulmonary epithelial cells in vivo and HeLa cells in vitro by Nocardia asteroides; Beaman BL et al.; The interactions of Nocardia asteroides GUH-2 with pulmonary epithelial cells of C57BL/6 mice and with HeLa cells were studied . Electron microscopy demonstrated that only the tips of log-phase cells penetrated pulmonary epithelial cells following intranasal administration, and nocardiae were recovered from the brain . Coccobacillary cells neither invaded nor disseminated . Serum from immunized mice (IMS) decreased attachment to and penetration of pulmonary epithelial cell surfaces by log-phase GUH-2 and inhibited spread to the brain . IMS was adsorbed against stationary-phase cells . Western immunoblots suggested that this adsorbed IMS was reactive primarily with 43- and 62-kDa proteins . Immunofluorescence showed that adsorbed IMS preferentially labeled the tips of log-phase GUH-2 cells . Since this IMS was reactive to culture filtrate antigens, several of these proteins were cut from gels, and mice were immunized . Sera against 62-, 55-, 43-, 36-, 31-, and 25-kDa antigens were obtained . The antisera against the 43- and 36-kDa proteins labeled the filament tips of GUH-2 cells . Only the antiserum against the 43-kDa antigen increased pulmonary clearance, inhibited apical attachment to and penetration of pulmonary epithelial cells, and prevented spread to the brain . An in vitro model with HeLa cells demonstrated that the tips of log-phase cells of GUH-2 adhered to and penetrated the surface of HeLa cells . Invasion assays with amikacin treatment demonstrated that nocardiae were internalized . Adsorbed IMS blocked attachment to and invasion of these cells . These data suggested that a filament tip-associated 43-kDa protein was involved in attachment to and invasion of pulmonary epithelial cells and HeLa cells by N . asteroides GUH-2.

Audiol Neurootol, 1998 Nov-Dec, 3(6), 361 - 72
Basal cochlear lesions result in increased amplitude of otoacoustic emissions; Kakigi A et al.; We have measured the changes in transient otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) during and after ototoxic amikacin treatment in an animal (chinchilla) model . TEOAE and DPOAE were recorded from 6 adult chinchillas over a 6-week time course starting just before a 5-day or 7-day treatment period with amikacin sulphate (400 mg/kg/day, i.m.) . After final recordings, cochlear morphology was assessed by scanning electron microscopy . Generally, both DPOAE and TEOAE amplitudes change during and after treatment in a systematic fashion . High-frequency components change first, followed by lower-frequency components . We note that there is often a long latency to the onset of changes in otoacoustic emissions (OAE), and that these changes can continue for weeks after treatment . Most importantly we report that when the basal region of the cochlea is damaged in the frequency region above the OAE recording bandwidth (0.6-6 kHz for TEOAE; 1-6.7 kHz for DPOAE), we often find an increase in OAE amplitudes . More specifically, we note that as a cochlear lesion progresses apically, there is often a transient increase in a frequency-specific OAE before it reduces or is lost . Our results suggest that the increase in OAE amplitudes precedes the expression of detectable cochlear pathology.

Neth J Med, 1998 Jul, 53(1), 7 - 14
Treatment of pulmonary tuberculosis; van Loenhout-Rooyackers JH et al.; Recently the duration of treatment for pulmonary tuberculosis in The Netherlands was shortened from nine to six months . A six months regimen containing isoniazid (H), rifampicin (R) and pyrazinamid (Z) daily for two months, followed by H and R daily for another four months (2HRZ/2HR) has been proven effective for the treatment of pulmonary tuberculosis, provided the cause is a fully susceptible strain of M . tuberculosis . Worldwide there is an increase in drug-resistant tuberculosis . Since at the start of treatment susceptibility tests often are not available, a fourth drug must be added in the intensive phase . Ethambutol is the drug preferred . This means that one always starts with 4 drugs unless the patient is a contact of an index-case with proven susceptibility and one is sure that he will be compliant or the patient is infected in the past before 1940, he received never tuberculostatic drugs and one is sure that there is no exogenous reinfection . If the patient has been treated previously and anti-tuberculosis drug resistance is likely, treatment regimens should contain at least two drugs with which he has not been treated before, while a fifth drug routinely must be added in the intensive phase . Amikacin is preferred, since there is no cross-resistance to streptomycin . Consensus on the duration of treatment for extra-pulmonary tuberculosis has not yet been reached, but basically the principles for treatment are the same . This is also true for HIV infected tuberculosis patients . In some serious clinical situations (meningitis, miliary, spine tb) duration of treatment still is 9-12 months . Early involvement of the public health nurse of the municipal health department (GGD) is necessary to ensure patient compliance and treatment supervision.

Proc Natl Acad Sci U S A, 1998 Aug 18, 95(17), 9791 - 5
Neomycin inhibits angiogenin-induced angiogenesis; Hu GF; A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor . Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis . The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect . In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin . Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner . At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability . Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation . Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg . These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy.

Pharmacotherapy, 1998 Jul-Aug, 18(4), 738 - 47
Current strategies for the prevention and treatment of disseminated Mycobacterium avium complex infection in patients with AIDS; Wright J; Disseminated Mycobacterium avium complex (MAC) infection is a common opportunistic disease in patients with acquired immunodeficiency syndrome and is associated with significant morbidity and mortality . Macrolides effectively prevented and treated the disease in clinical trials . In general, prophylaxis with clarithromycin or azithromycin is indicated for patients with CD4 cell counts below 50 cells/mm3 . Treatment of disseminated MAC infection is lifelong and must include two agents with antimycobacterial activity . Clarithromycin plus ethambutol is considered the standard regimen . Potential alternatives are azithromycin, rifabutin, ciprofloxacin, clofazamine, and amikacin . Several factors influence drug selection, such as the patient's immune status, evidence of treatment safety and efficacy, drug interactions, and potential for resistance.

Int J Tuberc Lung Dis, 1998 Jul, 2(7), 580 - 4
Drug resistance in Mycobacterium tuberculosis strains isolated from re-treatment cases of pulmonary tuberculosis in Ethiopia: susceptibility to first-line and alternative drugs; Abate G et al.; SETTING: Addis Ababa Tuberculosis Demonstration and Training Center, Ethiopia . OBJECTIVES: To determine the pattern of drug resistance among re-treatment cases of pulmonary tuberculosis (TB), to determine the risk factors associated with multi-drug resistant (MDR) TB, and to propose re-treatment regimens based on the patterns of susceptibility to first-line and alternative drugs . DESIGN: One hundred and seven Mycobacterium tuberculosis strains isolated from an equal number of re-treatment cases of pulmonary TB were included in the study . Drug susceptibility was determined by the Bactec method . RESULTS: About 50% of the strains were resistant to one or more of the first-line drugs and 12% of the strains were multi-drug resistant, i.e., resistant to both isoniazid and rifampicin . Previous treatment with rifampicin was the most important predictor of MDR-TB . All MDR strains were susceptible to amikacin, ciprofloxacin, ethambutol, ethionamide and clofazimine . CONCLUSION: The WHO re-treatment regimen would theoretically be effective for the treatment of all non-MDR-TB patients in this study . A proposed 12-month re-treatment regimen for MDR-TB patients would include a fluoroquinolone in combination with streptomycin, pyrazinamide, isoniazid, ethambutol and clofazimine . There is an urgent need for more research to define safe and inexpensive treatment regimens for MDR-TB patients in low-income countries.

JPEN J Parenter Enteral Nutr, 1998 Jul-Aug, 22(4), 234 - 7
Central venous catheters versus peripheral veins for sampling blood levels of commonly used drugs; Shulman RJ et al.; BACKGROUND: Our objective was to compare the accuracy of drug levels in blood samples obtained from central venous catheters with those from peripheral blood samples taken to monitor various drug levels . METHODS: Pediatric patients with central venous catheters receiving aminoglycosides, vancomycin, or cyclosporine had central and peripheral blood samples obtained within 5 minutes of each other and analyzed simultaneously . We ascertained how well blood levels from central venous catheters compared with those from peripheral blood (the criterion standard) . RESULTS: There were no clinically significant differences between central and peripheral values for amikacin, gentamicin, tobramycin, and vancomycin (both peaks and troughs) . Preliminary data indicated that oral cyclosporine can be monitored via central venous catheter . In contrast, there was poor agreement between peripheral and central values when cyclosporine was administered by IV . CONCLUSIONS: Amikacin, gentamicin, tobramycin, vancomycin, and probably oral cyclosporine can be monitored accurately via central venous catheter . In contrast, IV cyclosporine should be monitored via peripheral blood.

Jpn J Antibiot, 1998 Apr, 51(4), 298 - 304
{Clinical evaluation of combination therapy with cefpirome and amikacin for infections associated with hematological disorders}; Fukuda M et al.; Cefpirome (CPR) and amikacin (AMK) were used concomitantly to treat infections complicated by hematological diseases . A total of 100 subjects were evaluated, and the allover efficacy rate was 72.0% . Acute leukemia was found in the largest number of patient, 55, followed by 12 cases of malignant lymphoma and 6 cases of chronic myelogenous leukemia . By type of infection, patients having suspected sepsis were the largest in number, being 50, and the efficacy rate was 68.0% . The efficacy rates for sepsis and pneumonia were 57.1% (7 cases) and 61.1% (18 cases), respectively . The efficacy rates by neutrophil counts before administration of CPR and AMK and at 7 days after administration were both 71.9% in the group of less than 500/microliter, both 60.0% in the group of less than 100/microliter . The efficacy rate was 75.0% in the group of granulocyte colony stimulating factor (G-CSF) concomitant usage, and 70.0% in the non-concomitant usage group . Concomitant treatment with CPR and AMK exhibited a high level of safety and efficacy rates in infections complicated by hematological diseases and high.

Br J Oral Maxillofac Surg, 1998 Apr, 36(2), 119 - 22
Atypical cervico-facial mycobacterial infections in childhood; Makhani S et al.; We describe three patients who presented with atypical mycobacterial infection . Although antituberculous drugs are ineffective, combination treatment with clarithromycin or amikacin and ciprofloxacin (with or without cotrimoxazole) leads to eventual resolution of the lesions . The treatment of choice, however, remains complete excision of the affected area which obviates the need for prolonged chemotherapy and minimizes the scarring which may otherwise develop after conservative treatment.

Antimicrob Agents Chemother, 1998 Jun, 42(6), 1506 - 8
Characterization of the 6'-N-aminoglycoside acetyltransferase gene aac(6')-Iq from the integron of a natural multiresistance plasmid; Centron D et al.; The nucleotide sequence of a newly identified amikacin resistance gene, aac(6')-Iq (551 bp), is reported . It has 68.4 and 94.4% homology with the aac(6')-Ia gene and the recently described aac(6')-Ip gene, respectively . Analysis of its flanking sequences indicated that it is in the first cassette of a class I integron and has an attC site (59-base element) 108 bp in length.

Bull Math Biol, 1998 May, 60(3), 545 - 67
In vivo simulation of human pharmacokinetics in the rabbit; Bugnon D et al.; The evaluation of drugs in vivo is often based on experimental models using small animals such as mice, rats and rabbits . However, these models could be improved to correspond more closely to the human situation if the pharmacokinetics of the drugs tested in animals were similar to that observed in humans . The use of a computer-controlled pump allowing an adequate flow of tobramycin and amikacin to be infused into rabbits enabled us to simulate the human pharmacokinetics of these antibiotics in vivo in this study . The function defining the rate of infusion required to perform the simulation of an intravenous bolus was first determined generally and symbolically for linear pharmacokinetic models independently from the number of compartments involved . The practical simulation of a decreasing monoexponential serum profile with a half-life of 2 h (one-compartment model for the human pharmacokinetics of aminoglycosides) was then studied for tobramycin and amikacin on the basis of a two-compartment model in the animal . The kinetics obtained had an apparent elimination half-life of 1.97 and 1.86 h, respectively . Linearity of the semilogarithmic regressions of the profiles obtained was quite sound . Finally, an a posteriori analysis of the pharmacokinetic model and its parameters is proposed on the basis of the results obtained after simulation.

J Infect Dis, 1998 Jun, 177(6), 1573 - 81
A single 16S ribosomal RNA substitution is responsible for resistance to amikacin and other 2-deoxystreptamine aminoglycosides in Mycobacterium abscessus and Mycobacterium chelonae; Prammananan T et al.; Twenty-six clinical isolates of Mycobacterium abscessus resistant to amikacin were identified . Most isolates were from patients with posttympanostomy tube placement otitis media or patients with cystic fibrosis who had received aminoglycoside therapy . Isolates were highly resistant (MICs > 1024 microg/mL) to amikacin, kanamycin, gentamicin, tobramycin, and neomycin (all 2-deoxystreptamine aminoglycosides) but not to streptomycin . Sequencing of their 16S ribosomal (r) RNA revealed that 16 (94%) of 17 had an A-->G mutation at position 1408 . In vitro-selected amikacin-resistant mutants of M . abscessus and Mycobacterium chelonae had the same resistance phenotype, and 15 mutants all had the same A-->G substitution at position 1408 . Introducing an rRNA operon from Mycobacterium smegmatis with a mutated A-->G at this position into a single functional allelic rRNA mutant of M . smegmatis produced the same aminoglycoside resistance phenotype . These studies demonstrate this 16S rRNA mutation is responsible for amikacin resistance in M . abscessus, which has only one copy of the rRNA operon.

Arch Otolaryngol Head Neck Surg, 1998 May, 124(5), 529 - 33
Sensorineural hearing loss in children after liver transplantation; Deutsch ES et al.; OBJECTIVE: To investigate risk factors for sensorineural hearing loss (SNHL) in children after liver transplantation . DESIGN: Retrospective medical record review . SETTING: Pediatric tertiary care hospital . PATIENTS: One hundred twenty-five consecutive children who received liver transplants between March 1, 1987, and June 30, 1996 . MAIN OUTCOME MEASURES: The presence of SNHL (bone conduction threshold of >35 dB of hearing loss in at least 1 frequency) and the cause of the liver abnormality in all 125 patients . In addition, among the subset of children who had biliary atresia and underwent transplantation before 2 years of age, the total dose (milligrams per kilogram of body weight) of aminoglycoside antibiotic medications (tobramycin sulfate, gentamicin sulfate, and amikacin sulfate) and of intravenous loop diuretic agents (furosemide) was compared between children with and without SNHL . RESULTS: Audiologic evaluations were available for 66 of 125 patients, 15 (12%) of whom have SNHL . Of 5 survivors with the short-bowel syndrome, 4 have severe to profound SNHL . Of 46 children who have biliary atresia and who underwent transplantation before 2 years of age, 8 (17%) have SNHL . Among the 26 evaluable children with biliary atresia undergoing liver transplantation before 2 years of age, logistic regression analysis revealed that the most important risk factor for SNHL was the cumulative dose of amikacin (P = .05) . CONCLUSIONS: Children receiving liver transplants are at an increased risk for SNHL . Those with the short-bowel syndrome have the greatest prevalence of SNHL . Among the subset of children with biliary atresia receiving liver transplants before 2 years of age, statistical analysis demonstrates a dose-response relationship between the receipt of amikacin and the occurrence of SNHL.

Antimicrob Agents Chemother, 1998 May, 42(5), 1295 - 7
Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis; Alangaden GJ et al.; An A1400G mutation of the rrs gene was identified in Mycobacterium tuberculosis (MTB) strain ATCC 35827 and in 13 MTB clinical isolates resistant to amikacin-kanamycin (MICs, >128 microg/ml) . High-level cross-resistance may result from such a mutation since MTB has a single copy of the rrs gene . Another mechanism(s) may account for high-level amikacin-kanamycin resistance in two mutants and lower levels of resistance in four clinical isolates, all lacking the A1400G mutation.

J Drug Target, 1998, 5(2), 99 - 108
Surface-modified amikacin-liposomes: organ distribution and interaction with plasma proteins; Bucke WE et al.; Amikacin-loaded liposomes were produced and surface-modified by adsorption of PEG 4000, Tween 80, poloxamer 407 and gelatin . The organ distribution was studied in mice by analysing the amikacin content in liver, spleen, lung, kidneys and serum . Highest serum levels were obtained with the PEG- and Tween 80 modified liposomes (at 2 hours p.inj.) . Modification of the liposomes with gelatin as opsonization promoting agent distinctly increased the amikacin concentration in the liver from 36 to 66 mg/kg . Highest spleen concentrations were observed with non-modified and poloxamer 407 liposomes (242 mg/kg and 248 mg/kg, respectively) . The data suggest that modification by a simple adsorption process is sufficient to effectively alter the organ distribution . The liposomes differing in organ distribution exhibited also different plasma protein adsorption patterns, up to 115 spots were detected by 2-D PAGE . Hydrophilic albumin was present in a conc . of appr . 80% on liposomes modified with ethoxylated compounds . On the gelatin liposomes, 14% of alpha-2-Macroglobulin were adsorbed which is a protein typically found on particles rapidly cleared by the RES . IgM, Apo A-I, Apo C-II and alpha-1-Antitrypsin were other detected proteins.

Head Neck, 1998 May, 20(3), 245 - 9
Cervical lymphadenitis caused by nontuberculous mycobacteria in immunocompetent children: clinical and therapeutic experience; Losurdo G et al.; BACKGROUND: Cervical lymphadenitis is a frequent manifestation of nontuberculous mycobacteria (NTM) infection in immunocompetent children . Surgical excision, the treatment of choice, is often incomplete and may be difficult . A medical approach could reduce treatment morbidity . METHODS: Systemic antibiotic therapy was administered to seven children for at least 6 months as treatment for cervical lymphadenitis due to NTM: rifabutin and clarithromycin in 4 cases; rifabutin, clarithromicyn, and ethambutol in 2 cases; rifabutin, amikacin, and cycloserine in 1 case . RESULTS: All patients, six followed for a mean of 3 years and one for 6 months, were initially seen with regression of local signs of infection without relapse . Toxicity, likely due to rifabutin, was represented by neutropenia in three patients and yellow skin pigmentation in one patient . CONCLUSIONS: Systemic antibiotic therapy was safe and effective in children with lymphadenitis due to NTM . This approach could represent a sound alternative or adjunct to surgery.

Antimicrob Agents Chemother, 1998 Apr, 42(4), 849 - 56
Population pharmacokinetic study of amikacin administered once or twice daily to febrile, severely neutropenic adults; Tod M et al.; Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population . In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d . (n = 29) or 20 mg/kg o.d . (n = 28) and administered intravenously over 0.5 h . A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47) . Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique . A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software) . The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model . The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg . Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level . The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively . On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL{CR}) are proposed: for patients with normal renal function (CL{CR} of 80 to 130 ml/min), 20 mg/kg o.d . is recommended, whereas for patients with severe renal impairment (CL{CR}, 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.

Antimicrob Agents Chemother, 1998 Feb, 42(2), 344 - 7
Green fluorescent protein reporter microplate assay for high-throughput screening of compounds against Mycobacterium tuberculosis; Collins LA et al.; An optimal assay for high-throughput screening for new antituberculosis agents would combine the microplate format and low cost of firefly luciferase reporter assays and redox dyes with the ease of kinetic monitoring inherent in the BACTEC system . The green fluorescent protein (GFP) of the jellyfish Aequorea victoria is a useful reporter molecule which requires neither substrates nor cofactors due to the intrinsically fluorescent nature of the protein . The gene encoding a red-shifted, higher-intensity GFP variant was introduced by electroporation into Mycobacterium tuberculosis H37Ra and M . tuberculosis H37Rv on expression vector pFPV2 . A microplate-based fluorescence assay (GFP microplate assay {GFPMA}) was developed and evaluated by determining the MICs of existing antimycobacterial agents . The MICs of isoniazid, rifampin, ethambutol, streptomycin, amikacin, ofloxacin, ethionamide, thiacetazone, and capreomycin, but not cycloserine, determined by GFPMA were within 1 log2 dilution of those determined with the BACTEC 460 system and were available in 7 days . Equivalent MICs of antituberculosis agents in the BACTEC 460 system for both the reporter and parent strains suggested that introduction of pFPV2 did not influence drug susceptibility, in general . GFPMA provides a unique tool with which the dynamic response of M . tuberculosis to the existing and potential antituberculosis agents can easily, rapidly, and inexpensively be monitored.

Antimicrob Agents Chemother, 1998 Mar, 42(3), 712 - 4
Activities of isoniazid alone and in combination with other drugs against Mycobacterium avium infection in beige mice; Fattorini L et al.; Monotherapy with isoniazid or amikacin or clarithromycin or combinations of two of these drugs showed nil to modest therapeutic activity in beige mice infected with Mycobacterium avium . However, the combination of all three, isoniazid-amikacin-clarithromycin, markedly reduced CFUs in both spleens and lungs after 91 days of infection.

Eur J Clin Pharmacol, 1998 Jan, 53(5), 337 - 41
Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models; Botha JH et al.; OBJECTIVE: The population pharmacokinetics of amikacin, in neonates, was investigated using the nonlinear mixed effects model (NONMEM) . METHODS: One hundred and six steady-state amikacin serum levels were obtained from 53 black neonates with a mean gestational age of 35.1 weeks and mean age at the start of treatment of 3.1 days . A one-compartment model was used to fit the data . RESULTS: The final models for clearance (CL) and volume of distribution (V) were: CL(l.h(-1)) = 0.031WT(1.45) x P and V(l) = 0.316WT(1.44) where WT = birth weight (kg) and P = 1.28 for girls and 1.0 for boys . Inclusion of other fixed effect parameters in the model did not significantly improve the fit of the data . The inter-individual variability for CL and V were 18% and 13% . respectively . Intra-individual variability was 29% . Mean (95% CI) values of CL, V and half-life were 0.048 (0.045, 0.051) l.h(-1).kg(-1), 0.434 (0.414, 0.453) l.kg(-1) and 6.4 (6.2, 6.6) h respectively . CONCLUSION: Birth weight was an important determinant of both CL and V and, in this data set, gender was also found to influence CL . Mean population pharmacokinetic values were within the range of those previously derived for other neonatal populations using traditional methods.

Blood Purif, 1998, 16(1), 49 - 56
Elimination of drugs by the new polyamide hemofilter FH77H during various in vitro conditions; Kroh UF et al.; BACKGROUND/AIMS: Multiple organ failure alters the dosage of drugs during hemofiltration . To separate factors, we utilized in vitro hemofiltration to investigate different blood flows, protein concentrations and intracellular drug partition with the FH77H polyamide membrane . METHODS: One liter of warm heparinized fresh human blood was hemofiltrated in two series: (1) with digoxin, netilmycin, phenobarbital, ceftriaxone and teicoplanin, and (2) with amikacin, theophylline, ceftazidim, phenytoin and vancomycin and, in addition, with cell-free fresh frozen plasma . RESULTS: The increased volumes of distribution of aminoglycosides and theophylline were a combined result of partition into cells and adsorption into the filter membrane . The deviations of drug sieving from predicted values were due to different affinities of the drugs on whole blood binding sites . CONCLUSION: The in vitro composition of drugs and blood improved the detection of factors that influence drug elimination during hemofiltration . The FH77H polyamide hemofilter facilitates more precise predictions of drug dosages by low adsorption rates to the membrane.

Neuroreport, 1998 Feb 16, 9(3), 431 - 6
Amikacin intoxication induces apoptosis and cell proliferation in rat organ of Corti; Vago P et al.; Recently, an attempt at cochlear hair cell neodifferentiation has been reported in amikacin-treated rats . In the present study, we aimed to ascertain whether hair cell losses are mediated by apoptosis and whether cell proliferation occurs in damaged intoxicated cochleas . The results show that apoptosis is responsible for hair cell losses and that cell proliferation occurs in the region of the outer spiral sulcus but not in the region of Deiters cells and pre-existing hair cells . We suggest that cell proliferation maintains a certain homeostasis in the number of non-sensory cells and participates in epithelial scar formation . Neodifferentiated cells therefore probably arise from direct transdifferentiation, which could be triggered by phagocytosis of apoptotic bodies.

Pediatr Nephrol, 1998 Jan, 12(1), 67 - 8
Mycobacterium phlei peritonitis: a rare complication of chronic peritoneal dialysis; Paul E et al.; We report the first case of chronic ambulatory peritoneal dialysis-associated peritonitis caused by Mycobacterium phlei . This organism was isolated from the peritoneal fluid of a patient who presented with recurrent episodes of "culture-negative" peritonitis . The therapeutic regimen was based on previous experience with other rapidly growing atypical mycobacteria, and included removal of the Tenckhoff catheter, institution of hemodialysis, and anti-mycobacterial therapy with amikacin, cefoxitin, and doxycycline . This successfully eradicated the organism, and permitted subsequent cadaveric renal transplantation with routine immunosuppression.

Ann Pharmacother, 1998 Feb, 32(2), 170 - 5
Collaboration between pharmacy and laboratory: defining total allowable error limits for therapeutically monitored drugs; Radomski KM et al.; OBJECTIVE: To define the total allowable variability that is clinically tolerated for certain drug assays performed by the therapeutic drug monitoring (TDM) laboratory at our institution . METHODS: The monthly coefficient of variation (CV) for 13 of the most commonly performed drug assays was recorded for two concentrations: the upper and lower limits of the therapeutic range for each drug . A dosing simulation was performed for each drug by using population parameters to estimate the doses that would yield the two target concentrations in an adult patient . The smallest practical dosage adjustment that could be implemented in clinical practice was determined and the serum concentration resulting from this dosage change was estimated . Each change was equated to two standard deviations from the original drug concentration, and the corresponding CV or total allowable error (TEa) was calculated and compared with the laboratory's CV value . RESULTS: The laboratory CV was greater than the clinically defined TEa for amikacin at both trough and peak ranges, and for gentamicin and tobramycin at the trough range . Simulations for a patient with compromised renal function produced TEa values less than the reported CV for amikacin at both trough and peak ranges . Simulations for an obese patient produced TEa values less than the reported CV for amikacin, gentamicin, and tobramycin at both trough and peak ranges . The assay variability for these aminoglycosides is greater than the expected change in serum drug concentrations produced by the dosage changes used in the simulations . The TEa for all other drugs exceeded the laboratory CV, demonstrating assay variability within the clinically tolerated range . CONCLUSIONS: Knowledge of how the variability of a drug assay compares with its TEa allows clinicians to assess the usefulness of a serum drug concentration as a clinical tool.

Ophthalmology, 1998 Feb, 105(2), 269 - 72
Topical ciprofloxacin for treating nontuberculous mycobacterial keratitis; Hu FR et al.; OBJECTIVE: This study aimed to evaluate the clinical efficacy of topical ciprofloxacin for treating Mycobacterium fortuitum and Mycobacterium chelonae keratitis refractory to amikacin therapy . DESIGN: A prospective clinical trial of topical ciprofloxacin treatment for nontuberculous mycobacterial keratitis was conducted . PARTICIPANTS: Eleven patients with nontuberculous mycobacterial keratitis diagnosed from 1992 to 1996 were enrolled . INTERVENTION: All 11 patients were treated initially with topical fortified amikacin, but only 2 patients responded . The other nine patients, four with M . fortuitum and five with M . chelonae keratitis, were refractory to amikacin therapy and received topical ciprofloxacin treatment . Bacterial culture and drug susceptibility tests using the broth microdilution method were performed on all 11 patients . MAIN OUTCOME MEASURES: The clinical response to amikacin or ciprofloxacin treatment was judged by corneal re-epithelialization and density and/or size of corneal infiltrates . RESULTS: M . chelonae isolates were more resistant to amikacin and ciprofloxacin than M . fortuitum isolates based on the in vitro susceptibility test . Clinically, three patients with M . fortuitum keratitis were responsive to ciprofloxacin therapy; however, only one patient with M . chelonae keratitis responded to the same therapy . CONCLUSIONS: Topical ciprofloxacin offers a therapeutic alternative for nontuberculous mycobacterial keratitis, which was refractory to amikacin treatment . However, topical ciprofloxacin was more effective for treating M . fortuitum keratitis than for M . chelonae keratitis.

J Clin Microbiol, 1998 Jan, 36(1), 64 - 7
Evaluation of a new method for rapid drug susceptibility testing of Mycobacterium avium complex isolates by using the mycobacteria growth indicator tube; Piersimoni C et al.; The reliability of the Mycobacteria Growth Indicator Tube (MGIT {BBL}) for rapid drug susceptibility testing of Mycobacterium avium complex (MAC) isolates was evaluated . MICs of amikacin, clarithromycin, clofazimine, ethambutol, and rifabutin were determined by the MGIT system for 16 MAC strains . The results were compared with those obtained by the BACTEC broth macrodilution method . The turnaround times were 6 to 8 days (median, 7 days) for the MGIT and 5 to 7 days (median, 6 days) for the BACTEC system . Agreements with BACTEC system-determined MICs, within +/-1 log2 dilution, were 100, 100, 88, 63, and 44% for amikacin, clofazimine, rifabutin, clarithromycin, and ethambutol, respectively . Within +/-2 log2 dilutions, agreement with BACTEC system-determined MICs increased to 100% for all the tested drugs . In addition, if MGIT-determined MICs were evaluated according to the thresholds adopted for the interpretation of BACTEC system-determined ones, ethambutol was the only drug for which susceptible strains were frequently misclassified as resistant . It is concluded that the MGIT system is a promising, nonradiometric alternative to the BACTEC method for rapid susceptibility testing of MAC isolates; however, additional studies are required to confirm our results and to determine the optimal criteria for the interpretation of ethambutol MICs.

Cancer Res, 1998 Feb 1, 58(3), 468 - 72
Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions; Haaz MC et al.; Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer . Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-{4-N-(5-aminopentanoic acid)-1-piperidino} carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P . Rivory et al, Cancer Res., 56: 3689-3694, 1996) . As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media . The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes . The formation of APC was characterized by the following parameters: Km = 18.4 +/- 1.4 and 39.7 +/- 11.6 microM; and Vmax = 26.0 +/- 0.6 and 13.4 +/- 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively . This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6beta hydroxylation, an activity specifically mediated by CYP 3A . The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM . Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively . These concentrations exceed those expected in vivo . APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.

Vet Res, 1997 Nov-Dec, 28(6), 565 - 70
Comparative pharmacokinetics of amikacin following a single intramuscular or subcutaneous administration in goats (Capra hircus); Uppal RP et al.; The pharmacokinetics of amikacin sulfate was investigated following a single intramuscular (i.m.) or subcutaneous (s.c.) administration (10 mg/kg) . The plasma concentration versus time data were analysed using the biexponential equation for first-order absorption and elimination phases for both the i.m . and s.c . routes . The absorption half life values for the i.m . and s.c . routes were found to be 14.64 and 12.36 min, respectively . The biological half-life values of amikacin following i.m . and s.c . routes were found to be 84.46 and 93.96 min, respectively . The systemic availability of amikacin for both the i.m . (102.15 +/- 5.08%) and s.c . (106.82 +/- 12.95%) routes was found to be almost complete . Thus, based on the data of short absorption half life, almost complete systemic availability, slightly longer biological half life and ease of administration, we suggest that the s.c . route be preferred over the i.m . route for amikacin administration in goats . Amikacin at a dose level of 8 mg/kg body weight at 12 h intervals would result in a therapeutic peak plasma concentration (Cpmax) of 32.30 micrograms/mL, which is not expected to produce any oto- or nephropathic effects.

Ann Trop Paediatr, 1997 Sep, 17(3), 253 - 61
A comparison of two amikacin dosing regimens in paediatric surgical patients; Forsyth NB et al.; This investigation aimed to compare the efficacy and toxicity of two amikacin dosing regimens in seriously ill paediatric surgical patients . Children (0.6-12 years old) received amikacin intravenously either once daily (15 mg/kg, n = 27) or twice daily (7.5 mg/kg, n = 27) . Concomitant medication was given as prescribed . Mean (SD) peak serum amikacin levels were significantly different (p < 0.05) between the once and twice daily groups (37.7 (6.9) mg/l and 19.5 (3.7) mg/l, respectively) . Cumulative dose and duration of therapy were also significantly higher in the once-daily group . Regimen efficacy (favourable, unfavourable or indeterminate outcome) was assessed by patient temperatures, clinical improvement and white cell counts . Serum creatinine measurements and post-therapy, pure tone air conduction audiometry assessed nephro- and ototoxicity, respectively . No statistically significant differences were found between the groups in terms of outcome (18/24 and 22/25 patients in the once- and twice-daily groups had favourable outcomes; there were no unfavourable outcomes), nephrotoxicity (none of the patients assessed developed nephrotoxicity) or ototoxicity (2/20 and 5/20 patients, respectively, had mild high frequency hearing deficits which were predominantly unilateral and reversible) . Although the regimens were similar in this study, other investigations will further clarify the optimal dosing approach in paediatric patients.

Br J Ophthalmol, 1997 Sep, 81(9), 719 - 25
Assessment of a standard treatment protocol on visual outcome following presumed bacterial endophthalmitis; Okhravi N et al.; AIMS: The aim of this prospective study was, firstly, to judge the effect of early aggressive treatment with a standardised regimen of high dose broad spectrum intraocular and systemic antibiotics on visual outcome and, secondly, to assess the sensitivity of isolated organisms to the treatment regimen utilised . METHODS: Thirty two consecutive patients presenting with presumed bacterial endophthalmitis were treated and completed follow up . In every case, intraocular sampling was undertaken and treatment with intraocular vancomycin, amikacin, and systemic ciprofloxacin was commenced immediately, followed by systemic steroids 1 day later . RESULTS: In 69% of patients vision improved with 47% achieving a final visual acuity of 6/36 or better and 31% achieving 6/12 or better . Of the intraocular samples taken from post-surgical and post-traumatic cases, 10/27 (37%) and 3/5 (60%) were culture positive, respectively . All the bacteria isolated were sensitive to at least one of the three antibiotics used . CONCLUSIONS: The study demonstrated that the combination of vancomycin, amikacin, and ciprofloxacin is adequate as a standard regimen for the treatment of most patients with suspected bacterial endophthalmitis . The prognosis for a good visual outcome, however, remains poor with 15/27 (55%) post-surgical and 2/5 (40%) post-traumatic cases achieving a final acuity of 6/60 or less.

Pediatr Pulmonol, 1997 Oct, 24(4), 287 - 91
Mediastinal lymphadenopathy caused by Mycobacterium avium-intracellulare complex in a child with normal immunity: successful treatment with anti-mycobacterial drugs and laser bronchoscopy; Piedimonte G et al.; We report on the case of a 9-month-old Caucasian girl referred to our institution with a history of fever of unknown origin and wheezing, unresponsive to bronchodilator and anti-inflammatory therapy . Subsequent investigation led to a diagnosis of mediastinal lymphadenopathy caused by Mycobacterium avium-intracellulare (MAI) . The infected lymph tissue infiltrated and obstructed the right bronchus and significantly compressed the left bronchus to the point of near closure . Given the high degree of morbidity and potential mortality from thoracic surgery in this patient, we treated her with a combination of anti-mycobacterial drugs (rifabutin, clarithromycin, ciprofloxacin, clofazimine, amikacin, ethambutol) and glucocorticoids to relieve airway compression . The endobronchial granulation tissue was resected by laser bronchoscopy . This combined approach led to eventual normalization of radiologic and endoscopic findings, and the anti-mycobacterial chemotherapy was discontinued 12 months after the first bronchoalveolar lavage culture was negative for MAI . The patient remains asymptomatic 1 year after completion of this course of therapy . We suggest that mediastinal lymphadenopathy with bronchial infiltration and extrinsic airway compression caused by MAI in otherwise healthy children can be successfully treated with aggressive chemotherapy, glucocorticoids, and laser bronchoscopy.

Therapie, 1997 May-Jun, 52(3), 219 - 26
{Non-parametric estimation of pharmacokinetic parameters of amikacin in patients with non-insulin-dependent diabetes mellitus}; Corvaisier S et al.; To establish a reference for MAP Bayesian adaptive control of amikacin therapy in non-insulin-dependent diabetic patients, 30 patients (age: 63.5 +/- 10.1 years) were studied . Weight (84.2 +/- 15.4 kg) and body mass index (28.0 +/- 4.3 kg/m2 for males and 30.5 +/- 6.4 kg/m2 for females) were stable during treatment . Creatinine clearance (CCr) was 70.3 +/- 27.2 ml/min/1.73 m2 before treatment and 69.6 +/- 24.3 ml/min/1.73 m2 (NS) at the end of treatment (2 to 15 days) . 129 serum concentrations were drawn (4.8 +/- 2.6 levels per patient) . The one-compartment model was parameterized as having Vs (l.kg-1) and Kslope (min/ml.h) for each unit of CCr (Kel = Kintercept + Kslope x CCr) . The non-renal Kintercept was fixed at 0.00693 h-1 . The NPEM computes the joint probability densities . The mean, median, and SD were respectively: Vs = 0.3574, 0.3654, 0.0825 l.kg-1; Kslope = 0.0026, 0.0027, 0.0007 min/ml.h . For the a priori first doses determination, precision is higher with the new population . No difference in adaptive control was observed . In additive, the full joint density probability should be used to develop stochastic multiple model linear quadratic (MMLQ) adaptive control strategies.

Drugs, 1997, 54 Suppl 2, 23 - 7; discussion 28-9
Prevention of the selection of clarithromycin-resistant Mycobacterium avium-intracellulare complex; Grosset J et al.; The prevalence of clarithromycin-resistant mutants in untreated bacterial populations of Mycobacterium avium-intracellulare complex (MAC) has been demonstrated to be between 10(-7) and 10(-8) colony-forming units (CFUs) in the beige mouse model . Selection of these mutants occurred during clarithromycin monotherapy if treatment was initiated when the bacterial population size reached approximately 10(8) CFUs per spleen . Likewise, selection of clarithromycin-resistant MAC was induced in AIDS patients during therapy with clarithromycin alone or in combination with drugs that were ineffective for the treatment or prevention of MAC infection . Because the emergence of clarithromycin resistance during preventive therapy was observed exclusively in AIDS patients with CD4+ cell counts < or = 25 cells/microliter, clarithromycin monotherapy can be recommended for the prevention of MAC infection in AIDS patients with CD4+ cell counts of > or = 50 cells/microliter . However, a clarithromycin-containing combination regimen is recommended for patients with CD4+ cell counts < 50 cells/microliter . Since preliminary animal experiments and clinical trials indicate that amikacin, ethambutol or rifabutin in combination with clarithromycin may prevent, or at least delay, the selection of clarithromycin-resistant mutants, further preventive trials are urgently needed to confirm these observations.

Arch Ophthalmol, 1997 Oct, 115(10), 1316 - 8
Mycobacterium chelonae keratitis after excimer laser photorefractive keratectomy; Brancato R et al.; This is the first report of a severe case of Mycobacterium chelonae keratitis; it occurred in a 26-year-old man after he had undergone excimer laser photorefractive keratectomy for the correction of severe myopia, once the epithelium was already healed . The diagnosis was made by culture results and acid-fast staining of corneal scrapings . Topical ciprofloxacin sodium, 0.3 mg/mL, plus amikacin sodium, 10 mg/mL, and oral clarithromycin sodium led to remission of the ulceration after 3 months of therapy . Subsequent topical corticosteroid therapy led to complete visual recovery during 1 year of follow-up . There may be an increased risk of severe keratitis during the first postoperative months in eyes that have already undergone photorefractive keratectomy, due to the presence of some microepithelial defects symptomatically negative and not easily detectable by slit-lamp examination.

Chemotherapy, 1997 Sep-Oct, 43(5), 358 - 66
Cost-effectiveness of ceftriaxone and amikacin as single daily dose for the empirical management of febrile granulocytopenic children with cancer; Pession A et al.; In children undergoing anticancer chemotherapy, a granulocytopenic febrile episode is a life-threatening condition . Prompt initiation of empirical broad-spectrum antibiotics is essential to limit morbidity and mortality . To evaluate the cost-effectiveness of combination antibiotics consisting of a third generation cephalosporin and an aminoglycoside, a retrospective review of all febrile granulocytopenic patients admitted to our institution was conducted . Between June 1994 and August 1996, 183 febrile episodes in granulocytopenic children with cancer were empirically treated with ceftriaxone and amikacin in a single daily dose . 96/183 (52%) patients had absolute granulocyte count lower than 100/mm3 at the onset; 68 (37%) were affected by acute leukemia or lymphoma, 3 (1%) by chronic leukemia, 94 (51%) by solid tumors, and 21 (11%) patients underwent bone marrow transplantation . Ceftriaxone plus amikacin was effective in 135/183 (74%) patients with a median time to defervescence of 3 days (range 1-11) . Economic evaluation (cost minimization analysis) was limited to the cost savings for nonreusable materials, and difference in direct drug costs in comparison with another combination regimen such as ceftazidime and amikacin . This analysis showed that compared to a 3 times daily regimen, administration of single daily doses of ceftriaxone would result in a net cost saving of US$ 11 (17,500 Italian liras) and US$ 65.6 (105,000 Italian liras) for a 1-day and a 6-day treatment period, respectively, for the treatment of a child of 30 kg body weight . Moreover, once daily therapy has the potential to lead to savings in the time of the nursing staff and may well contribute to an improved quality of life for febrile granulocytopenic children . For these reasons, in our department, ceftriaxone plus amikacin still remain the standard regimen for the empirical treatment of febrile granulocytopenic children with cancer.

Infect Immun, 1997 Sep, 65(9), 3768 - 73
Exposure to low oxygen tension and increased osmolarity enhance the ability of Mycobacterium avium to enter intestinal epithelial (HT-29) cells; Bermudez LE et al.; Current evidence indicates that Mycobacterium avium infection in patients with AIDS is acquired mostly through the gastrointestinal (GI) tract and that M . avium binds to and invades GI mucosal cells in vitro . Since M . avium is exposed to specific environmental conditions in the GI tract such as changes in pH, low oxygen (O2) tension, increased osmolarity, and low concentration of iron, we investigated the effects of these conditions on the bacterium's ability to enter HT-29 intestinal cells . M . avium 101 (serovar 1) was cultured in 7H9 broth and then exposed to pH 4.5 to 8.0, low O2 tension, 0.1 to 0.3 M dextrose, and absence of iron for 2 h . After washing, bacteria (10(7)/ml) were used in the invasion assay . Confluent HT-29 cells were exposed to 10(6) bacteria for 1 h and then treated with amikacin (200 microg/ml) for 2 h to selectively kill extracellular but not intracellular M . avium . The supernatant was then removed, the monolayer was lysed, and the lysate was plated onto 7H10 agar plates . While exposure to acidic and basic pHs, as well as iron-free medium, had no significant effect on M . avium invasion of intestinal epithelial cells, low O2 tension and increased osmolarity enhanced invasion 11- and 9-fold, respectively, compared with the control . Exposure of M . avium to the combination of low O2 concentration and hyperosmolarity resulted in an approximate 10- to 15-fold increase in penetration of HT-29 cells . Hyperosmolarity and low O2 tension induced the invasive M . avium phenotype and can be useful for the identification of genes associated with M . avium invasion of intestinal mucosa.

J Clin Microbiol, 1997 Sep, 35(9), 2235 - 42
Recognition of a Nocardia transvalensis complex by resistance to aminoglycosides, including amikacin, and PCR-restriction fragment length polymorphism analysis; Wilson RW et al.; Amikacin resistance, rare among nocardiae, was observed in 58 clinical isolates of nocardiae . All of these isolates hydrolyzed hypoxanthine, and 75 to 100% utilized citrate, D-galactose, and D-trehalose as sole carbon sources . Based on utilization of I-erythritol, D-glucitol, i-myo-inositol, D-mannitol, and ribitol and susceptibility to amoxicillin-clavulanic acid, the 58 isolates were separable into four groups . One group was negative for I-erythritol and ribitol and included all the isolates belonging to Nocardia asteroides complex antibiogram type IV . The remaining three groups were positive for I-erythritol and ribitol and were grouped within Nocardia transvalensis . The group that included the type strain was designated N . transvalensis sensu stricto, and the other two groups were designated new taxons 1 and 2 . PCR-restriction fragment length polymorphism (RFLP) analysis of a 439-bp segment of the 65-kDa heat shock protein gene with XhoI and HinfI produced identical patterns for 53 (91%) and 58 (100%) isolates, respectively, and differentiated them from all other Nocardia taxa . NarI- and HaeIII-derived RFLP patterns clearly differentiated each of the four biochemically defined taxa . These four groups were also distinguishable by using the chromogenic substrates in Dade MicroScan test panels . By high-performance liquid chromatography, these isolates exhibited the same unique mycolic acid-ester elution patterns that differed from those of all other clinically significant nocardiae . Gas-liquid chromatographic analysis of fatty acids also produced similar patterns for all isolates that distinguished them from all other Nocardia taxa, but did not differentiate the four taxa within the complex . We propose the designation N . transvalensis complex for these four groups of nocardiae, pending further genetic evaluation.

J Chemother, 1997 Aug, 9(4), 247 - 50
Rapid drug susceptibility of Mycobacterium avium complex using a fluorescence quenching method; Marone P et al.; Mycobacteria Growth Indicator Tube (MGIT) is a recently introduced rapid growth detection method which uses an oxygen quenched fluorescent indicator . The present study evaluated the ability of this new method to determine the drug susceptibility of Mycobacterium avium complex (MAC) . Thirty strains recovered from patients with AIDS were tested for susceptibility to clarithromycin, rifabutin, ciprofloxacin, azithromycin and amikacin using MGIT . Results were compared to susceptibilities determined by the agar dilution method . The results obtained showed a 100% correlation between MGIT and the agar dilution method for rifabutin and clarithromycin . There was a 100% correlation between the two methods for azithromycin against 27 strains . MGIT was well correlated with the agar dilution method for detecting resistance to clarithromycin, rifabutin and azithromycin in 4 days, but the correlation was poor when susceptibilities to ciprofloxacin and amikacin were determined . This rapid method is non-radiometric, noninvasive and does not require any special instruments.

Am J Ophthalmol, 1997 Jul, 124(1), 114 - 5
Shewannela putrefaciens endophthalmitis after penetrating keratoplasty; Hou YC et al.; PURPOSE: To report a case of Shewannela putrefaciens endophthalmitis after penetrating keratoplasty . METHODS: Case report . Vitreous of the recipient and the preservative medium of donor cornea were cultured . RESULTS: Vitreous of the recipient eye and the donor eye corneal preservative medium both grew S putrefaciens . The patient failed to respond to intravitreal, topical, and systemic amikacin and cefotaxime . Vision was lost rapidly . Evisceration was performed . CONCLUSION: Shewannela putrefaciens should be considered as a potential pathogen contaminating donor cornea . Shewannela putrefaciens endophthalmitis is devastating and responds poorly to medical treatment.

J Antimicrob Chemother, 1997 Jun, 39(6), 677 - 86
Once-daily dosing of aminoglycosides: review and recommendations for clinical practice; Freeman CD et al.; The use of higher-dose, extended interval (i.e., once-daily) aminoglycoside regimens to optimize bacterial killing is justified by a pharmacodynamic principle of aminoglycosides, namely concentration-dependent killing, and by the partial attribution of the toxicity of aminoglycosides to prolonged serum concentrations . Numerous in-vitro and animal studies have supported using once-daily aminoglycoside dosing . Clinical studies show at least equal effectiveness and no greater toxicity when compared with traditional regimens . A dose of 5-7 mg/kg of gentamicin, tobramycin, or netilmicin, with at least a 24 h dosing interval should be employed and a similar regimen can be applied to amikacin dosing . As yet, there are some patient populations that have not been adequately studied to determine whether or not once-daily aminoglycoside dosing would be a better choice than traditional dosing regimens.

J Zoo Wildl Med, 1997 Mar, 28(1), 49 - 54
Disposition of single-dose intravenously administered amikacin in emus (Dromaius novaehollandiae); Helmick KE et al.; The pharmacokinetics of amikacin in emus (Dromaius novaehollandiae) was examined following parenteral administration . A mean 7.2 +/- 0.12 mg/kg dose was administered as a single i.v . bolus, and serum samples were collected at predetermined intervals over a 24-hr period . Amikacin levels were measured using a fluorescence polarization immunoassay, and the resulting concentration-versus-time curve was analyzed using nonlinear regression with least squares parameter estimation . The data were best represented by a three-compartment model with a mean elimination half-life (t1/2 beta) of 0.87 hr, with a longer rate of elimination from the third compartment (t1/2 gamma = 6.06 hr) . Mean model-independent parameters obtained were area under the curve (269.66 micrograms.hr/ml), mean residence time (6.48 hr), apparent volume of distribution (0.18 L/kg), and total body drug clearance (0.03 L/hr/kg) . Mean serum concentrations exceeded a target peak of 32.0 micrograms/ml and remained above an estimated inhibitory concentration of 8.0 micrograms/ml for approximately 12 hr . Mean serum levels had declined below a target trough of 4 micrograms/ml at 24 hr.

J Am Anim Hosp Assoc, 1997 Mar-Apr, 33(2), 126 - 8
Hepatocellular necrosis associated with the subcutaneous injection of an intranasal Bordetella bronchiseptica-canine parainfluenza vaccine; Toshach K et al.; A three-year-old wire fox terrier inadvertently was given an intranasal Bordetella bronchiseptica and canine parainfluenza vaccine subcutaneously . The dog subsequently developed both a local inflammatory reaction at the injection site and acute, nonseptic hepatocellular degeneration and necrosis . The patient was treated successfully with intravenous fluids and amikacin . Two months after the injection, the serum bile acid concentrations and hepatic histopathology indicated the presence of continued hepatocellular disease.

J Antimicrob Chemother, 1997 Mar, 39(3), 431 - 3
Pharmacokinetics and bronchial diffusion of single daily dose amikacin in cystic fibrosis patients; Canis F et al.; A single daily dose of amikacin 35 mg/kg by i.v . infusion over 30 min in 18 cystic fibrosis patients achieved mean serum peak and trough concentrations of 121.4 mg/L (+/- 37.3) and 0.88 mg/L (+/- 0.62), respectively . Pharmacokinetic parameters and bronchial diffusion of amikacin showed marked inter-patient variability . The highest concentrations in sputum were obtained at 2 h (10.95 +/- 7.55 mg/L) and decreased slowly to reach a mean concentration of 2.14 mg/L (range 0.2-3.8 mg/L) just before the following infusion . An increase in the body clearance of amikacin and a decrease in the volume of distribution according to age were observed.

J Antimicrob Chemother, 1997 Mar, 39(3), 355 - 61
Evaluation of Innofluor fluorescence polarization immunoassay kits for the determination of serum concentrations of gentamicin, tobramycin, amikacin and vancomycin.lesassays@ukneqasaa.win-uk.net; White LO et al.; The Innofluor fluorescence polarization immunoassay (FPIA) kits for gentamicin, tobramycin, amikacin and vancomycin were evaluated on an Abbott TDX analyser . Intra-assay reproducibility was excellent with a coefficient of variation of <3% for all analytes . The coefficient of variation for inter-assay reproducibility was usually <5% . Assay linearity was good and standard curve stability was seen with kits of the same batch for at least 32 days . Using clinical samples, the results obtained with the Innofluor FPIA reagents correlated well with those obtained using Abbott FPIA reagents, but Innofluor gentamicin and amikacin results were slightly higher than Abbott results (P < 0.001) . Results of UK NEQAS returns showed acceptable accuracy for the Innofluor kits, but mean Innofluor gentamicin returns were 4% higher (P = 0.001) and mean vancomycin returns were 5% lower (P = 0.001) than overall mean returns . Innofluor and Abbott vancomycin assay reagents showed similar cross-reactivity to degraded vancomycin.

J Ky Med Assoc, 1997 Mar, 95(3), 98 - 101
Tuberculosis in Kentucky: current recommendations for empiric therapy; Wojda B et al.; Current guidelines for empiric therapy for pulmonary tuberculosis depend on the presence of INH or INH and rifampin resistance (MDRTB) in the community . The objective of this study was to determine the susceptibility of MTB in Kentucky and to consider which therapeutic modality for empiric therapy should be followed . The total number and rate of pulmonary tuberculosis was analyzed and compared to national trends . Data of susceptibility were analyzed based on INH and rifampin resistance . There were 4753 cases of TB in Kentucky between 1984 and 1994 . Data of susceptibility were available from 1989 through 1994 . Total number of MTB decreased by 14% in 1994 from 1993 but resistance to INH doubled from 3.2% to 7.6% . MDRTB increased from 1.2% to 3.2% . INH resistance > 4% on initial isolates was recorded in Allen, Bell, Estill, Fleming, Jefferson, Kenton, Knott, Oldham, Rowan, and Wolfe counties . Outbreak of MDRTB was documented in Estill County . There was no HIV infection documented in this group . In the rest of the state, INH resistance was < 4% . In counties with INH resistance < 4%, empiric therapy for TB should include 3 drugs: INH and rifampin for 6 months and PZA added for the first 2 months . In counties with INH resistance > 4%, empiric therapy should include 4 drugs: INH, rifampin, PZA, ethambutol or streptomycin . In Estill County with documented MDRTB, empiric therapy should include 5 to 6 drugs: INH, rifampin, PZA, ethambutol, streptomycin, and amikacin . If INH and rifampin resistance is present, the therapy should include at least 3 drugs to which the organism is sensitive . This regimen should be continued until sputum cultures become negative . Further therapy should be continued with 2 drugs for 1 year . HIV infected patients constitute a separate category and therapy for them should be individualized.

Rev Panam Salud Publica, 1997 Feb, 1(2), 119 - 24
{Auditory provoked potentials in children with neonatal risk for hypoacusia}; Garza Morales S et al.; Auditory evoked potentials of the brain stem (AEPBS) provide a simple noninvasive method of evaluating hearing function and have been widely used for early detection of hypoacusis in children . Between April 1992 and May 1994, a study was done of 400 Mexican children who presented at least one neonatal risk factor for hearing impairment . The average age of the children studied was 6.6 months and their average gestational age at birth was 35.1 weeks . Just over half of them (51%) had been treated with amikacin . The study found 1427 risk factors (3.5 per child), the most common ones being exposure to ototoxic substances, hyperbilirubinemia, and birthweight of less that 1500 g . In 27% of the children, peripheral auditory changes were found, and 13% did not respond to auditory stimuli . Low birthweight and young gestational age at birth, high serum concentration of bilirubin, sepsis, subependymal or intraventricular hemorrhage, mechanical ventilation, and exposure to ototoxic substances were significantly associated with the presence of severe or profound hypoacusis.

Clin Pharmacokinet, 1997 Feb, 32(2), 132 - 44
Mycobacterium avium complex infection . Pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes; Peloquin CA; Mycobacterium avium complex (MAC) is an infrequent pulmonary pathogen in immunocompetent hosts . In patients with AIDS, MAC causes disseminated infection (DMAC) in up to 50% of those with CD4+ counts less than 100 cells/mm3 . A significant portion of the total body burden of MAC is found inside macrophages, and the distribution of organisms has implications for drug therapy . Clarithromycin, azithromycin, and rifabutin all appear to enter these cells well; rifampicin (rifampin), ethambutol, ciprofloxacin, and other agents also appear to enter these cells . MAC susceptibility is probably best tested using the radiometric method (BACTEC) . Susceptibility break-points have been proposed for the various anti-MAC agents; however, solid clinical correlations have been achieved only for clarithromycin . Further research is required to establish break-points for the other agents . Based on current data, azithromycin and clarithromycin appear to be key drugs in the treatment of MAC, while rifabutin has been used more often than rifampicin in studies involving patients with AIDS . Among the drugs traditionally used for M . tuberculosis (TB), ethambutol, rifampicin and streptomycin are perhaps the most useful for MAC . Amikacin and clofazimine may also be useful . The limited data available on AIDS patients with MAC, plus additional data from AIDS patients with TB, suggest that malabsorption of the oral antimycobacterial drugs is common . Some drugs (rifampicin and ethambutol) appear to be particularly affected . Because most of the studies of DMAC have not evaluated the pharmacokinetics of the drugs, questions of drug efficacy cannot be separated from questions of biovailability . This significant oversight in study design should be eliminated from future investigations . Patient-specific susceptibility data combined with therapeutic drug monitoring and dosage individualisation is one way to identify problems with drug therapy and to overcome them . Because many of the drugs used in patients with AIDS affect the metabolism of concurrently used drugs, therapeutic drug monitoring is a valuable asset for untangling multiple drug interactions . Since drug therapy is the only aspect of a mycobacterial infection within our control, the better we control the drug therapy, the better our patients should do.

J Bacteriol, 1997 Feb, 179(4), 1029 - 34
The Cpx two-component signal transduction pathway is activated in Escherichia coli mutant strains lacking phosphatidylethanolamine; Mileykovskaya E et al.; The CpxA-CpxR two-component signal transduction pathway of Escherichia coli was studied in a mutant (pss-93) lacking phosphatidylethanolamine (PE) . Several properties of this mutant are comparable to phenotypes of cpxA point mutants, indicating that this two-component pathway is activated in PE-deficient cells . In contrast to point mutants, cpx operon null mutants have a wild-type phenotype . By use of this information, a cpx operon null allele was introduced into a pss-93 mutant . Certain altered properties of PE-deficient mutants, which were consistent with activation of the Cpx pathway, returned to the wild-type phenotype, namely, active accumulation of proline and thiomethyl-beta-D-galactopyranoside was partially restored to wild-type levels, increased resistance to amikacin returned to wild-type sensitivity, and high levels of degP expression returned to repressed wild-type levels . Elevated levels of acetyl phosphate and nlpE gene product can result in activation of the Cpx pathway . However, inactivation of the nlpE gene or mutations eliminating the ability to make acetyl phosphate did not alter the high level of degP expression in pss-93 mutants . We propose that the lack of PE results in an alteration in cell envelope structure or physical properties, leading to direct activation of the Cpx pathway.

Am J Health Syst Pharm, 1997 Jan 15, 54(2), 181 - 4
Compatibility of commonly used bone marrow transplant drugs during Y-site delivery; Najari Z et al.; The Y-site compatibility of medications routinely used in bone marrow transplant patients was studied . Two methods were used to evaluate the compatibility of pairs of various i.v . drugs and nutrient fluids . In the first, the drugs were combined in a 1:1 ratio in test tubes, which were visually evaluated immediately and at 1, 4, and 24 hours under normal light and against a white background . The second method involved simulated infusion through a Y-site and a membrane filter . Filter disks were examined under 51 x magnification for precipitates . "Administration" time ranged from one minute to five hours . Most of the combinations were compatible . Exceptions (incompatibilities or inconclusive findings) were amikacin plus a total parenteral nutrient (TPN) admixture; cyclosporine plus dopamine hydrochloride, magnesium sulfate, ondansetron, a parenteral nutrient solution, the TPN admixture, or the TPN admixture with phytonadione; and heparin sodium in either 5% dextrose injection or 0.9% sodium chloride injection plus the TPN admixture or vancomycin . The two study methods were in agreement for all drug combinations except those involving cyclosporine . Cyclosporine in 0.9% sodium chloride injection yielded many fine particles on the filter disk . The combination of cyclosporine with other drugs did not appear to increase the number of particles on the disk, but the results must still be considered inconclusive . Two methods used to determine the compatibility of bone marrow transplant agents when mixed in a Y injection site yielded the same results, except for combinations involving cyclosporine . Most of the combinations were compatible.

Enferm Infecc Microbiol Clin, 1997 Jan, 15(1), 19 - 21
{Pulmonary nocardiosis: presentation of 3 clinical cases}; Ugedo J et al.; INTRODUCTION: Nocardiosis is an infectious disease that frequently involves to the respiratory tract . Nocardia asteroides is the predominant human pathogen . Nocardiosis is difficult to diagnose and that's why its incidence is not well established . CASES: Three cases diagnosed in a Pneumology Section are reported . None of them was affected by AIDS and all of them were initially diagnosed from bronchopneumonia . Empirical antibiotherapy was initiated and because of the unsatisfactory progress, bronchoscopy was performed in all cases and in one case a transthoracic puncture was made . Nocardia spp . was then isolated and this let to began with a specific treatment . All the patients progress satisfactorily in their respiratory infection . DISCUSSION: Although there are usually factors that predispose to nocardiosis, it can also occur in absence of these, as it happened in one of report patients . The clinical and radiological manifestations are not, in many cases enough to reach the diagnosis . Thus germ isolation is very important, and invasive procedures are often essential to obtain a quality samples to cultivate . Sulfonamides were considered drugs of choice, but nowadays, many authors propose trimethoprim-sulfamethoxazole . Imipenem, amikacin have also proved to be effective.

Int J Clin Pharmacol Ther, 1997 Jan, 35(1), 24 - 7
Population pharmacokinetics of amikacin in geriatric patients studied with the NPEM-2 algorithm; Debord J et al.; The population pharmacokinetics of amikacin were studied in 40 geriatric medicine patients (aged 59-95 years, average 78 years) by the NPEM-2 algorithm, using a 2-compartment model . The fitted parameters were: renal clearance of amikacin, expressed as a fraction of creatinine clearance (CLS) and volume of the central compartment, expressed as a fraction of body weight (VS) . The nonrenal clearance of amikacin (CLi) and the transfer constants between the 2 compartments (k12 and k21) were held constant . The distribution of each pharmacokinetic parameter was characterized by the median and the 50% dispersion factor (DF50) which is the interval between the 25th and 75th percentiles, divided by 1.32 . The parameters were thus estimated by the following values: CLs = 0.91 +/- 0.45 and Vs = 0.29 +/- 0.10 l x kg-1 . The volume of distribution was increased with respect to the usual value of 0.20 l x kg-1 . The interindividual variability was high, particularly for clearance . Although the median value of CLs was close to unity, indicating that for most patients the elimination kinetics of amikacin followed that of creatinine, there was a slight probability to observe much higher values of CLs (up to 5), indicating that for some aged patients the elimination of amikacin was less altered than that of creatinine . These parameters were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 20 patients by the Bayesian method, with 2 blood samples per patient . For each patient the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 hours with no significant bias and a precision of 3.5 mg x 1(-1) . This study confirms the ability of the NPEM-2 algorithm to provide reference population values for use in Bayesian monitoring of aminoglycoside therapy.

Clin Infect Dis, 1997 Jan, 24(1), 41 - 51
Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study . The French Cefepime Study Group; Cordonnier C et al.; We conducted a randomized multicenter study to compare the efficacy and safety of two antibiotic regimens (cefepime {2 g b.i.d.} plus amikacin or ceftazidime {2 g t.i.d.} plus amikacin) as first-line therapy for fever in patients with hematologic malignancies and neutropenia . A total of 353 patients were randomized according to a 2:1 (cefepime:ceftazidime) ratio . Two hundred-twelve patients in the cefepime group and 107 in the ceftazidime group (90% of all patients) were evaluable for efficacy . The polymorphonuclear neutrophil count was < 100/mm3 on enrollment for 70% of the patients . The mean duration of neutropenia was 26 days . The efficacy in both study arms was comparable, although a trend in favor of cefepime was seen in terms of therapeutic success (response rate, 27% vs . 21% for the ceftazidime group) . The overall response rate after glycopeptides were added to the regimens was 60% for the cefepime group and 51% for the ceftazidime group; the bacterial eradication rates were 81% vs . 76%, respectively, and the rates of new bacterial infections were 14% vs . 18%, respectively . We conclude that the combination cefepime/amikacin is at least as effective as the reference regimen of ceftazidime/amikacin in this setting.

J Chromatogr B Biomed Appl, 1996 Nov 15, 686(2), 205 - 10
Determination of amikacin in human plasma by high-performance capillary electrophoresis with fluorescence detection; Oguri S et al.; A selective and reproducible high-performance capillary electrophoretic (HPCE) method for the quantification of amikacin (AMK), an aminocyclitol antibiotic, in human plasma, has been developed for use in clinical laboratory tests . The method involves ultrafiltration (UF) of plasma before derivatization with the fluorescence derivatization reagent 1-methoxy-carbonylindolizine-3, 5-dicarbaldehyde at room temperature for 15 min in the dark . An aliquot of the derivatives is directly introduced into the fused-silica capillary {75 cm (effective length) x 50 microns I.D.} at the anode side by dynamic compression injection (50 hPa for 6 s) . After electrophoresis with 40 mM SDS-20 mM phosphate-borate buffer (pH 7) in the micellar electrokinetic chromatography (MEKC) mode at 30 kV, the derivative had a retention time of 16.7 min and was detected by fluorescence intensity at 482 nm (with irradiation at 414 nm) . The precision (n = 5) of the method is 4.08 and 1.59% (C.V.) at the 50 and 100 micrograms AMK/ml plasma levels, respectively . Linearity (r = 0.998) was established over the concentration range 5-100 mg of AMK/ml plasma and the detection limit (at a signal-to-noise ratio of 3) is 0.5 microgram AMK/ml plasma . This assay method could potentially have wider application in the determination of other aminocyclitol antibiotics, such as arbekacin, dibekacin, kanamycin, in human plasma as well as of AMK.

Bratisl Lek Listy, 1996 Nov, 97(11), 647 - 51
Imipenem-resistant Ps . aeruginosa bacteraemia in cancer patients: risk factors, clinical features and outcome; Krcmery V Jr et al.; Ninety nine patients with 101 bacteraemic episodes due to Ps . aeruginosa (PA) within 6 years were divided into two groups according to their resistance to imipenem-91 due to imipenem sensitive (ISPA) and 10 due to resistant (IRPA) . Risk factors, the clinical course and the outcome were evaluated and compared . Acute leukaemia, prolonged neutropenia, previous therapy with amikacin, third generation of cephalosporins, imipenem and prophylaxis by quinolones were significantly more frequently associated with IRPA . Imipenem resistant PA bacteraemia were associated with higher incidence of septic shock (40% vs 19.8%, p < 0.02) and death (33.3%) than ISPA bacteraemias . Since 1992, when first IRPA appeared, the incidence of imipenem resistance increased tenfold, and in 1994, up to 10% of PA causing bloodstream infections in cancer patients in our center were imipenem resistant . (Tab . 3, Ref . 8.).

Br J Ophthalmol, 1996 Nov, 80(11), 962 - 8
Non-tuberculous mycobacterial keratitis: a study of 22 cases; Huang SC et al.; AIM: To investigate causes and clinical findings of non-tuberculous mycobacterial keratitis, and to study its response to topical antibiotic therapy and surgical extirpative keratectomy . METHOD: A single centre, retrospective review of 22 patients with non-tuberculous mycobacterial keratitis seen in a 3 year period . Laboratory diagnoses were established with Ziehl-Nielsen acid fast staining and Lowenstein-Jensen cultures . RESULTS: In 20 patients (91%), there was an antecedent history of foreign body eye trauma (18 patients) or elective surgery (two patients) . There were 19 cases of Mycobacterium chelonei, and three of M fortuitum . Clinical signs included epithelial defects, satellite or ring stromal infiltrates, crystalline keratopathy, and hypopyon . For topical antibiotic therapy, 20 patients received amikacin, while one patient received rifampin and another received ciprofloxacin, each in accordance with the results of the in vitro drug sensitivities . An extirpative keratectomy was performed in 15 cases; four of these cases additionally required a temporary conjunctival flap in order to finally eradicate the infection . At the end of the follow up period (median 18 months; range 3 months to 3 years) all eyes were stable and free of infection, with 19 (86%) having final visual acuities of 20/200 or better . CONCLUSION: Early clinical recognition and prompt laboratory diagnosis, together with aggressive topical antibiotic therapy and early keratectomy, may shorten morbidity and improve the clinical outcome of non-tuberculous mycobacterial keratitis.

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