Cephalosporin

Microbiol Mol Biol Rev, 1998 Sep, 62(3), 547 - 85
Molecular regulation of beta-lactam biosynthesis in filamentous fungi; Brakhage AA; The most commonly used beta-lactam antibiotics for the therapy of infectious diseases are penicillin and cephalosporin . Penicillin is produced as an end product by some fungi, most notably by Aspergillus (Emericella) nidulans and Penicillium chrysogenum . Cephalosporins are synthesized by both bacteria and fungi, e.g., by the fungus Acremonium chrysogenum (Cephalosporium acremonium) . The biosynthetic pathways leading to both secondary metabolites start from the same three amino acid precursors and have the first two enzymatic reactions in common . Penicillin biosynthesis is catalyzed by three enzymes encoded by acvA (pcbAB), ipnA (pcbC), and aatA (penDE) . The genes are organized into a cluster . In A . chrysogenum, in addition to acvA and ipnA, a second cluster contains the genes encoding enzymes that catalyze the reactions of the later steps of the cephalosporin pathway (cefEF and cefG) . Within the last few years, several studies have indicated that the fungal beta-lactam biosynthesis genes are controlled by a complex regulatory network, e . g., by the ambient pH, carbon source, and amino acids . A comparison with the regulatory mechanisms (regulatory proteins and DNA elements) involved in the regulation of genes of primary metabolism in lower eukaryotes is thus of great interest . This has already led to the elucidation of new regulatory mechanisms . Furthermore, such investigations have contributed to the elucidation of signals leading to the production of beta-lactams and their physiological meaning for the producing fungi, and they can be expected to have a major impact on rational strain improvement programs . The knowledge of biosynthesis genes has already been used to produce new compounds.

Acta Otolaryngol, 1998 Jul, 118(4), 557 - 62
Epidemiology and treatment of otitis media with effusion in children in the first year of primary school; Marchisio P et al.; In this multicentre study we evaluated the prevalence and risk factors of otitis media with effusion (OME) in Italian school-children and the effectiveness of medical treatment of chronic OME with a new cephalosporin, ceftibuten . During two winter periods, 3413 children, aged 5 to 7 years, were examined for the presence of OME by means of pneumotoscopy and a portable, hand-held tympanometer . The prevalence of asymptomatic OME was 14.2%, with no difference as regards sex, age, month of examination or geographic area . Younger children had significantly more bilateral than unilateral effusion . A recent episode of acute otitis media and previous tonsillectomy or adenoidectomy were associated with an increased risk of OME in multivariate logistic regression models . The presence of OME was unrelated to such factors as birthweight, prematurity, sibling or parental history of allergy, duration of daycare attendance, family history of ear infections . After 12 weeks, 26.6% of children with OME still had middle-ear fluid: 52 were randomized to ceftibuten (9 mg/kg q.d . for 14 days) and 59 to no treatment (nasal saline drops allowed) . Children treated with ceftibuten had a significantly better resolution of middle-ear effusion after 4 and 8 weeks . As mass screening programmes for OME in the year of school entry are questioned, a focus only on children with known risk factors seems advisable . Ceftibuten can be useful in reducing the duration of middle-ear effusion.

J Antimicrob Chemother, 1998 Jul, 42(1), 95 - 8
Interaction of ceftriaxone with penicillin-binding proteins of Escherichia coli in the presence of human serum albumin; Fontana R et al.; The binding of ceftriaxone, a cephalosporin that exhibits high serum protein binding and prolonged serum half-life, to penicillin-binding proteins (PBPs) of Escherichia coli K12 in the presence of human serum albumin was compared with plasma concentrations of cefotaxime, a cephalosporin with low serum protein binding and a short serum half-life . Ceftriaxone concentrations equivalent to those maintained in plasma for 8 h after an intravenous infusion of 1 g saturated PBPs 2 and 3 . Cefotaxime saturated both PBPs at concentrations equivalent to those maintained for 2 h, and PBP 3 only at concentrations maintained for 2-8 h . These results indicate that high serum protein binding does not impair the ability of ceftriaxone to inhibit essential PBPs, and explain the high in-vivo efficacy of the drug.

J Pharm Biomed Anal, 1998 Aug, 17(4-5), 871 - 5
ESR spectroscopy applied to the study of pharmaceuticals radiosterilization: cefoperazone; Basly JP et al.; As an alternative to heat and gas exposure sterilization, ionizing radiation is gaining interest as a sterilization process for medicinal products . Nevertheless, essentially for economic profits, an unauthorized and uncontrolled use of radiation process may be expected . In this context, it is necessary to find methods distinguishing between irradiated and unirradiated pharmaceuticals and, in the absence of suitable detection methods, our attention was focused on ESR spectrometry . In this paper, we examine the potential of ESR as an analytical tool in cefoperazone radiosterilization; this cephalosporin is a potential candidate for radiation treatment due to its thermosensitivity . While the ESR spectra of unirradiated sample present no intensity, a signal, dependent of the irradiation dose, is found exclusively in irradiated samples . The number of free radicals (2 x 10(17) radicals per g at 25 kGy) was estimated by comparison of the second integral from radiosterilized samples and DPPH . From this, the G-value could be estimated to 0.3 . Limit of detection and limit of quantification are 0.5 kGy and 1 kGy, respectively . Aside from qualitative detection, ESR can be used for dose estimation . The dose-ESR response curves can be simulated by bi-exponential or power functions and the linear function can't be used for simulation even for low doses . Decay of radicals upon storage were simulated using bi-exponential function . The limit of detection of free radicals after irradiation at 25 kGy is 140 days.

Antimicrob Agents Chemother, 1998 Jul, 42(7), 1718 - 21
Pharmacokinetic study of an oral cephalosporin, cefdinir, in hemodialysis patients; Hishida A et al.; The pharmacokinetics of cefdinir were investigated in six hemodialysis patients . For the present study, two tests were carried out, one with 4 h of hemodialysis and the other without hemodialysis . Cefdinir was given orally to each patient in a dose of 100 mg, and blood was collected serially for 48 h after dosing in the test without dialysis and for 72 h in the test with dialysis . In the test without dialysis, the maximum plasma concentration (Cmax) was 2.36 +/- 0.53 micrograms/ml (mean +/- standard deviation) and the time to Cmax was 9.00 +/- 2.45 h . The terminal elimination half-life (t1/2) and area under the concentration-time curve (AUC) were 16.95 +/- 1.20 h and 69.05 +/- 14.84 micrograms.h/ml, respectively . In the test with dialysis, t1/2 during hemodialysis decreased approximately to one-sixth of that obtained in the test without dialysis, although t1/2 in the latter elimination phase did not differ from that in the nondialysis test . AUC was reduced to 43% of that in the test without dialysis . The fractional removal of cefdinir by hemodialysis was 61% . These findings indicate that clearance of cefdinir is prolonged in patients with renal failure, and cefdinir is well removed by introduction of hemodialysis, although t1/2 (during hemodialysis) and AUC were two and eight times higher than the data previously reported for healthy volunteers, respectively . The pharmacokinetic data suggest that 100 mg of oral cefdinir once a day would result in a sufficient concentration in plasma in hemodialysis patients, but this remains to be confirmed by multiple-dose studies.

Semin Neurol, 1998, 18(2), 185 - 96
Pearls and pitfalls in the diagnosis and management of central nervous system infectious diseases; Roos KL; Laboratory techniques for the diagnosis of central nervous system (CNS) infections are rapidly improving but at present have limitations that necessitate our guarded enthusiasm . Enteroviruses are the most common infectious agents of viral meningitis for which an etiology can be determined, and it is anticipated that the use of the reverse transcriptase polymerase chain reaction (RT-PCR) technique should significantly improve the identification of the etiologic agent of aseptic meningitis . The combination of the polymerase chain reaction technique with laboratory methods for the determination of intrathecal antibody production to herpes simplex virus and varicella-zoster virus have improved the rapidity with which these viral infections can be diagnosed . The pearls and pitfalls of the use of these laboratory techniques in the diagnosis of viral meningitis, recurrent meningitis, and focal encephalitis are included . Recommendations for the empiric therapy of bacterial meningitis in children and adults have changed because of the emergence of penicillin and cephalosporin-resistant pneumococcal organisms . The currently recommended antibiotics and their dosages are included . The evidence for the efficacy of dexamethasone therapy in bacterial meningitis is provided . Meningitis due to Mycobacterium tuberculosis is increasingly recognized, and the initiation of empiric antituberculous chemotherapy should not await the results of CSF cultures . Toxoplasma encephalitis and primary CNS lymphoma are the most common cause of mass lesions in patients with HIV, and the diagnostic techniques to distinguish between these two infections is reviewed . A short discussion of the best test for the diagnosis of neurosyphilis is provided.

Folia Microbiol (Praha), 1998, 43(1), 68 - 70
In vitro susceptibility of 90 penicillin-susceptible and -resistant pneumococci to penicillin G, amoxicillin, amoxicillin/clavulanate, cefaclor, cefuroxime, cefpodoxime, cefixime and imipenem; Hupkova H et al.; In vitro susceptibility of eight antibiotics was compared using three groups of pneumococci and agar dilution method comprising 30 penicillin-susceptible, 30 intermediately penicillin-resistant, and 30 highly penicillin-resistant pneumococci . Decreased sensitivity to all beta-lactam agents of intermediately penicillin-resistant and highly penicillin-resistant pneumococci is shown . MIC50 and MIC90 was lower with amoxicillin with and without clavulanate by one dilution than with penicillin . Cephalosporin MIC90s were all significantly higher for intermediately resistant and fully resistant strains . Only imipenem was more active than penicillin with MIC90 of susceptible pneumococci 0.015 mg/L, intermediately resistant pneumococci 0.25 mg/L, resistant pneumococci 1 mg/L.

Antimicrob Agents Chemother, 1998 Apr, 42(4), 921 - 6
Overexpression, purification, and characterization of the cloned metallo-beta-lactamase L1 from Stenotrophomonas maltophilia; Crowder MW et al.; The metallo-beta-lactamase L1 from Stenotrophomonas maltophilia was cloned, overexpressed, and characterized by spectrometric and biochemical techniques . Results of metal analyses were consistent with the cloned enzyme having 2 mol of tightly bound Zn(II) per monomer . Gel filtration chromatography demonstrated that the cloned enzyme exists as a tightly held tetramer with a molecular mass of ca . 115 kDa, and matrix-assisted laser desorption ionization and time-of-flight mass spectrometry indicated a monomeric molecular mass of 28.8 kDa . Steady-state kinetic studies with a number of diverse penicillin and cephalosporin antibiotics demonstrated that L1 effectively hydrolyzes all tested compounds, with k(cat)/Km values ranging between 0.002 and 5.5 microM(-1) s(-1) . These characteristics of the recombinant enzyme are contrasted to those previously reported for metallo-beta-lactamases isolated directly from S . maltophilia.

Bioconjug Chem, 1998 Mar-Apr, 9(2), 255 - 9
Development and activities of a new melphalan prodrug designed for tumor-selective activation; Kerr DE et al.; The synthesis of C-Mel, a cephalosporin carbamate derivative of the clinically used alkylating agent melphalan, is described . C-Mel was designed as an anticancer nitrogen mustard prodrug that releases melphalan upon tumor-specific activation by targeted beta-lactamase (bL) . The Km and kcat values for bL hydrolysis of C-Mel were 218 microM and 980 s(-1), respectively . In vitro cytotoxicity assays with 3677 human melanoma cells demonstrated that C-Mel was 40-fold less toxic than melphalan and was activated in an immunologically specific manner by L49-sFv-bL, a recombinant fusion protein that binds to the melanotransferrin antigen on melanomas and on some carcinomas . L49-sFv-bL in combination with C-Mel led to regressions and cures of established subcutaneous 3677 tumors in nude mice . The effects were significantly greater than those of melphalan, which did not result in any long-term regressions in this tumor model . The therapeutic effects were comparable to those obtained in mice treated with the previously described L49-sFv-bL/7-(4-carboxybutanamido)-cephalosporin mustard (CCM) combination . However, C-Mel may be more attractive than CCM for clinical development since the released drug is clinically approved.

Chest, 1998 Mar, 113(3 Suppl), 183S - 187S
Community-acquired pneumonia guidelines--an international comparison: a view from Europe; Woodhead M; Following an outline that details the pathogens causing community-acquired pneumonia (CAP) identified in studies from Europe, this article reviews the guidelines for the management of CAP in four European countries--France, Italy, Spain, and the United Kingdom . The method behind the development of each document is described, followed by a comparison of the scope of each document . All four documents provide guidelines for the management of two groups of patients--the severely ill and the nonseverely ill patient . A penicillin or macrolide feature for the nonseverely ill and the combination of a third-generation cephalosporin plus a macrolide for the severely ill patient are described in all four guidelines . Despite their different origins and methods, these four guidelines have more similarities than differences--the latter serving to emphasize some of the areas that require further research in this important condition . An important area for research is the impact that these guidelines have on practice and especially on clinical outcomes.

Toxicol Pathol, 1998 Jan-Feb, 26(1), 52 - 7
The role of transport in chemical nephrotoxicity; Berndt WO; Various physiologic factors play a role in determining the extent of chemical-induced nephrotoxicity . One such factor relates to the transport systems that exist in the kidney . Several examples can be given of organic substances that are nephrotoxic only after being transported into renal tubular cells . Some of the cephalosporin antibiotics have been shown to produce proximal tubular necrosis after transport into those cells . Blockade of transport by competitors eliminates or reduces the nephrotoxic response . Citrinin, a secondary product of fungal metabolism, also produces proximal tubular necrosis, but only after transport into proximal tubular cells . Both the cephalosporins and citrinin utilize the organic anion transporter for entry into the cells, a transporter present in adult animals of all species and probably important physiologically for moving metabolic substrates into cells . Various glutathione conjugates (e.g., S-(1,2-dichlorovinyl) glutathione {DCVG}) also are transported into proximal tubular cells with a resulting nephrotoxicity . DCVG utilizes the sodium-dependent transport process that moves glutathione into proximal tubular cells, a process that is inhibited by probenecid . Finally, certain heavy metals also are transported into renal tubular cells . For example, mercuric ion enters proximal cells both from the luminal and peritubular sides and sulfhydryl compounds modify the transport . Movement of mercury from the peritubular side of the cell may be modified by certain organic anions . The characteristics of these mechanisms are less well understood than the mechanisms for the organic compounds.

Otolaryngol Pol, 1997, 51(4), 390 - 5
{The evaluation of ceftibuten (Cedax) effectiveness in the prevention of perioperative infections}; Szmeja Z et al.; Cedax is the antibiotic drug of the third generation cephalosporin type . In the Department of Otolaryngology of the University Medical School in Poznan tests were carried out on the effectiveness of this drug in the prevention of perioperative infections (tonsillectomy, adenotomy, septoplastics, nasal polypectomy, mucotomy) . The experiment comprised 50 patients who were administered Cedax once a day of the period of five consecutive days, beginning on the day of the surgery . Control group compare 50 patients who did not receive the antibiotic cover . For the comparison of both groups the following symptoms were taken into account: general condition of the patient, body temperature in the first few days after the surgery, the healing of the operative wound (the condition of mucosa, healing "per primam" or "per secundam"), the presence and type of nasal discharge . A high degree of efficiency of ceftibuten has observed.

Clin Chem, 1998 Feb, 44(2), 408 - 14
Clinical outcome and economic impact of aminoglycoside peak concentrations in febrile immunocompromised patients with hematologic malignancies; Binder L et al.; The aim of this study was to investigate the clinical and economic significance of aminoglycoside peak concentrations in febrile neutropenic patients with hematologic malignancies . Sixty-one patients were treated according to protocol II of the Paul-Ehrlich-Gesellschaft: initial application of gentamicin or tobramycin in combination with a cephalosporin or ureidopenicillin and, after 3 days, a potential change of antibiosis to be decided in case of nonresponse . At the same time, samples were collected by an independent controller . We found a significant dependence of clinical outcome on aminoglycoside peak concentrations (P = 0.004) . Twelve of 17 patients with peak concentrations > 4.8 mg/L, but only 13 of 44 patients with concentrations < or = 4.8 mg/L, responded to initial therapy . Average infection-related costs per patient with peak values > 4.8 mg/L were US$1429, $1790, and $1701 for nursing, diagnostics, and therapeutics, respectively (total $4920) . Expenses for patients with peak concentrations < or = 4.8 mg/L were approximately 1.8-fold higher (average total $8718) . If all 61 patients had achieved peaks > 4.8 mg/L, the potential savings would have totalled $167,112 . We conclude that neutropenic patients form a target group for successful pharmacokinetic intervention and cost saving.

J Pediatr, 1998 Jan, 132(1), 137 - 43
Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge; Pichichero ME et al.; The specificity of pediatrician-diagnosed allergy reactions to penicillin, amoxicillin, and oral cephalosporins, which was based on contemporaneous examination of the patient, was evaluated by an elective skin testing program . Children and adolescents (n = 247) experiencing an adverse reaction to penicillin, amoxicillin, and/or an oral cephalosporin sufficient to lead to the recommendation to avoid further use were enrolled . Skin testing with penicillin G, commercial benzylpenicilloyl phosphate, penicillin minor determinate mixture, ampicillin, cefazolin, cefuroxime, and ceftriaxone was performed according to the suspected drug allergy followed by an oral challenge, repeat testing, and prospective follow-up if no reactions were observed . Overall, 84 (34.0%) of 247 patients had an IgE-type reaction on skin testing or oral challenge . Twenty-seven (32%) of 85 suspected penicillin reactions, 53 (34%) of 156 suspected amoxicillin reactions, and 13 (50%) of 26 suspected cephalosporin reactions were shown to be IgE mediated . Positive skin tests were observed in 20 patients with non-IgE-type clinical adverse reactions, including 15 patients with only a pruritic polymorphous rash . No reactions to oral challenge were severe after negative skin testing . One hundred sixty-three patients received multiple treatment courses with beta-lactam antibiotics after a negative skin testing procedure and three (1.8%) had adverse IgE reactions, all of which were mild . Physician-diagnosed allergic reactions to beta-lactam antibiotics based on patient examination at the time of the reaction is more accurate than patient history alone but still overestimates the rate of possible true allergy in 66% of patients . Elective penicillin, amoxicillin, and cephalosporin skin testing and oral challenge protocols are necessary to identify patients not at risk.

Pharmacotherapy, 1998 Jan-Feb, 18(1), 175 - 83
Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections; Messick CR et al.; We conducted a retrospective pharmacoeconomic analysis of a prospective, multicenter, double-blind, randomized, controlled trial comparing the beta-lactamase inhibitor combination ampicillin-sulbactam (96 patients) and the cephalosporin cefoxitin (101) in the treatment of intraabdominal infections . An institutional perspective was adopted for the analysis . The primary outcomes of interest were cure and failure rates, development of new infection, and antibiotic-related adverse events . Epidemiologic data pertaining to outcomes was retrieved primarily from the trial, although results of other published studies were taken into consideration through extensive sensitivity analyses . Data pertaining to potential resource use and economic impact were retrieved mainly from the University Health Consortium and hospital-specific sources . When considering only costs associated with drug acquisition through cost-minimization analysis, a potential savings of $37.24/patient may be realized with ampicillin-sulbactam relative to cefoxitin based on an average 7-day regimen . Outcome data collected for the entire hospitalization during the trial revealed an approximately 9% greater frequency of failure with cefoxitin relative to ampicillin-sulbactam . When considering all outcomes of interest in the initial base-case analysis, a potential cost savings of approximately $890/patient may be realized with ampicillin-sulbactam relative to cefoxitin . In assessing the impact of the significant variability in probability and cost estimates, Monte Carlo analysis revealed a savings of $425/patient for ampicillin-sulbactam over cefoxitin (95% CI -$618 to $1516 {corrected}) . Given the model assumptions, our analysis suggests a 78% certainty level that savings will be experienced when ampicillin-sulbactam is chosen over cefoxitin.

Chem Biol, 1995 Apr, 2(4), 223 - 7
Synthesis and beta-lactamase-mediated activation of a cephalosporin-taxol prodrug; Rodrigues ML et al.; BACKGROUND: Enzyme-activatable prodrugs in conjunction with antibody-enzyme fusion proteins may enhance the anti-tumor efficacy of antibodies and reduce the toxic side effects of conventional chemotherapeutics . Cephalosporins have proven to be highly versatile triggers for the enzymatic activation of such prodrugs . RESULTS: A cephem prodrug of taxol (PROTAX) was synthesized by substituting the C-3' position of cephalothin with 2'-(gamma-aminobutyryl) taxol . Hydrolysis of PROTAX by beta-lactamase rapidly released 2'-(gamma-aminobutyryl) taxol (kcat/K(M) = (1.4 +/- 0.1) x 10(5) s-1 M-1), which yielded taxol following intramolecular displacement . PROTAX is inactive in a microtubule assembly assay in vitro but has similar activity to taxol following prolonged activation with beta-lactamase . PROTAX is approximately 10-fold less toxic than taxol against SK-BR-3 breast tumor cells in vitro but has activity approaching that of taxol following prolonged activation with a fusion protein comprising beta-lactamase fused to a tumor-targeting antibody fragment . CONCLUSIONS: Tubulin polymerization activity is abolished and cytotoxicity is reduced in the PROTAX prodrug compared to taxol . Activation of PROTAX by beta-lactamase followed by self-immolation restores the activity of PROTAX to that of free taxol.

J Pharm Sci, 1998 Jan, 87(1), 53 - 8
A kinetic oxymoron: concentration-dependent first-order rate constants for hydrolysis of ceftazidime; Fubara JO et al.; The influence of pH, temperature, and buffers on the hydrolysis of 10(-4) M ceftazidime was previously reported . The pH-rate profiles showed that maximum stability occurred in the pH-independent region from 4.5 to 6.5 . In the present study, hydrolysis rates of 0.031, 0.14, 0.25, and 0.35 M ceftazidime were measured at 30 and 65 degrees C, pH 5.5-6.2 . The data were consistent with beta-lactam hydrolysis and the rapid release of pyridine . The sum of the time-dependent concentrations of ceftazidime and pyridine provided mass balance . Simultaneous nonlinear regression for ceftazidime loss and pyridine formation provided similar rate constants (k) to those determined from first-order plots of ceftazidime loss . Although the loss of ceftazidime was first-order for each initial concentration, the k values increased as the initial concentrations increased . Plots of k versus initial concentration were linear with intercepts similar to the k values for 10(-4) M solutions, thus implying that ceftazidime catalyzed its own degradation . At the pH of these studies ceftazidime exists as a base . The ceftazidime catalytic constant, calculated from the slope of the plot, was similar to that found for the general-base catalyst, HPO4(2-) . Therefore, it is feasible that ceftazidime also behaved as a intermolecular general-base catalyst . However, first-order plots exhibited excellent linearity even though the catalyst (ceftazidime) was consumed . This would require that the catalytic moieties on ceftazidime remained relatively constant throughout its hydrolysis . This hypothesis was shown to be consistent with literature reports which indicate that the general-base catalytic groups can remain relatively constant during cephalosporin hydrolysis.

J Ind Microbiol Biotechnol, 1997 Nov-Dec, 19(5-6), 334 - 43
Evolving enzyme technology for pharmaceutical applications: case studies; Yeh WK; The case studies focus on two types of enzyme applications for pharmaceutical development . Demethylmacrocin O-methyltransferase, macrocin O-methyltransferase (both putatively rate-limiting) and tylosin reductase were purified from Streptomyces fradiae, characterized and the genes manipulated for increasing tylosin biosynthesis in S . fradiae . The rate-limiting enzyme, deacetoxycephalosporin C (DAOC) synthase/hydroxylase (expandase/ hydroxylase), was purified from Cephalosporium acremonium, its gene over-expressed, and cephalosporin C biosynthesis improved in C . acremonium . Also, heterologous expression of penicillin N epimerase and DAOC synthase (expandase) genes of Streptomyces clavuligerus in Penicillium chrysogenum permitted DAOC production in the fungal strain . Second, serine hydroxymethyltransferase of Escherichia coli and phthalyl amidase of Xanthobacter agilis were employed in chemo-enzymatic synthesis of carbacephem . Similarly, echinocandin B deacylase of Actinoplanes utahensis was used in the second-type synthesis of the ECB antifungal agent.

BMJ, 1997 Dec 20-27, 315(7123), 1645 - 9
Risk factors for winter outbreak of acute diarrhoea in France: case-control study; Letrilliart L et al.; OBJECTIVES: To assess the potential role of consumption of shellfish (particularly raw oysters) and tap water in the winter epidemic of acute diarrhoea in France . DESIGN: Population based, case-control study during the 1995-6 winter epidemic of acute diarrhoea in France . SETTING: A national network comprising 1% of general practitioners in France . SUBJECTS: 568 pairs of cases and controls consulting in general practice and interviewed by 209 doctors from 26 December 1995 to 31 January 1996 . Cases and controls were matched for age, doctor, and time of consultation . MAIN OUTCOME MEASURES: Adjusted relative risk of diarrhoea estimated from conditional logistic regression . RESULTS: The risk of acute diarrhoea was not increased in people who had recently eaten raw oysters (odds ratio 1.1; 95% confidence interval 0.9% to 1.4%) or other shellfish such as clams, cockles, and mussels, or in those people who usually consumed tap water rather than bottled water (0.8; 0.6% to 1.1%) . The risk was, however, increased in people who had had recent contact wit ha person with diarrhoea either within the household (adjusted odds ratio 5.0) or in the workplace (3.1), and in people who lived with a child < or = 2 years of age (1.6) . Recent treatment with either oral penicillin or cephalosporin was also independently associated with acute diarrhoea in winter . CONCLUSIONS: The winter epidemic of acute diarrhoea in France is probably not caused by consumption of either shellfish or tap water . A viral aetiology, however, is suggested by the speed with which the acute diarrhoea is transmitted.

J Orthop Trauma, 1998 Jan, 12(1), 1 - 7
Treatment of type II, IIIA, and IIIB open fractures of the tibial shaft: a prospective comparison of unreamed interlocking intramedullary nails and half-pin external fixators; Henley MB et al.; OBJECTIVE: To compare unreamed intramedullary nailing (IMN) with external fixation (EF) in patients with Type II, IIIA, and IIIB open fractures of the tibial shaft . DESIGN: An inception cohort of consecutive patients with Type II, IIIA, and IIIB tibial fractures incurred between January 1988 and March 1993 were systematically allocated into one of two treatment groups . Patients were treated and followed with a prospectively designed protocol . PATIENTS AND SETTING: All patients were skeletally mature and had incurred a fracture of the tibial diaphysis within twenty-four hours of presentation to the tertiary care hospital, a Level I Trauma Center . One hundred seventy-four fractures in 168 patients were stabilized with either IMN (104) or half-pin EF (70) . There were 132 men and thirty-six women, with an average age of thirty-three years (range, 14 to 77 years) . INTERVENTION: Except for the selection of the fixation device, open fracture care was similar in the two treatment groups . All patients underwent emergent irrigation and debridement with concomitant skeletal stabilization . Cephalosporin antibiotics were administered perioperatively for twenty-four to forty-eight hours . No wounds were closed primarily . Delayed primary closure, skin grafting, and/or myoplasty were performed between three and ten days after injury . MAIN OUTCOME MEASURES: The main outcome measures were final fracture alignment, presence of infection or inflammation, hardware failure, time to union, and the number of operative procedures . RESULTS: The IMN group had significantly fewer incidences of malalignment than did the EF group {8 vs . 31 percent; p = 0.00005; confidence interval (CI) = 0.18, 0.76} and had significantly fewer subsequent procedures (mean of 1.7 vs . mean of 2.7 per fracture; p = 0.001; CI = 0.45, 1.59) . IMN resulted in fewer infections/ inflammatory problems than did EF at the injury site (13 vs . 21 percent; p = 0.73; CI = -0.63, 0.45) and significantly fewer at surgical interfaces (i.e., pin sites, nail and interlocking screw insertion sites; 2 vs . 50 percent; p = 0.000; CI = 0.39, 0.60) . No significant difference was found in the healing rates for the two implant groups . The more severe Gustilo injury types had longer healing times regardless of the type of fixation . CONCLUSIONS: Results suggest that unreamed interlocking intramedullary nails are more efficacious than half-pin external fixators, in particular with regard to maintenance of limb alignment . However, the severity of soft tissue injury rather than the choice of implant appears to be the predominant factor influencing rapidity of bone healing and rate of injury site infection.

Appl Microbiol Biotechnol, 1997 Nov, 48(5), 606 - 14
Expression of the cefG gene is limiting for cephalosporin biosynthesis in Acremonium chrysogenum; Gutierrez S et al.; The conversion of deacetylcephalosporin C to cephalosporin C is inefficient in most Acremonium chrysogenum strains . The cefG gene, which encodes deacetylcephalosporin C acetyltransferase, is expressed very poorly in A . chrysogenum as compared to other genes of the cephalosporin pathway . Introduction of additional copies of the cefG gene with its native promoter (in two different constructions with upstream regions of 1056 bp and 538 bp respectively) did not produce a significant increase of the steady-state level of the cefG transcript . Expression of the cefG gene from the promoters of (i) the glyceraldehyde-3-phosphate dehydrogenase (gpd) gene of Aspergillus nidulans, (ii) the glucoamylase (gla) gene of Aspergillus niger, (iii) the glutamate dehydrogenase (gdh) and (iv) the isopenicillin N synthase (pcbC) genes of Penicillium chrysogenum, led to very high steady-state levels of cefG transcript and to increased deacetylcephalosporin-C acetyltransferase protein concentration (as shown by immunoblotting) and enzyme activity in the transformants . Southern analysis showed that integration of the new constructions occurred at sites different from that of the endogenous cefG gene . Cephalosporin production was increased two- to threefold in A . chrysogenum C10 transformed with constructions in which the cefG gene was expressed from the gdh or gpd promoters as a result of a more efficient acetylation of deacetylcephalosporin C.

J AOAC Int, 1997 Nov-Dec, 80(6), 1220 - 8
Induction and characterization of multianalyte antibodies against penicillins in egg yolk; de Leuw P et al.; Antibodies against penicillins were induced in eggs of laying hens after immunization with 6-aminopenicillanic acid (6-APA) coupled to key-hole limpet hemocyanin (KLH) . Development of the antibody titer was monitored by an indirect enzyme-linked immunosorbent assay (ELISA), with 6-APA coupled to ovalbumin as antigen for coating microtiter plates . Different characteristics (time course, affinity) of the immune reaction were observed by testing eggs of individual hens . Titer values varied between 150 and 2000 . Antibodies were isolated by polyethylene glycol precipitation and affinity chromatography, using a hapten sorbent with 6-APA as ligand . Glycine buffer, pH 3.0, was used to elute the immunoglobulins . Antibody specificity was determined in a competitive ELISA with 7 penicillins and the cephalosporin cephalexin as competitors . Cross reactivities for the penicillins were between 100 and 290% (6-APA = 100%) . Cephalexin cross reacted only marginally (3%).

Enferm Infecc Microbiol Clin, 1997 Oct, 15 Suppl 3, 41 - 6
{Severe community-acquired pneumonia}; Insausti J et al.; There is no precise definition for severe community-acquired pneumonia (SEHP), but there are a number of factors which are associated with a greater severity, and which therefore recommended the admission of these patients in an intensive care unit (ICU) . In the present article, we mainly refer to SEHP in the immune competent population . SEHP makes up 8-10% of the total number of admissions of an ICU although this depends greatly on the type of unit concerned . The majority of patients admitted, do so because they need mechanical ventilation, because they present a shock situation, or because they develop a multi-organ failure in the course of the disease . The battery of usual tests recommended basically includes a chest x-ray, arterial gas, a count of red and white blood cells, biochemical profile, blood cultures, analysis and culture of the pleural liquid (if this is present), and respiratory samples . The therapeutic strategies tend to guarantee the simultaneous coverage of S . pneumoniae, H . influenzae, and the so-called atypical pathogens . Keeping in mind the considerable percentage of penicillin resistant pneumococcus existing in our country, in a general manner it is recommended to use a combination of a macrolide with a 3rd generation cephalosporin against this organism . They should be detected early, especially those situations in which there is respiratory failure and shock which shall require the use of mechanical ventilation and inotropics as well as an adequate monitoring.

Appl Environ Microbiol, 1997 Dec, 63(12), 4807 - 11
Purification and characterization of a cephalosporin esterase from Rhodosporidium toruloides; Politino M et al.; A novel cephalosporin esterase (EC 3.1.1.41) from Rhodosporidium toruloides was purified to gel electrophoretic homogeneity . The enzyme is a glycoprotein with a molecular mass of 80 kDa . Upon deglycosylation, several forms of the enzyme were observed with a molecular mass range between 60 and 66 kDa . The isoelectric point of the enzyme is approximately 5.6, with the pH optimum for activity occurring at 6.0 . The optimal activity of the enzyme occurred at 25 degrees C, with the enzyme rapidly losing activity at temperatures above 25 degrees C . The enzyme deacetylated a variety of cephalosporin derivatives, including cephalosporin C; the Km for this substrate is 51.8 mM, and the Vmax is 7.9 mumol/min/mg . In addition to cephalosporins, the enzyme hydrolyzed short-chain p-nitrophenyl esters, with the activity decreasing with increasing ester chain length . The enzyme also has the ability to acetylate desacetyl cephalosporins in high yields under mild conditions in the presence of various acetyl donors . A comparison of the physical properties of the esterase with those of other well-characterized cephalosporin esterases indicates that the enzyme is unique in this class.

Allergol Immunopathol (Madr), 1997 Sep-Oct, 25(5), 247 - 8
Fixed drug eruption from amoxycillin; Jimenez I et al.; We present a case of fixed drug eruption on the genital mucosa induced by amoxycillin . Topical provocation was carried out, applying amoxycilin (10% pet) on the glans penis . No reaction was observed . Oral challenge with amoxycillin was followed by pruritic erythema on the glans penis 6 hours after the intake of 125 mg . The study of cross-reactivity to other betalactams showed good tolerance of phenoxymethyl-penicillin, which shares an identical nuclear structure with amoxycillin . The patient also tolerated cephadroxil, a cephalosporin with a side chain identical to that of amoxycillin . On reviewing the literature we have only found three reports of fixed drug eruption fue to amoxycillin.

Am J Obstet Gynecol, 1997 Oct, 177(4), 831 - 4
Randomized trial of single-dose versus multiple-dose cefotetan for the postpartum treatment of intrapartum chorioamnionitis; Chapman SJ et al.; OBJECTIVE: Our purpose was to determine whether a single postpartum dose of a cephalosporin would effectively treat women with intrapartum chorioamnionitis and decrease the length of hospitalization . STUDY DESIGN: After vaginal delivery consenting women who had received antibiotics for chorioamnionitis were assigned to postpartum treatment with either a single 2 gm intravenous dose of cefotetan or to cefotetan 2 gm given intravenously every 12 hours for a minimum of 48 hours . Chorioamnionitis was defined as an intrapartum temperature of > or = 100.4 degrees F and maternal or fetal tachycardia, maternal leukocytosis, or uterine tenderness . Patients were discharged when they had received their assigned dosage of cefotetan, were afebrile (temperature < 100.4 degrees F) and > or = 24 hours from delivery . RESULTS: We studied 109 women (55 single dose, 54 multiple dose) with chorioamnionitis . The two groups were similar with regard to demographic and intrapartum characteristics . The median (range) interval from delivery to discharge was 24 hours lower in the single-dose group (33 {16 to 190} vs 57 {36 to 190} hours, p = 0.0001) . The incidence of failed therapy was similar (single dose: 6/55, 11%, vs multiple dose: 2/54, 3.7%, p = 0.27) . CONCLUSIONS: A single postpartum dose of cefotetan appears to be effective treatment for intrapartum chorioamnionitis after a vaginal delivery and decreases the length of hospital stay.

J Biol Chem, 1997 Nov 14, 272(46), 28833 - 6
Insertion mutagenesis as a tool in the modification of protein function . Extended substrate specificity conferred by pentapeptide insertions in the omega-loop of TEM-1 beta-lactamase; Hayes F et al.; The TEM-1 beta-lactamase enzyme efficiently hydrolyzes beta-lactam antibiotics such as ampicillin but cleaves third generation cephalosporin antibiotics poorly . Variant beta-lactamases that conferred elevated levels of resistance to the cephalosporin ceftazidime were identified in a set of beta-lactamase derivatives previously generated by pentapeptide scanning mutagenesis in which a variable 5-amino acid cassette was introduced randomly in the target protein . This mutagenesis procedure was also modified to allow the direct selection of variant beta-lactamases with pentapeptide insertions that conferred extended substrate specificities . All insertions associated with enhanced resistance to ceftazidime were targetted to the 19-amino acid Omega-loop region, which forms part of the catalytic pocket of the beta-lactamase enzyme . However, pentapeptide insertions in the C- and N-terminal halves of this region had different effects on the ability of the enzyme to hydrolyze ampicillin in vivo . Larger insertions that increased the length of the Omega-loop by up to 2-fold also retained catalytic activity toward ampicillin and/or ceftazidime in vivo . In accord with previous substitution mutation studies, these results emphasize the extreme flexibility of the Omega-loop with regards the primary structure requirements for ceftazidime hydrolysis by beta-lactamase . The potential of pentapeptide scanning mutagenesis in mimicking evolution events that result from the insertion and excision of transposons in nature is discussed.

Bioconjug Chem, 1997 Sep-Oct, 8(5), 772 - 9
Synthesis of 17 beta-hydroxy esters of 4-estren-17 beta-ol-3-one and carbenicillin, ticarcillin, or functionalized oxacillin: potentially useful conjugates for beta-lactamase-based homogeneous immunoassays; Kohl M et al.; On the basis of the large range of kinetic constants of their substrates, beta-lactamases seem to be interesting enzymes for the development of homogeneous immunoassays . For this purpose, hapten-penicillin or -cephalosporin conjugates have to be prepared . The aim of this work is to couple the anabolizing steroid nandrolone to several penicillins characterized by extremely low K(m) and kcat values: ticarcillin, carbenicillin, and oxacillin . The easy decarboxylation of derivatives of phenylmalonic acid (carbenicillin) and thienylmalonic acid (ticarcillin) imposes the choice of very mild procedures which have been specifically adapted to each substance investigated . 4-Estren-17 beta-ol-3-one hemiphenylmalonate is conjugated to 6-aminopenicillanic acid after 1,1'-carbonyldiimidazole activation, while 4-estren-17 beta-ol-3-one hemi(3-thiophene)malonate is coupled to 6-aminopenicillanic acid after activation using methanesulfonyl chloride . Before conjugation of oxacillin, a carboxylated analogue of its side chain has been prepared . A procedure resorting to tert-butyl ester protection of the carboxyl group present on the isoxazole ring allows the binding of nandrolone to the remaining carboxyl followed, after specific deprotection, by the conjugation to 6-aminopenicillanic acid giving the oxacillin derivative . In this way, conjugates retaining immunological properties of nandrolone and high inhibiting power of beta-lactamases should be obtained.

J Med Chem, 1997 Oct 10, 40(21), 3423 - 33
7-alkylidenecephalosporin esters as inhibitors of human leukocyte elastase; Buynak JD et al.; A series of 7-alkylidenecephalosporins and 7-vinylidenecephalosporins, as their benzhydryl esters, have been tested as inhibitors of both porcine pancreatic elastase and human leukocyte elastase . Selected 7-alkylidenecephalosporin esters are found to be potent inhibitors of HLE . One category of new inhibitors is the 7-(haloalkylidene)cephalosporins . In contrast to previously reported cephalosporin-based elastase inhibitors, these haloalkylidene cephems show optimum inhibitory activity as sulfides, rather than as sulfones . They are efficient and irreversible inhibitors . A second class of active compounds is represented by the benzhydryl ester 7-(cyanomethylidene)cephalosporin sulfone . In contrast to the activity of these new inhibitors, the benzhydryl ester of the mechanism-based beta-lactamase inhibitor, 7-{(2'-pyridyl)methylidene}-cephalosporin sulfone showed little inhibitory activity as an elastase inhibitor . 7-Vinylidenecephalosporins were also relatively poor inhibitors, although the terminally unsubstituted allene sulfide showed activity as an inhibitor of PPE . A modeling analysis suggests the 7-alkylidene substituents can be readily accommodated in the S1 pocket . A potential mechanism of inhibition is proposed.

J Bacteriol, 1997 Oct, 179(19), 6112 - 21
AmpC and AmpH, proteins related to the class C beta-lactamases, bind penicillin and contribute to the normal morphology of Escherichia coli; Henderson TA et al.; Two proteins that bind penicillin were observed in Escherichia coli infected with lambda phages 141, 142, 650, and 651 from the Kohara genomic library . These phages carry chromosomal DNA fragments that do not contain any known penicillin binding protein (PBP) genes, indicating that unrecognized gene products were exhibiting penicillin binding activity . The genes encoding these proteins were subcloned, sequenced, and identified . One gene was ampC, which encodes a chromosomal class C beta-lactamase . The second gene was located at about 8.5 min on the E . coli genomic map and is a previously uncharacterized open reading frame, here named ampH, that encodes a protein closely related to the class C beta-lactamases . The predicted AmpH protein is similar in length to AmpC, but there are extensive alterations in the amino acid sequence between the SXXK and YXN motifs of the two proteins . AmpH bound strongly to penicillin G, cefoxitin, and cephalosporin C; was temperature sensitive; and disappeared from cells after overnight incubation in stationary phase . Although closely related to AmpC and other class C beta-lactamases, AmpH showed no beta-lactamase activity toward the substrate nitrocefin . Mutation of the ampC and/or ampH genes in E . coli lacking PBPs 1a and 5 produced morphologically aberrant cells, particularly in cell filaments induced by aztreonam . Thus, these two members of the beta-lactamase family exhibit characteristics similar to those of the classical PBPs, and their absence affects cell morphology . These traits suggest that AmpC and AmpH may play roles in the normal course of peptidoglycan synthesis, remodeling, or recycling.

Clin Infect Dis, 1997 Sep, 25 Suppl 2, S272 - 4
beta-lactamase production by oral pigmented Prevotella species isolated from young children; Kononen E et al.; The frequency of beta-lactamase production by oral pigmented Prevotella species isolated from 23 healthy young children and the minimal inhibitory concentrations (MICs) for 186 available beta-lactamase-positive isolates were examined by using the chromogenic cephalosporin disk test (AB BIODISK, Solna, Sweden) and the Etest (AB BIODISK) and/or the agar dilution method of the National Committee for Clinical Laboratory Standards (Villanova, PA, USA), respectively . beta-Lactamase-positive Prevotella melaninogenica strains were isolated from all children, and more than two-thirds of the Prevotella denticola and Prevotella loescheii strains isolated from the children were beta-lactamase-positive . The beta-lactamase-producing Prevotella intermedia group consisted of Prevotella nigrescens and the P . intermedia/ P . nigrescens-like organism (PINLO); P . intermedia was not found . Only two P . nigrescens isolates but most of the PINLO isolates produced beta-lactamase . The MICs for beta-lactamase-producing strains varied between 0.38 and 64 micrograms/mL . beta-Lactamase production by oral pigmented Prevotella species colonizing young children is already frequent . The phenomenon should be taken into account in the treatment of pediatric anaerobic infections of oral origin.

Arch Biochem Biophys, 1997 Sep 15, 345(2), 311 - 7
Protein carbonyl formation in blood plasma by cephalosporins; Jung Y et al.; Cephalosporin antibiotics caused the formation of carbonyl groups in the plasma proteins both in vivo and in vitro . After the administration of either moxalactam (3 g/day) or cefotaxime (2 g/day) to patients for 7 days, the carbonyl contents in the plasma proteins increased markedly as determined by the 2,4-dinitrophenylhydrazine (DNPH) method . The increase in protein carbonyl groups was also visualized by the conjugation of plasma proteins with fluorescein thiosemicarbazide (FTSC) and subsequent electrophoresis . When blood plasma was incubated with cephalosporins, most of the cephalosporins tested caused the carbonyl formation in plasma proteins to significant degrees in a concentration-dependent manner . Although a number of plasma proteins and other nonplasma proteins could be modified by cephalosporins in vitro, the plasma albumin was most markedly modified in vivo as well as in vitro . The protein carbonyl formation by cephalosporins was inhibited by ascorbic acid, reduced glutathione, and cysteine, but it was not affected by FeSO4, CuSO4, desferrioxamine, EDTA, catalase, superoxide dismutase, uric acid, alpha-tocopherol, and mannitol . Sodium borohydride, when applied to moxalactam-treated plasma proteins, markedly reduced the reactivities of the protein with FTSC or DNPH, indicating that the observed reactivities of the cephalosporin-treated proteins toward FTSC or DNPH are actually due to the protein carbonyl groups . These data suggest that cephalosporins can oxidatively modify proteins in blood plasma and other tissues and that the oxidative modification of proteins may be involved in the adverse reactions observed frequently following cephalosporin therapy.

FEBS Lett, 1997 Sep 1, 414(1), 74 - 8
Penicillin biosynthesis: intermediates of biosynthesis of delta-L-alpha-aminoadipyl-L-cysteinyl-D-valine formed by ACV synthetase from Acremonium chrysogenum; Kallow W et al.; The tripeptide delta-L-alpha-aminoadipyl-L-cysteinyl-D-valine (LLD-ACV) is synthesised by the multifunctional enzyme ACV synthetase integrating four steps of the penicillin and cephalosporin biosynthetic pathway . Peptide synthesis follows the thiotemplate mechanism from intermediates bound as thioesters to the enzyme . The formation of delta-(L-alpha-aminoadipyl)-L-cysteinyl-thioester in the absence of L-valine was shown by isolation of the enzyme-substrate complex and cleavage of the covalently bound intermediate with performic acid . The dipeptide was recovered as cysteic acid or cysteic acid oxime and detected by HPLC and MALDI-TOF mass spectrometry . We conclude that the first peptide bond is formed between delta-carboxyl of L-aminoadipic acid and L-cysteine, followed by addition of the dipeptidyl intermediate to L-valine.

Geriatrics, 1997 Aug, 52(8), 43 - 4, 47-50, 55
Meningitis in older patients: how to diagnose and treat a deadly infection; Miller LG et al.; Studies of bacterial meningitis have documented a peak of incidence among persons age 60 and older . The most common bacterial pathogens in these patients differ from those seen in children . Presentation of meningitis in older patients may be atypical; fever is not a consistent finding, and nonspecific symptoms such as confusion are often seen . Nuchal rigidity is not as sensitive nor as specific a sign as in younger patients . Definitive diagnosis relies on interpretation of CSF studies . Ampicillin plus a third-generation cephalosporin should be administered for community-acquired meningitis until Gram's stain and culture results return . Cases of S pneumoniae meningitis may require varying strategies, based upon the degree of penicillin resistance.

Appl Microbiol Biotechnol, 1997 Jul, 48(1), 58 - 65
Efficient synthesis of the blood-coagulation inhibitor hirudin in the filamentous fungus Acremonium chrysogenum; Radzio R et al.; The isopenicillin-N-synthetase-encoding pcbC gene from the filamentous fungus Acremonium chrysogenum is differentially expressed in strains showing either a high or low cephalosporin C production . For a case study to demonstrate heterologous protein synthesis in A . chrysogenum, we have chosen a synthetic 195-bp gene encoding the thrombin inhibitor hirudin from the leech Hirudo medicinalis . The hirudin gene was fused with the 5' and 3' regions of the pcbC gene, resulting in four different expression vectors, which we named pHIR1 to pHIR4 . In order to achieve secretion of the heterologous polypeptide, two out of four vectors carry, in addition, secretion signal sequences of an alkaline protease gene originating either from Fusarium sp . or from A . chrysogenum . After DNA-mediated transformation of the two A . chrysogenum strains, transformants were further analysed on the transcriptional and translational level . Irrespective of the vector used for transformation, all transformants show a hirudin-gene-specific transcript in Northern hybridizations . In further analysis, hirudin synthesis was determined with a thrombin-inhibition assay, but was detectable only in those strains carrying expression plasmids with the secretion signals . In this case, hirudin was secreted into the culture medium . Transformants from strains with a high cephalosporin C production showed a three- to eightfold higher expression of the hirudin gene compared to low cephalosporin-C-producing strains . The amount of recombinant hirudin was quantified further by ELISA and Western blotting, using a monoclonal antibody directed against recombinant hirudin . Finally, the time course of hirudin gene expression was investigated in a selected transformant that has hirudin activities of 8.0 ATU/ml culture medium . Northern hybridization experiments revealed the highest hirudin transcript level after 2-5 days of cultivation, showing the strongest signal after 3 days . After 4-5 days, we detected the highest hirudin activity, as was confirmed by Western blotting . The level of heterologous hirudin synthesis in A . chrysogenum is discussed in relation to other eukaryotic expression systems.

J Dermatol, 1997 Jul, 24(7), 485 - 7
Disseminated superficial porokeratosis in a patient with chronic liver disease; Park BS et al.; A 55-year-old male suffering from liver cirrhosis presented with diffuse annular hyperkeratotic papules of abrupt onset on the trunk and extremities . Histopathologic examination revealed cornoid lamella and eosinophilic spongiosis . He did not receive any medications other than cephalosporin for spontaneous bacterial peritonitis . A review of the literature revealed that three cases developed porokeratosis when their liver function declined and that, in one case, the porokeratosis disappeared spontaneously with liver transplantation . Although the precise mechanism is unclear, there is evidence demonstrating immunoincompetence in cirrhosis . Even though we did not perform immunologic studies or exclude the possibility of drug-induced porokeratosis in our case, it is conceivable that porokeratosis can be triggered by immunosuppression due to liver cirrhosis per se.

Biochem Pharmacol, 1997 May 9, 53(9), 1223 - 8
Interaction of oligonucleotide-conjugates with the dipeptide transporter system in Caco-2 cells; Moore VA et al.; Oligonucleotide-based therapies represent novel strategies for manipulating the expression and function of target proteins and are undergoing clinical evaluation for the treatment of viral diseases and malignancies . However, poor biological stability and cellular delivery represent potential limitations to the therapeutic development of oligonucleotides . Conjugation of oligonucleotides to lipophilic groups can improve delivery to cells but the enhanced cellular binding may also facilitate nonspecific interactions . In this report, we show that phosphorothioate oligonucleotides conjugated to lipophilic groups, either tocopherol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhibit the functioning of the dipeptide transporter system (DTS) in cultured Caco-2 intestinal cells . Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cephalosporin and penicillin antibiotics, this finding has important implications in relation to the potential toxicity of lipophilic conjugates in vivo . It also suggests a potential drug interaction with lipophilic oligonucleotide-conjugates if they were to be delivered orally.

J Pharm Pharmacol, 1997 May, 49(5), 516 - 9
Characteristics of cefdinir uptake by rabbit small intestinal brush-border membrane vesicles; Kitagawa S et al.; Aminocephalosporins with peptide-like structures have been shown to be absorbed by the intestinal peptide carrier . We investigated the transport mechanism of cefdinir, an oral monocarboxylic acid cephalosporin, using rabbit small intestinal brush-border membrane vesicles . Transport of cefdinir showed a slow and almost linear uptake rate for concentrations up to 30 mM with and without and inward H+ gradient . No overshoot phenomenon was observed in the presence of an inward H+ gradient . The uptake rate increased only slightly with decreasing extravesicular pH, and a protonophore had little effect on the uptake . Aminocephalosporins such as cephalexin only slightly inhibited cefdinir uptake even in the presence of an inward H+ gradient, and vice-versa . Monocarboxylic acids such as acetic acid and salicylic acid had little effect on cefdinir uptake . These findings suggest that in contrast with other oral cephalosporins cefdinir uptake through the brush-border membrane is slow and involves a mechanism similar to passive diffusion.

J Pharm Sci, 1997 May, 86(5), 526 - 39
Isolation and structure elucidation of the major degradation products of cefaclor formed under aqueous acidic conditions; Baertschi SW et al.; The aqueous acidic degradation of the oral cephalosporin cefaclor was investigated . A number of degradation products were isolated and characterized . The degradation products can be loosely classified into three categories: thiazole derivatives, pyrazine derivatives, and simple hydrolysis or rearrangement products . Degradation pathways are proposed that involve (1) hydrolysis of the beta-lactam carbonyl with subsequent rearrangement, (2) ring contraction of the six-membered cephem nucleus to five-membered thiazole derivatives through an episulfonium ion intermediate, and (3) attack of the primary amine of the phenylglycyl side chain on the "masked aldehyde" at carbon-6 to form fluorescent substituted pyrazines.

J Ind Microbiol Biotechnol, 1997 Apr, 18(4), 241 - 6
Partial purification, characterization and nitrogen regulation of the lysine epsilon-aminotransferase of Streptomyces clavuligerus; Romero J et al.; The L-lysine epsilon-aminotransferase (LAT) of Streptomyces clavuligerus was partially purified and characterized . The 51.3-kDa enzyme exhibited optimal activity at pH 7.0-7.5 and 30 degrees C . It catalyzed transfer of the terminal amino group of L-lysine or L-ornithine to alpha-ketoglutarate . Oxalacetate and pyruvate were also used as acceptors of the amino group but with very low efficiency . Increasing ammonium concentrations added to chemically-defined medium MM enhanced the formation of LAT and decreased production of cephalosporins by S . clavuligerus . In cultures grown in the absence of lysine, greater enhancement of LAT formation by ammonium and less repression of cephalosporin biosynthesis were observed . In the chemically-defined GSPG medium, ammonium ions decreased cephalosporin production without showing an effect on LAT formation.

Biochim Biophys Acta, 1997 Mar 13, 1324(2), 296 - 308
Interaction of anionic cephalosporins with the intestinal and renal peptide transporters PEPT 1 and PEPT 2; Ganapathy ME et al.; The present study was undertaken to investigate the interaction of anionic cephalosporins (cefixime, ceftibuten, and cefdinir) with the renal peptide transporter (PEPT 2) and the intestinal peptide transporter (PEPT 1) using four different experimental model systems . In the first approach, the human colon carcinoma cell line Caco-2 which expresses PEPT 1 and the SHR rat kidney cell line SKPT which expresses PEPT 2 were used . The uptake of the dipeptide Gly-Sar mediated by PEPT 1 or PEPT 2 in these cells was inhibited significantly by the anionic cephalosporins, with the following order of potency: ceftibuten > cefixime > cefdinir . The inhibition was competitive in nature . Even though the order of potency was the same for PEPT 1 and PEPT 2, PEPT 1 exhibited much lesser sensitivity to inhibition than PEPT 2 . In the second approach, the cloned human PEPT 1 and PEPT 2 were functionally expressed in HeLa cells following which the cells were used to study the interaction of anionic cephalosporins with PEPT 1 and PEPT 2 . Again, Gly-Sar uptake mediated by the human PEPT 1 and PEPT 2 in HeLa cells was found to be inhibited by the anionic cephalosporins with the same order potency as in Caco-2 and SKPT cells . In the third approach, brush border membrane vesicles isolated from rat kidneys were employed . In this approach also it was found that PEPT 2-mediated Gly-Sar uptake was inhibited by cefixime and ceftibuten . In the fourth approach, the human PEPT 1 was expressed in Xenopus laevis oocytes and PEPT 1-mediated transport of ceftibuten was investigated directly by electrophysiological methods . Ceftibuten evoked inward currents in PEPT 1-expressing oocytes but not in water-injected oocytes, showing that the transport of the anionic cephalosporin via PEPT 1 is associated with transfer of positive charge . The ceftibuten-evoked currents were saturable with respect to ceftibuten concentration and were markedly dependent on membrane potential . It is concluded that anionic cephalosporins interact with the peptide transporters expressed in the intestine (PEPT 1) as well as in the kidney (PEPT 2).

J Chromatogr B Biomed Sci Appl, 1997 Mar 7, 690(1-2), 321 - 6
Application of capillary zone electrophoresis in cephalosporin analysis; Mrestani Y et al.; Cephalosporins have structures and antibiotic activity similar to those of penicillins which represent a class of compounds with closely related structures . Most of the cephalosporins contain aromatic groups and show distinctive UV spectra . Separating the different types of cephalosporins is a challenging task for HPLC . but the resolving power of capillary zone electrophoresis (CZE) makes this separation fast and simple . The present study reports the application of CZE for cephalosporin analysis and the separation of cephalosporins from plasma . Both field strength and temperature were shown to influence the plate number . The influence of injection time on the peak height was studied . Furthermore, the influence of pH value on the separation of cephalosporins by CZE was investigated . The low sample amount required and the relatively short analysis time are the main advantages of this method.

Diagn Microbiol Infect Dis, 1997 Mar, 27(3), 99 - 101
Use of ceftizoxime screening for the detection of cephalosporin-resistant pneumococci; Schutze GE et al.; Two hundred and ten pneumococcal isolates underwent ceftizoxime disk (30 micrograms) screening to predict cephalosporin resistance . Forty-six isolates failed screening with 36 (78%) demonstrating intermediate/resistant MICs . Sensitivity and specificity were 100 and 95%, respectively . The ceftizoxime disk screen is an effective method of identifying potentially cephalosporin-resistant isolates.

Clin Infect Dis, 1997 Mar, 24(3), 487 - 93
The evolution of resistance to cephalosporins; Moosdeen F; The expression of resistance to cephalosporins is highly varied and due to various mechanisms . The greatest disadvantage of the cephalosporins is that they are inactivated by the array of beta-lactamases produced by bacteria . The high levels of chromosomal enzymes produced by these organisms are a major cause of cephalosporin resistance . Plasmid-mediated beta-lactamases (PMBLs) have also been implicated as causes of resistance, and other cephalosporinases have been described . Point mutations of specific amino acids of well-recognized PMBLs (e.g., TEM-1 and SHV-1) have also produced enzymes capable of attacking a wider spectrum of beta-lactam agents . The availability of newer beta-lactams may be conducive to the development of such beta-lactamases, in which chromosomal and newer plasmid derivatives that may or may not contain the AmpC gene are selected . The occurrence of such enzymes is likely to continue to increase.

Ann Pharmacother, 1997 Feb, 31(2), 180 - 4
Hypoprothrombinemia associated with cefmetazole; Breen GA et al.; OBJECTIVE: To report a case of hypoprothrombinemia associated with the use of cefmetazole sodium, define patients at risk for this adverse effect, and identify options to prevent this problem . CASE SUMMARY: A malnourished patient with endstage renal disease received cefmetazole following a below-the-knee amputation of the right leg . Three days later, a prothrombin time (PT) and an international normalized ratio (INR) were obtained and were markedly elevated from baseline; however, the patient had no clinical symptoms of bleeding . Cefmetazole was discontinued . Vitamin K and fresh frozen plasma were administered . The PT and INR normalized within 24 hours and remained normal throughout the remainder of hospitalization . DISCUSSION: The incidence of hypoprothrombinemia associated with cefmetazole reported in the literature is conflicting and not consistent . There are three proposed mechanisms of cephalosporin-associated hypoprothrombinemia, two of which involve the N-methylthiotetrazole (NMTT) chain . The most plausible mechanism is NMTT inhibition of vitamin K epoxide reductase in the liver . Patients at an increased risk for this adverse event include those with low vitamin K stores, specifically patients who are malnourished, with low albumin concentrations and poor food intake . The elderly and patients with liver or renal dysfunction are examples of populations at risk . CONCLUSIONS: Hypoprothrombinemia may occur with cephalosporins and is especially problematic with those containing an NMTT side chain . Clinicians need to identify patients at risk for developing antibiotic-associated hypoprothrombinemia, monitor them closely, and give vitamin K as prophylaxis accordingly.

Am J Physiol, 1997 Jan, 272(1 Pt 2), R217 - 25
H(+)-glycyl-L-proline cotransport in brush-border membrane vesicles of eel (Anguilla anguilla) intestine; Maffia M et al.; A plasma membrane H(+)-glycyl-L-proline (Gly-L-Pro) cotransport mechanism has been identified in isolated eel intestinal brush-border membrane vesicles (BBMV) by both measuring radiolabeled Gly-L-Pro uptake and monitoring Gly-L-Pro-dependent H+ influx with the pH-sensitive dye acridine orange . The application of an inside negative membrane potential resulted in increasing Gly-L-Pro uptake, as well as the application of inwardly directed H+ gradient (although only when an inside negative membrane potential was present) . Furthermore, vesicular H+ influx was found specifically associated with the presence of Gly-L-Pro in the extravesicular medium . The carrier-mediated nature of H(+)-Gly-L-Pro cotransport was assessed, and its concentration that yielded one-half maximal Gly-L-Pro influx was approximately 1.30 mM when measured by either radioactive or fluorescent tracers . Different dipeptides strongly inhibited Gly-L-Pro uptake by eel intestinal BBMV, as well as the cephalosporin antibiotic cephalexin, suggesting that dipeptide molecules and cephalosporin antibiotics may share a common transport system in eel intestinal BBMV.

Clin Chest Med, 1996 Dec, 17(4), 767 - 85
Approach to the patient with pulmonary disease; Vander Els NJ et al.; The approach to the HIV-infected patient with pulmonary disease is summarized by the algorithms in Figures 3 and 4 . These are not intended to be followed in a rigid step-wise fashion . Rather, the practitioner's knowledge of the patient with his or her accompanying medical risks influences the path taken, including the depth and the speed of the evaluation . For example, the patient with cough who is afebrile and breathing at 18 breaths a minute, with a normal chest radiograph and a CD4 count of 350 cells/mm3, is reasonably treated with a macrolide or cephalosporin for bacterial bronchitis and clinical follow-up while awaiting cultures (see Fig . 4) . A febrile patient with a cough productive of thin mucus, but known to have a CD4 count of 60 cells/mm3 should be started on anti-PCP therapy while being evaluated for PCP with an induced sputum and if nondiagnostic, a bronchoscope despite a normal chest radiograph . Screening can be as simple as placing an oximeter on the patient's finger in the clinic . If the oxygen saturation of a patient with a normal chest radiograph is low, then the patient should be hospitalized and begun on treatment for PCP while diagnostic evaluation is initiated . If the oxygen saturation is normal, the patient can be exercised to elicit desaturation . If there is no desaturation, PCP is unlikely . If the results are equivocal (i.e., a decrease in saturation, but less than 3%), rest and exercise arterial blood gases can be performed, along with a Dlco-Gallium scanning can be done in patients known to have abnormal Dlco or those who cannot exercise . Patients with focal infiltrates who have acute onset of symptoms (see Fig . 4) commonly have bacterial infections, but the possibility of PCP or TB should not be dismissed . Induced sputum should be examined if TB or PCP is suspected . Patients who are severely ill might go quickly to bronchoscopy without awaiting improvement on empiric therapy . The patient with diffuse infiltrates (see Fig . 4) needs no screening because the presence of disease is apparent from the radiograph . The diagnostic part quickly leads to bronchoscopy for these patients and the initiation of therapy for PCP when suspected . In patients with known pulmonary KS, gallium scanning can be helpful to rule out acute infection, but bronchoscopy is warranted if the patient is severely ill, or at high risk for PCP . This approach should avoid unnecessary procedures in patients with simple bacterial infections, without missing opportunistic infections and tumors.

Clin Pharmacol Ther, 1996 Dec, 60(6), 645 - 50
Multiple-dose pharmacokinetics of cefpirome in long-term hemodialysis with high-flux membranes; Thalhammer F et al.; Cefpirome is a cephalosporin eliminated primarily by kidneys that requires dosage reduction in patients with renal failure . The pharmacokinetic parameters were studied in 10 patients with end-stage renal disease who were receiving hemodialysis . Repeated intravenous administration of 2 gm cefpirome three times a week resulted in trough levels of 12.2 +/- 5.4 micrograms/ml and peak serum concentrations of 99.6 +/- 82.1 micrograms/ml . After 3 1/2 hours of hemodialysis with polysulfone high-flux membranes, 62.3% +/- 23.3% of cefpirome was removed . The interdialytic half-life was 9.35 +/- 0.99 hours, and the intradialytic half-life was 2.02 +/- 0.7 hours.

Clin Ther, 1996 Nov-Dec, 18(6), 1139 - 49
Comparative bioavailability of ceftibuten in capsule and suspension forms; Lin CC et al.; The comparative bioavailability of ceftibuten, a new third-generation cephalosporin antibiotic given orally once daily, in capsule and suspension dosage forms, was assessed in healthy male subjects . In three separate studies, subjects received either a 400-mg dose as a suspension or one laboratory-batch, 400-mg capsule; one laboratory-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules; or one production-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules . Plasma samples were assayed for ceftibuten using high-performance liquid chromatography, and the data were assessed using pharmacokinetic and statistical methods . Confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve extrapolated to infinity were within 80% to 125% of guidelines, demonstrating the bioequivalence of the two treatments within each of the three studies . One 400-mg capsule (laboratory or production batch) was bioequivalent to two 200-mg capsules used in a clinical efficacy trial; the 400-mg suspension was bioequivalent to a 400-mg capsule (laboratory batch) . Thus we concluded that the capsule and the suspension dosage forms were bioequivalent.

J Biotechnol, 1996 Nov 1, 51(2), 137 - 48
The inhibitory mechanisms of glucose and carbon dioxide on the biosyntheses of penicillins and cephalosporins; Yang ZF et al.; The inhibitory mechanism of glucose and CO2 on the biosyntheses of penicillins and cephalosporins is discussed in the present paper . 6-aminopenicillanic acid (6-APA) is considered to be an intermediate product, and the reaction between 6-APA and glucose may play an important role in the yield and rate of biosyntheses of beta-lactam antibiotics . According to this hypothesis the experimental phenomena taking place in biosynthesis of penicillin and cephalosporin, such as the inhibition by glucose and carbon dioxide and the reduction of the yield, can be satisfactorily explained . The stability of 6-aminopenicillanic acid (6-APA) in bicarbonate solution, the reaction of 6-APA with sugars, the determination of the concentration of the 6-APA-sugar compound and the effect of these reactions on the biosynthesis of penicillin G are investigated to present evidences for this hypothesis.

Minerva Med, 1996 Oct, 87(10), 479 - 85
{Effectiveness of and tolerance to ceftibuten in the treatment of chronic bacterial bronchitis exacerbations in an elderly population}; Allegra L et al.; 117 patients suffering for bacterial exacerbation of chronic bronchitis were treated with ceftibuten, a new orally administered cephalosporin, at the dosage of 400 mg once a day for 7.9 days (range 5-14) . The results, referring to 105 evaluable patients, underlyne ceftibutent's efficacy (good clinical results in 96.1% of 102 treated patients) and safety; before and after treatment values of spirometric tests were notable in terms of improvement of lung functions.

J Pharm Biomed Anal, 1996 Oct, 15(1), 49 - 61
Quantitation of cefepime.2HCl dihydrate in cefepime.2HCl monohydrate by diffuse reflectance IR and powder X-ray diffraction techniques; Bugay DE et al.; The identification, characterization and quantitation of crystal forms is becoming increasingly important within the pharmaceutical industry . Multi-disciplinary, physical analytical techniques are necessary for this task . In this work, diffuse reflectance mid-infrared (IR) and powder X-ray diffraction (XRD) analyses were used to identify two different hydrated forms of cefepime.2HCl, a cephalosporin . Characterization of the mono- and dihydrate forms led to separate IR and XRD quantitative assays for the determination of dihydrate content in cefepime.2HCl monohydrate bulk material . For the IR assay, a working range of 1.0-8% (w/w) was established with a minimum quantifiable level (MQL) of 1.0% (w/w) and a limit of detection (LD) of 0.3% (w/w) dihydrate in monohydrate material . The XRD assay displayed a working range of 2.5-15% (w/w) with an MQL of 2.5% (w/w) and an LD of 0.75% (w/w) . Cross validation was performed between the two techniques, with a good correlation displayed for each assay as compared with the known concentrations and as compared with each other . In addition, a full evaluation of potential assay errors was made.

J Biol Chem, 1996 Sep 13, 271(37), 22538 - 45
Selection and characterization of amino acid substitutions at residues 237-240 of TEM-1 beta-lactamase with altered substrate specificity for aztreonam and ceftazidime; Cantu C III et al.; Recently, natural variants of TEM-1 beta-lactamase with amino acid substitutions at residues 237-240 have been identified that have increased hydrolytic activity for extended-spectrum antibiotics such as ceftazidime . To identify the sequence requirements in this region for a given antibiotic, a random library was constructed that contained all possible amino acid combinations for the 3-residue region 237-240 (ABL numbering system) of TEM-1 beta-lactamase . An antibiotic disc diffusion method was used to select mutants with wild-type level activity or greater for the extended-spectrum cephalosporin ceftazidime and the monobactam aztreonam . Mutants that were selected for optimal ceftazidime hydrolysis contained a conserved Ala at position 237, a Ser for Gly substitution at position 238, and a Lys for Glu at position 240 . Mutants selected for aztreonam hydrolysis exhibited a Gly for Ala substitution at position 237, a Ser for Gly substitution at position 238, and a Lys/Arg for Glu at position 240 . The role of the A237G substitution in differentiating between ceftazidime and aztreonam was further investigated by kinetic analysis of the A237G, E240K, G238S:E240K, and A237G:G238S:E240K enzymes . The A237G single mutant and the G238S:E240K double mutant exhibited increases in catalytic efficiency for both ceftazidime and aztreonam . However, the triple mutant A237G:G238S:E240K, displayed a 12-fold decrease in catalytic efficiency for ceftazidime but a 3-fold increase for aztreonam relative to the G238S:E240K double mutant . Thus, the A237G substitution increases ceftazidime hydrolysis when present alone but antagonizes ceftazidime hydrolysis when it is combined with the G238S:E240K substitutions . In contrast, the A237G substitution acts additively with the G238S:E240K substitutions to increase aztreonam hydrolysis.

Microbiologia, 1996 Sep, 12(3), 359 - 70
Recombinant Acremonium chrysogenum strains for the industrial production of cephalosporin; Diez B et al.; Conventional strain improvement programs based on random mutagenesis and rational screening have meant valuable results to the antibiotic producing companies . The development of recombinant DNA techniques and their applications to the industrially-used cephalosporin-producing fungus Acremonium chrysogenum has provided a new tool, complementary to classical mutation, promoting the design of alternative biosynthetic pathways making it possible to obtain new antibiotics and to improve cephalosporin production . Yield increases have been achieved by increasing the dosage of the biosynthetic genes cefEF (deacetoxycephalosporin C expandase/hydroxylase) and cefG (deacetylcephalosporin C acetyltransferase) or enhancing the oxygen uptake by expressing a bacterial oxygen-binding heme protein (Vitreoscilla hemoglobin) . New biosynthetic capacities such as the production of 7-aminocephalosporanic acid (7-ACA) or penicillin G have been achieved through the expression of the foreign genes dao (D-amino acid oxidase) coupled with cephalosporin acylase or penDE(acyl-CoA:6-APA acyltransferase) respectively . Confined manipulation of the above-mentioned recombinant strains must be performed according to standing rules.

J Pharm Sci, 1996 Sep, 85(9), 984 - 9
Degradation kinetics and isomerization of cefdinir, a new oral cephalosporin, in aqueous solution . 2 . Hydrolytic degradation pathway and mechanism for beta-lactam ring opened lactones; Okamoto Y et al.; Hydrolysis of cefdinir leads to pH-dependent isomerizations and beta-lactam ring-opening . Lactam ring opened gamma-lactones were produced as a mixture of four diastereoisomers based on the lactone methyl, and C-6 isomerizations in acidic to neutral solutions . Cefdinir and its 7-epimer were hydrolyzed to clarify the pathway leading to these lactones and the mechanism of C-6 epimerization with the aid of chiral separation techniques . Chiral separation using a bovine serum albumin column was employed to detect the beta-lactam ring opened products of cefdinir and its 7-epimer; the C-6 and C-7 isomerization was thereby observed; however, it was found to be pH-dependent at pH > or = 9 . Optical activity detection applied to the lactones produced from cefdinir and its 7-epimer demonstrated that the corresponding peaks of these lactones were enantiomeric pairs . In addition, the smallest rate constant at pH 4 was observed for C-6 epimerization of the lactones, and it was found to proceed without deprotonation at C-6 by 1H-NMR spectroscopy . From the results of these studies, a plausible mechanism for C-6 epimerization has been proposed . Additionally, it was confirmed that two degradation pathways were involved during hydrolysis of cefdinir to the lactone.

J Pharm Sci, 1996 Sep, 85(9), 976 - 83
Degradation kinetics and isomerization of cefdinir, a new oral cephalosporin, in aqueous solution . 1; Okamoto Y et al.; Hydrolytic degradation products of cefdinir were studied in acidic (pH 1), neutral (pH 6), and basic (pH 9) solutions . Seven major degradation products were isolated by preparative and/or high-performance liquid chromatography and characterized by UV, IR, 1H-NMR, and mass spectra . To clarify degradation pathways in each pH solution, kinetic and product analyses during hydrolysis of cefdinir were carried out along with the followup reaction of representative degradation products . Cefdinir was shown to degrade via two major degradation routes: beta-lactam ring-opening and pH-dependent isomerizations (lactonization, epimerization at C-6 or C-7, syn-anti isomerization of N-oxime function).

J Allergy Clin Immunol, 1996 Sep, 98(3), 671 - 7
Cross-reactivity between a penicillin and a cephalosporin with the same side chain; Miranda A et al.; BACKGROUND: The cross-reactivity between penicillins and cephalosporins can be influenced by different factors, which are not all well known . The chemical structure of the side chain may contribute to the cross-reactivity . OBJECTIVE: The study was carried out in allergic subjects who are selectively responsive to amoxicillin to determine allergenic cross-reactivity with a cephalosporin containing a side chain identical to that of amoxicillin, cefadroxil, and one containing a different side chain, cefamandole . METHODS: Allergic subjects with a selective response to amoxicillin were chosen according to the following criteria: history of an immediate allergic reaction to amoxicillin, negative skin test responses to benzylpenicilloyl and minor determinant mixture of benzylpenicillin, negative RAST response to benzylpenicilloyl, and good tolerance to benzylpenicillin and phenoxymethyl penicillin challenges . In addition, subjects had to have a positive skin test response to amoxicillin and/or positive RAST response to amoxicilloyl or, if these test results were negative, a positive challenge test response to amoxicillin . In vivo cross-reactivity to cefadroxil was assessed by giving oral cefadroxil at increasing doses from 5 to 500 mg . In vitro cross-reactivity was determined by RAST inhibition studies with amoxicilloyl RAST disks and the following monomeric conjugates in the fluid phase: amoxicillin-butylamine, cefadroxil-butylamine, and the side chain para-hydroxy-phenylglycine . Tolerance to cefamandole was determined by giving 100 mg and then 500 mg parenterally . RESULTS: Twenty-one patients with a selective response to amoxicillin were included in the study . Eight subjects (38%) had a positive response to cefadroxil, and none reacted to cefamandole . In vitro RAST inhibition studies indicated that cefadroxil-butylamine monomers cross-reacted with amoxicillin butylamine and the side chain contributed relevantly to the inhibition . CONCLUSIONS: These results indicate that the percentage of cross-reactivity between penicillins and cephalosporins with an identical side chain is high and that this critical part of the molecule seems to be an important contributor to these results . The value is higher than previously reported data from similar studies of non-side-chain-related cephalosporins.

J Biotechnol, 1996 Jul 18, 48(1-2), 59 - 66
Effect of oxygen on the respiratory system and cephalosporin-C production in Acremonium chrysogenum; Kozma J et al.; In this paper in vivo studies on the overall and cyanide-resistant respiration of Acremonium chrysogenum in connection with different oxygen transfer rates are discussed . Two parameters of the cyanide-resistant respiration, the activity and the capacity were examined separately during cultivation together with the possibly respiration-influencing factors like NADH/NAD content and ADP-limitation . It was finally concluded that the cyanide-resistant respiration seems to be independent of the amount and proportion of oxidized/reduced coenzymes and not limited by ADP or phosphate, but it is strongly affected by the oxygen available . It was also established that the examined path must have an important role in cephalosporin-C overproduction.

J Mol Recognit, 1996 Jul-Aug, 9(4), 287 - 96
beta-Lactam drug allergens: fine structural recognition patterns of cephalosporin-reactive IgE antibodies; Pham NH et al.; Lack of experimental findings on the spectrum of cephalosporin allergenic determinants has hindered diagnosis of adverse reactions to these drugs and retarded understanding of allergenic cross-reactions between cephalosporins and between cephalosporins and penicillins . Subjects allergic to the widely used cephalosporin antibiotic cefaclor have serum immuno globulin (Ig) E antibodies that react with the drug . Quantitative hapten inhibition studies employing sera from subjects allergic to cefaclor revealed fine structural recognition differences between the combining site specificities of cefaclor-reactive IgE antibodies in the sera of different subjects . Unlike penicillins, where discrete side chain or thiazolidine ring determinants alone may be recognized, IgE binding determinants on cefaclor encompassed the entire molecule . Fine structural recognition specificity differences at positions R1 (side-chain) and R2 (substituent attached to dihydrothiazine ring) were detected between IgE antibodies in different sera . Some antibodies showed clear preferential recognition of the aminobenzyl group at position R1 and Cl at R2 while with others, a greater degree of recognition tolerance was seen at R1 where, for example, the aminohydroxybenzyl or aminodihydrobenzyl groups were recognized, and at R2 where a methyl or even an ester group was tolerated . As with the penicillins, cephalosporins as allergens cannot simply be considered as a group of compounds with a common allergenic determinant structure . IgE antibodies that bind to cefaclor show great heterogeneity indicated by clear, fine structural differences in recognition of the R1 and R2 groups on the drug.

Am J Med, 1996 Jun 24, 100(6A), 68S - 75S
Safety of cefepime: a new extended-spectrum parenteral cephalosporin; Neu HC; The purpose of this study was to compare the safety profile of cefepime, a new extended-spectrum, fourth-generation cephalosporin used to treat mild-to-severe bacterial infections, with that of ceftazidime . A total of 2,032 patients enrolled in North American and European cefepime trials were analyzed . The study population spanned adolescence to the elderly (15-100 years); the median age was 62 years . Cefepime was compared with ceftazidime (1,456 patients), a third-generation cephalosporin . Cefepime dosing was 1-4 g/day (0.5-2.0 g twice daily) for adults; ceftazidime dosing was 1-6 g/day (0.5 g every 12 hours to 2.0 g every 8 hours) . A limited number of cefepime-treated patients received 2 g every 8 hours . The median length of dosing for both cefepime and ceftazidime was 7 days . In randomized trials in which cefepime (2,032 patients) was compared with ceftazidime (1,456 patients), analysis of comparative data indicated that adverse events of probable or unknown relation to study drugs were observed in 13.8% of cefepime patients and 15.6% of ceftazidime patients . The most commonly observed adverse event for cefepime was headache (2.4%), followed by nausea (1.8%), rash (1.8%), and diarrhea (1.7%) . For ceftazidime, the most commonly observed adverse event was diarrhea (3.2%), followed by headache (2.5%), nausea (2.1%), rash (1.9%), and constipation (1.5%) . The incidence of positive Coombs' test was higher in high-dose cefepime recipients than in ceftazidime recipients (14.5% vs 8.7%; p = 0.043), although there was no evidence of hemolysis in either treatment group . Coadministration of analgesics, diuretics, and anticoagulants did not increase incidence of adverse events associated with study-drug therapy . Adverse renal and hematologic events, as well as anaphylaxis and death, were rare in both groups . In the comparative trials with cefepime, anaphylaxis was reported in no patients receiving cefepime and in one patient receiving ceftazidime . None of the three seizures reported in patients receiving cefepime and one of six seizures in patients receiving ceftazidime were of probable or possible relationship to the study drugs . None of the 12 cases of gastrointestinal hemorrhage reported in cefepime patients or five cases reported in ceftazidime patients were judged to be related to treatment drug . Tolerance for intravenous administration in both treatment groups was similar . Cefepime did not effect any significant or unusual allergic, hematologic, gastrointestinal, neurologic, or renal toxicity when administered to patients with mild-to-severe infections, including those receiving concomitant medications . The safety profile of cefepime is excellent and comparable to that of ceftazidime and those reported for other cephalosporins.

Allergy, 1996 Jun, 51(6), 383 - 86
Clinical cross-reactivity between amoxicillin and cephadroxil in patients allergic to amoxicillin and with good tolerance of penicillin; Sastre J et al.; In recent years, patients allergic to amoxicillin (AX) but with good tolerance of penicillin G (PG) have been described . It has been suggested that the epitope implicated in this type of sensitization might be located on the side-chain of the AX molecule . Thus, cross-reactivity between AX and cephadroxil (CEPH), a cephalosporin which shares an identical side-chain with AX, is suspected . This study aimed to demonstrate clinical cross-reactivity between AX and CEPH in patients allergic to AX and showing good tolerance of PG . In 76 of 576 subjects with suspected allergic reaction to PG and/or AX, the diagnosis of allergy was confirmed . All of these had specific IgE to PG, penicillin V, or AX, and/or positive skin tests to PPL (penicilloyl-polylysine), or MDM (minor determinant mixture), or PG, or AX, and/or positive challenge tests with PG and/or AX . Sixteen subjects (21%) allergic to AX (11 with positive skin test and five with positive challenge test to AX) and good tolerance of PG (all with negative parenteral challenge test) were selected . These 16 patients were subsequently challenged with CEPH (up to 500 mg) . Fourteen patients tolerated CEPH, and two (12%) had an immediate allergic reaction . Our study indicates that allergy to the side-chain of aminopenicillins seems to have little clinical relevance in patients with allergic reactions to aminopenicillins but with good tolerance of PG, as 88% of patients with this clinical characteristic tolerate a cephalosporin which shares an identical side-chain . It seems that IgE from most of these patients recognizes an epitope different from the side-chain and the beta-lactam ring.

Aust N Z J Med, 1996 Jun, 26(3), 386 - 90
An audit of third generation cephalosporin prescribing in a tertiary care hospital; LeMire M et al.; BACKGROUND: There is increasing resistance to commonly used antibiotics, including third generation cephalosporins, and an increasing cost burden . AIMS: To assess the appropriateness of prescribing of third generation cephalosporin antibiotics in a tertiary teaching hospital . METHODS: Prescriptions of third generation cephalosporins (ceftriaxone, cefotaxime and ceftazidime) to inpatients were identified prospectively by the Hospital Pharmacy Department for a six week period during May-June 1994 . Clinical data and indications were obtained from patient records and, when necessary, by interviewing the prescriber and by patient assessment . Criteria for appropriate prescribing were according to nationally accepted criteria outlined in the 1994-95 Antibiotic Guidelines handbook . All inpatients who were prescribed a third generation cephalosporin at Flinders Medical Centre for the duration of the audit period were eligible . This included medical, surgical, paediatric, obstetric and gynaecology inpatients . RESULTS: Sixty-five per cent of prescriptions for third generation cephalosporins were judged appropriate, 31% inappropriate and 4% doubtful . Inappropriate use was found particularly in the treatment of respiratory tract infections and abdominal sepsis, and in surgical prophylactic use . CONCLUSION: Third generation cephalosporin prescribing in a tertiary care teaching hospital is frequently inappropriate, as judged against widely available Australian guidelines.

Appl Microbiol Biotechnol, 1996 Jun, 45(5), 621 - 8
Effect of amplification or targeted disruption of the beta-lactamase gene of Nocardia lactamdurans on cephamycin biosynthesis; Kumar V et al.; The bla gene of the cephamycin cluster of Nocardia lactamdurans has been subeloned in the shuttle plasmids pULVK2 and pULVK2A and amplified in N . lactamdurans LC411 . The transformants showed two- to threefold higher beta-lactamase activity . Formation of beta-lactamase preceded the onset of cephamycin biosynthesis . The beta-lactamase of N . lactamdurans inactivated penicillins and, to a lesser extent, cephalosporin C but did not hydrolyse cephamycin C . This beta-lactamase was highly sensitive to clavulanic acid (50% inhibition was observed at 0.48 microgram/ml clavulanic acid) . The N . lactamdurans bla gene was disrupted in vivo by inertion of the kanamycin-resistance gene . Three bla-disrupted mutants, BD4, BD8 and BD12, were selected that lacked beta-lactamase activity . Overexpresion of the bla gene resulted in N . lactamdurans transformants that were resistant to penicillin whereas mutants in which the bla gene was disrupted were super-sensitive to this antibiotic . The three N . lactamdurans mutants with the bla gene disrupted showed a significant increase of cephamycin biosynthesis in solid medium, whereas transformants with the amplified bla gene produced reduced levels of cephamycin . The cephamycin-overproducing Merck strain N . lactamdurans MA4213 showed no detectable levels of beta-lactamase activity . The beta-lactamase plays a negative role in cephamycin biosynthesis in solid medium, but not in liquid medium.

Ann N Y Acad Sci, 1996 May 15, 782, 17 - 24
Metabolic engineering of cephalosporin biosynthesis in Streptomyces clavuligerus; Khetan A et al.; The biosynthesis of beta-lactams is one of the most thoroughly studied antibiotic pathways . The availability of the characteristics and the time profiles of activities of enzymes involved in the biosynthesis allows one to critically evaluate the potential rate-limiting steps in its production . Our approach to understanding the control of beta-lactam biosynthesis has been pursued using a two-stage strategy: (1) to predict the rate-limiting steps using a kinetic model and (2) to relax the rate-limiting steps by engineering the biosynthetic pathway or by altering the kinetic parameters of the predicted key rate-limiting enzyme . Kinetic analysis of the pathway dynamics of cephamycin C production in Streptomyces clavuligerus was performed using data obtained from wild type . Sensitivity analysis revealed that the availability of precursor alpha-aminoadipic acid and activity of ACV synthetase were the potential rate-limiting steps . Relaxation of the precursor limitation was accomplished by integration of an additional copy of the gene encoding lysine-epsilon-aminotransferase (lat) into the chromosome . The recombinant strain showed an increased level of cephamycin C production as expected . The intracellular levels of different intermediates in the pathway in batch cultures were analyzed.

J Biol Chem, 1996 May 3, 271(18), 10482 - 9
Structural basis of extended spectrum TEM beta-lactamases . Crystallographic, kinetic, and mass spectrometric investigations of enzyme mutants; Maveyraud L et al.; The E166Y and the E166Y/R164S TEM-1 beta-lactamase mutant enzymes display extended spectrum substrate specificities . Electrospray mass spectrometry demonstrates that, with penicillin G as substrate, the rate-limiting step in catalysis is the hydrolysis of the E166Y acyl-enzyme complex . Comparison of the 1.8-A resolution x-ray structures of the wild-type and of the E166Y mutant enzymes shows that the binding of cephalosporin substrates is improved, in the mutant enzyme, by the enlargement of the substrate binding site . This enlargement is due to the rigid body displacement of 60 residues driven by the movement of the omega-loop . These structural observations strongly suggest that the link between the position of the omega-loop and that of helix H5, plays a central role in the structural events leading to extended spectrum TEM-related enzymes . The increased omega-loop flexibility caused by the R164S mutation, which is found in several natural mutant TEM enzymes, may lead to similar structural effects . Comparisons of the kinetic data of the E166Y, E166Y/R164S, and R164S mutant enzymes supports this hypothesis.

Clin Chem, 1996 May, 42(5), 761 - 5
HPLC micromethod for amrinone and metabolites in patients receiving concurrent cephalosporin therapy; Pappas JB et al.; Amrinone (AMR), a bipyridine derivative, is receiving increasing use in postoperative cardiac patients as an inotrope and vasodilator . The hemodynamic response to amrinone in adults is linearly related to AMR concentrations, warranting therapeutic drug monitoring . We report a rapid microsample HPLC method for monitoring AMR and its principal metabolites, N-acetyl (N-ac) and N-glycolyl (N-gly) AMR . Serum was precipitated with acetonitrile, and the supernatant fluid was then injected into a C18 narrow-bore column . The mobile phase consisted of a 0.1 mol/L sodium phosphate buffer (pH 6) with a gradient of acetonitrile going from 50 to 100 mL/L of eluent . Detection with a diode-array detector (DAD) concurrently monitored the absorbances at 320 and 345 nm . Monitoring 320 nm allows optimal quantification of AMR, N-gly, and N-ac . Patients often receive concurrent cephalosporin therapy, which is detectable at 320 nm but not 345 nm . Because cephalosporins coelute with AMR or metabolites, monitoring at 345 nm allows separation of these antibiotics from AMR and metabolites while retaining a detection limit of 0.5 mg/L.

Am Surg, 1996 May, 62(5), 336 - 8
Laparoscopic ventral hernia repair: a community hospital experience; Saiz AA et al.; From October 1993 to April 1994, laparoscopic ventral hernia repair was performed on 10 patients, all of whom had a history of failed ventral hernia repair and at least two prior ventral hernia repair procedures . Patients presented with complaints of abdominal discomfort, painful mass at the hernia site, or vague abdominal discomfort . No operative deaths occurred . Two patients had minor complications: a seroma at the repair site, which resolved spontaneously, and a superficial wound infection at a trochar site, which responded to an oral cephalosporin . Six patients were discharged within 24 hours of surgery and one patient was operated on as an outpatient and discharged the same day . Follow-up of all patients ranged from 10 to 17 months . No evidence of hernia recurrence has been noted . Some recurrent ventral hernias are amenable to laparoscopic repair, and this technique may be preferable in some patients, especially those who have had an earlier failed open repair with mesh . We do not advocate use of our technique for the first repair of a ventral hernia . Long-term follow-up is still needed to determine recurrence rates compared with conventional open techniques.

FEMS Microbiol Lett, 1996 Apr 1, 137(2-3), 135 - 40
An inducible expression system of histidine-tagged proteins in Streptomyces lividans for one-step purification by Ni2+ affinity chromatography; Enguita FJ et al.; An expression and purification cassette containing the aminoglycoside phosphotransferase gene (aph) as selective marker has been constructed in the Escherichia coli vector pULHis2 . DNA fragments inserted in the cassette can be easily subcloned in pIJ699 to give vectors for overexpression of genes in Streptomyces and purification of proteins by a one-step procedure . The expression system uses the thiostrepton-inducible promoter tipA for expression and a six histidine coding nucleotide sequence that is fused in frame to the foreign gene inserted in the polylinker . The pULHis2-derived expression vector has been used satisfactorily to express and to purify the P7 and P8 proteins of Nocardia lactamdurans which carry out the methoxylation of cephalosporin C to 7-methoxycephalosporin C.

Biochem Pharmacol, 1996 Feb 23, 51(4), 557 - 61
Cephalosporin and carbacephem nephrotoxicity . Roles of tubular cell uptake and acylating potential; Tune BM et al.; Three beta-lactams, desacetylcephaloglycin, ampicillin, and loracarbef, were studied to test a hypothesis derived from retrospective analysis of previously studied cephalosporins: that beta-lactam nephrotoxicity develops in approximate proportion to tubular cell antibiotic concentrations and lactam ring reactivities . Concentrations of each beta-lactam (and insulin) in rabbit renal cortex and serum were measured at the end of 0.5-hr infusions of 100 mg antibiotic/kg body weight and 0.5 to 0.67 hr later . Total cortical AUCs (total areas under the curve of concentration and time in renal cortex) and transported cortical AUCs (total minus insulin-space beta lactam) were calculated from these measurements . Reactivities, determined by the rate constants of lactam-ring opening at pH 10, were taken from the literature . Nephrotoxicity was quantified by grades of proximal tubular cell necrosis and by serum creatinine concentrations 2 days after infusion of 100-1500 mg/kg of the antibiotics . Desacetylcephaloglycin was slightly less nephrotoxic than cephaloglycin; the AUCs reactivities, and toxicities of these two cephalosporins fit the proposed model, particularly when allowance is made for hepatic and renal deacetylation of cephaloglycin . The very low AUCs, limited reactivity, and absence of nephrotoxicity of ampicillin also fit the model . Loracarbef had a transported AUC less than three times, and reactivity one-thirtieth, those of cefaclor, respectively . Although only at 1500 mg/kg, loracarbef was significantly more nephrotic than cefaclor . If the relativity of loracarbef with its targeted bacterial proteins, which is essentially the same as that of cefaclor, is considered instead of the base hydrolysis rate constant, than loracarbef also fits the model . By the same analysis, the comparatively high in vitro stability of other carbacephems, although pharmaceutically convenient, may not limit their nephrotoxicity.

Cell Biol Toxicol, 1996 Feb, 12(1), 39 - 53
A cellular model for drug interactions on hematopoiesis: the use of human umbilical cord blood progenitors as a model for the study of drug-related myelosuppression of normal hematopoiesis; Leglise MC et al.; A cellular model of hematopoiesis which would be more convenient than bone marrow (BM) progenitors and directly relevant to human pathology is needed in order to investigate xenobiotic toxicity . Human umbilical cord blood (HCB), previously shown to be able to repopulate BM, provides a powerful in vitro model of normal human hematopoiesis . In order to validate the use of normal HCB progenitors as targets for dose-related myelosuppression, we used clonogenic assays and expansion in a liquid culture of progenitor-enriched cell suspensions from HCB . A series of 8 reference molecules, doxorubicin, cytosine-arabinoside, 5-fluorouracil, 3'-azido-3'-deoxythymidine, acetylsalicylic acid, sodium valproate and two cephalosporin antibiotics, were tested . In vitro 50% inhibition concentrations (IC50) were compared to those observed or reported with BM progenitors, and to the values of plasma concentrations from treated patients . HCB progenitors as in vitro targets for cytotoxic molecules were easy to access and handle, and their use was sensitive, specific and reproducible . They gave results similar to BM progenitors and allowed a qualitative approach to cellular metabolism and toxicity using morphological, flow cytometric and chromatographic methods.

Antimicrob Agents Chemother, 1996 Feb, 40(2), 481 - 4
Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents against 203 penicillin-susceptible and -resistant pneumococci; Spangler SK et al.; Agar dilution was used to determine the MICs of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents for 203 penicillin-susceptible and -resistant pneumococci . All pneumococci were inhibited by RPR 106972 at < or = 0.5 microgram/ml . Cefditoren was very active against all pneumococcal groups, with MICs of < or = 2.0 micrograms/ml . Amoxicillin with or without clavulanate was the next most active oral beta-lactam, followed by cefdinir, cefuroxime, cefpodoxime, and cefprozil . U-100592 and U-100766 were very active against all classes of pneumococci, with all MICs < or = 1.0 microgram/ml.

Free Radic Biol Med, 1996, 21(6), 827 - 32
Attack of cefotaxime by different radicals: comparison of the effects; Crucq AS et al.; Free radicals are physiological products and can react to administrated drugs . Metabolic transformations by radical mechanisms are, therefore, possible . A fundamental study of radio-induced degradation of aqueous solutions of sodium cefotaxime, a third generation cephalosporin, was realized to describe these possible radical mechanisms . Different radicals produced by the radiolysis method (.OH, N3., Br2.-, Tbut., eaq- + .OH, and exq- + Tbut.) were successively used to induce the radical mechanisms and their effects were compared . All these radicals induce the formation of a same main radiolysis product identified as anticefotaxime . Radical mechanisms induced by N3., Tbut., and eaq- include chain reactions to explain the formation of anticefotaxime contrary to those induced by .OH and Br2.-.

Fundam Clin Pharmacol, 1996, 10(3), 309 - 13
Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid; Radouane A et al.; The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF) . The lipophilicity was expressed as the chromatographic capacity factor (log k'w) determined by high-performance liquid chromatography in a reversed-phase system . The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg) . One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (CCSF) and in plasma (CP) . A significant parabolic relationship was sought between lipophilicity (log k'w) and the capacity of diffusion across the blood-brain barrier expressed as log (CCSF/CP) . The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF . A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin . These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively) . The AUC0-4h for both free plasma (AUCP) and cerebrospinal fluid (AUCCSF) concentrations were determined . The AUCCSF/AUCP ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone . In our experimental conditions, the ideal lipophilicity (log k'w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.

Antimicrob Agents Chemother, 1996 Jan, 40(1), 102 - 4
Pharmacokinetics of cefetamet in plasma and skin blister fluid; Zimmerli W et al.; Cefetamet pivoxil is an oral cephalosporin with enhanced affinity for the target penicillin-binding proteins 1 and 3 and an increased stability to beta-lactamases compared with older cephalosporins, such as cefalexin or cefaclor . The pharmacokinetics of cefetamet pivoxil was determined after the seventh and final dose of 500 mg of cefetamet pivoxil in eight healthy volunteers . Concentrations in plasma and cantharidin-induced skin blister fluid were determined by a high-performance liquid chromatography method . In addition, protein binding was assessed . Cmax was 4.8 +/- 1.7 micrograms/ml in skin blister fluid and 5.1 +/- 2.1 micrograms/ml in plasma . Tmax was delayed in skin blister fluid compared with plasma (3.9 +/- 1 versus 2.8 +/- 0.8 h; P < 0.001), and t1/2 was longer in skin blister fluid than in plasma (3.1 +/- 0.5 versus 2.3 +/- 0.3; P < 0.005) . The mean percent penetration into cantharide blister fluid was 129% +/- 24% when measured as total drug and 149% +/- 28% when measured as free drug (P < 0.001) . These data suggest that cefetamet has an excellent penetration into inflammatory interstitial fluid.

Appl Microbiol Biotechnol, 1996 Jan, 44(5), 589 - 96
Molecular analysis of the gene cluster involved in cephalosporin biosynthesis from Lysobacter lactamgenus YK90; Kimura H et al.; Determination of the nucleotide sequence downstream from the Lysobacter lactamgenus pcbC gene encoding isopenicillin N synthase revealed that five open-reading frames (ORF) including the pcbC gene were tightly linked in the same orientation . Each ORF has the remarkable feature of the protein-coding frame in the DNA sequence with a high G+C content . Expression in Escherichia coli and a comparison of the deduced amino acid sequences with published sequences showed that the gene cluster contained a deacetoxycephalosporin C synthetase (DAOCS) gene (cefE), an ORF having homology with the Cephalosporium acremonium DAOCS/deacetylcephalosporin C synthetase gene (cefEF), an isopenicillin N epimerase gene(cefD), and a beta-lactamase gene . The gene order was pcbC-cefE-ORF3-cefD-beta-lactamase.

Acad Med, 1996 Jan, 71(1), 86 - 8
When pharmaceutical manufacturers' employees present grand rounds, what do residents remember?
Spingarn RW, Berlin JA, Strom BL.
PURPOSE . To evaluate the educational effect on residents of a grand rounds given by a pharmaceutical company employee . METHOD . Using a retrospective cohort study design, the authors questioned 75 housestaff at a university hospital three months after a February 1990 grand rounds on Lyme disease to determine whether the residents' beliefs about the drug of choice for this disease differed between attendees and non-attendees . Odds ratios, 95% confidence intervals, and logistic regression were used for the analysis of results . RESULTS . The 22 housestaff who had attended the grand rounds were more likely to choose appropriately the cephalosporin manufactured by the speaker's company over other drugs for patients with Lyme disease presenting with second-degree heart block (adjusted odds ratio of 8.4; 95% CI 2.1-38.9) . However, they also chose it inappropriately for first-degree heart block (adjusted odds ratio of 7.8; 95% CI 1.6-45.5) . None of the attendees, compared with 11 (21%) of the non-attendees, named an oral antibiotic for both of two milder presentations, even though oral therapy would be more appropriate (p = .027) . CONCLUSION . The results suggest that grand rounds effectively change residents' beliefs, but a sponsoring company's drug may be favored . Information assimilated in this way may not be well supported by the scientific literature and could result in a choice of treatment that is more expensive than other acceptable treatments.

Obstet Gynecol, 1996 Jan, 87(1), 99 - 102
The effect of manual removal of the placenta on post-cesarean endometritis; Atkinson MW et al.; OBJECTIVE: To determine if intraoperative glove change and placental delivery method affect the post-cesarean endometritis rate . METHODS: After informed consent, women who required cesarean were randomly assigned to one of four study groups: 1) no glove change plus manual placental extraction, 2) no glove change plus spontaneous placental delivery, 3) glove change plus manual extraction, and 4) glove change plus spontaneous delivery . Bilateral glove change by both primary and assistant surgeons occurred immediately after delivery of the newborn and before delivery of the placenta . External uterine massage and traction on the umbilical cord were performed to assist spontaneous delivery of the placenta . A first-generation cephalosporin was routinely administered after umbilical cord clamping for prophylaxis of post-cesarean endometritis . RESULTS: Of 760 women entered into the study, we included 643 who did not have intrapartum chorioamnionitis or cesarean hysterectomy . The four groups were comparable with respect to selected maternal and intrapartum characteristics, including maternal and gestational age, parity, presence of labor, and the presence and duration of membrane rupture . The postoperative endometritis rate was significantly higher in women whose placentas were extracted manually (31 versus 22%, P = .01) . Operator glove change did not alter the incidence of endometritis (relative risk 1.0, 95% confidence interval 0.79-1.3) . CONCLUSION: Manual extraction of the placenta is associated with a significantly greater risk of post-cesarean endometritis than that observed with assisted spontaneous placental delivery . Intraoperative glove change does not decrease post-cesarean endometritis.

Ophthalmology, 1995 Dec, 102(12), 1943 - 8
The importance of initial management in the treatment of severe infectious corneal ulcers; McLeod SD et al.; PURPOSE: To identify factors that influence the outcome of patients with severe infectious corneal ulcers . METHOD: A retrospective review was performed of the hospital records of all such patients admitted to the Doheny Eye Hospital during a 30 month period . Outcome variables examined were change in visual acuity, duration of hospitalization, hospital charges, and percentage of patients who required penetrating keratoplasty . RESULTS: Sixty-two ulcers were included . An organism was identified and antibiotic sensitivities established in 52 patients (84%) . Inpatient therapy involved a combination of fortified aminoglycoside and cephalosporin antibiotics in 39 patients (63%) and was found to be appropriate on the basis of sensitivity studies in 49 (94%) of 52 patients . Inappropriate initial treatment was related to increased hospital charge (P = 0.024) as well as increased risk of penetrating keratoplasty (P = 0.001) . CONCLUSIONS: Appropriate initial therapy is most critical in the course of serious corneal ulcers, and aggressive, broad-spectrum antibiotic coverage is advocated.

Allergy, 1995 Nov, 50(11), 910 - 7
An analysis of beta-lactam-derived antigens on spleen cell and serum proteins by ELISA and Western blotting; Warbrick EV et al.; Penicillins and related beta-lactam antibiotics are known to conjugate to proteins to generate potentially antigenic (haptenic) determinants . In the present study, we used a rabbit polyclonal antibody raised against benzylpenicillin (BP) to investigate the capacity of six penicillins and one cephalosporin to generate haptenic groups in vitro on cultured mouse spleen cells and on serum proteins in the culture medium . All of the drugs tested, namely, BP, amoxicillin (AMX), ampicillin (AMP), cephalothin (CEP), cloxacillin (CLX), flucloxacillin (FLX), and phenoxymethylpenicillin (PMP) generated antigens in a concentration-dependent manner on cell and serum proteins, which could be detected by ELISA, although antigens generated by BP, CEP, FLX, or PMP in either cell- or serum-conjugated form were more readily detected than those generated by AMX, AMP, or CLX . Western blot analysis revealed that BP-derived antigens were generated relatively slowly on cell proteins (maximum binding was not yet reached after 8 h), compared to serum proteins (maximum binding within 1 h) . BP, CEP, and PMP all generated similar distinctive patterns of immunostaining of electrophoresed cell or serum proteins which did not reflect the relative abundance of different proteins as revealed by Coomassie brilliant blue staining . FLX, CLX, AMP, and AMX did not generate antigens that could be detected on Western blots . In conclusion, we have shown that various beta-lactam antibiotics generate antigens on cell and serum proteins that can be detected and characterized immunochemically with polyclonal antiserum . Further application of these methods may offer potential for further identification of immunologically relevant cellular and serum antigens generated by these drugs.

Pathol Biol (Paris), 1995 Nov, 43(9), 815 - 24
{Comparative trial of the clinical efficacy and tolerance of cefatrizine (Cefaperos) and cefpodoxime proxetil (Orelox) in superinfections of chronic obstructive bronchopneumopathies in adults in urban practice}; Brambilla C et al.; In order to compare the clinical efficacy and safety of cefatrizine (Cefaperos) and cefpodoxime proxetil (Orelox) in the treatment of secondarily infected chronic obstructive pulmonary disease (COPD) in adults, a multicentre, randomized, open study was conducted by 60 general practitioners in two parallel groups of patient suffering from COPD complicated by an acute episode of superinfection (Anthoniesen stages 2 and 3) . After verification of the eligibility criteria, written consent and randomization, the patients received, for 10 days, either cefatrizine at the dose of 1 g/day or cefpodoxime proxetil at the dose of 400 mg/day . A self-assessment form was given to the patient . A telephone visit was planned for D3 . The final visit on D11 +/- 1 evaluated clinical efficacy (success or failure) and safety . The study population was composed of 250 patients with a mean age of 59.9 +/- 15.9 years (sex ratio M/F = 1.5) . The principal etiology of COPD was chronic bronchitis in 67.5% of patients, longstanding asthma in 24.5% and emphysema in 6.8% . The mean history of the disease was 13.0 +/- 10.8 years . The Anthoniesen score was equal to 2 in 73.6% of patients, 3 in 8.8% of patients and 1 in 17.6% of patients . No significant difference concerning these criteria was observed between the two study groups . The clinical success rate was equivalent in the two groups . The time to regression of clinical signs tended to be shorter, up until the sixth day (mainly between D4 and D6) for patients treated with cefatrizine (p = 0.09; NS) . The clinical safety was considered to be good and was comparable in the two study groups . This study concluded on the equivalent clinical efficacy of cefatrizine and cefpodoxime proxetil in the treatment of superinfections of COPD in general practice (97.5% and 99%, respectively), with a satisfactory and comparable safety, but with a much lower cost of treatment for cefatrizine . This conclusion is particularly important in the context of opposable medical references, as, although the treatment of superinfections of COPD by second and third generation cephalosporins is frequently proposed, the prescription of a less expensive cephalosporin appears to be more relevant.

Biochem Mol Biol Int, 1995 Nov, 37(5), 909 - 15
An unknown hydrolase activity of human serum albumin: beta-lactamase activity; Nerli B et al.; The interaction of a chromogenic cephalosporin, 3-(2, 4 dinitrostyryl)-(6 R, 7 R) -7(2 thienylacetamido)-ceph 3-em-5-carboxylic acid) (nitrocefin) with human serum albumin was studied . Purified human albumin was showed to have a hydrolase activity, catalyzing the decomposition of the chromogenic cephalosporin . The dimeric and trimeric form of albumin also showed this hydrolase activity . The presence of the following amino acid residues at the catalytic site of albumin was demonstrated: tyrosyls 199 and 411, tryptophan 214, lysyls 195, 225 and 240, histidyl 146, also some argynyls were involucrated.

Appl Microbiol Biotechnol, 1995 Nov, 43(6), 1077 - 81
DNA-mediated transformation of a fungus employing a vector devoid of bacterial DNA sequences; Nowak C et al.; Acremonium chrysogenum, a producer of cephalosporin C, was subjected to DNA-mediated transformations using a vector without bacterial DNA sequences . Recombinant fungal strains were generated with a gel-purified DNA fragment, carrying only the mutated beta-tubulin gene from A . chrysogenum . The lack of any bacterial DNA was verified by Southern hybridization analysis and polymerase chain reaction amplifications to detect even residual DNA sequences . This procedure can be referred to as a self-cloning experiment for which less restricted working regulations are needed . Finally, the transfer of a synthetic hirudin gene by cotransformation demonstrated that any DNA molecule can be introduced into the A . chrysogenum genome without bacterial marker genes . This seems to be highly relevant for biotechnical processes in which safe recombinant producer strains are required to satisfy governmental restrictions.

Antimicrob Agents Chemother, 1995 Oct, 39(10), 2348 - 9
Pharmacokinetics of cefpirome in pediatric patients; Nahata MC et al.; Cefpirome is a new investigational cephalosporin . We designed a study to determine the pharmacokinetics and tolerance of cefpirome in pediatric patients . A single dose of cefpirome was administered intravenously over 15 min to 18 patients (age 0.5 to 18 years) . The doses were 10 mg/kg of body weight for five patients, 25 mg/kg of body weight for seven patients, and 50 mg/kg of body weight for six patients . Blood samples were collected at 0, 0.25, 0.5, 1, 3, 5, and 8 h after the dose, and cefpirome was measured by a high-performance liquid chromatography method . The maximum concentration in serum ranged from about 53.6 to 454 micrograms/ml after doses of 10 to 50 mg/kg . The total body clearance, apparent volume of distribution, and elimination half-life were 2.15 +/- 0.70 ml/min/kg, 0.32 +/- 0.32 liter/kg, and 1.8 +/- 1.3 h, respectively . No significant adverse effects were attributed to cefpirome . These data may be useful in conducting efficacy and safety studies of cefpirome in pediatric patients.

Pharm Res, 1995 Oct, 12(10), 1488 - 92
Transport characteristics of S-1090, a new oral cephem, in rat intestinal brush-border membrane vesicles; Muranushi N et al.; PURPOSE . Elucidating the transport characteristics of S-1090, a new orally active cephalosporin in rat small intestinal brush-border membranes . METHODS . A rapid filtration technique . RESULTS . The uptake of S-1090 was stimulated by an inwardly directed H(+)-gradient, but did not show overshooting uptake . To investigate the transport system, the inhibitory and countertransport effects of various compounds on S-1090 uptake were examined . Although the dipeptides and tripeptides composed of amino acids with aliphatic side chains did not inhibit the uptake of S-1090, those having histidine, proline or tryptophan as the N-terminal amino acid showed an inhibitory effect . Among the oral cephems tested, ceftibuten showed marked inhibition, while cefaclor and cephalexin had no inhibitory effect . Countertransport effects on S-1090 uptake were observed only when the vesicles were preloaded with histidyl peptides such as His-Gly or His-Ala, while other compounds which exhibited inhibition had no countertransport effect . CONCLUSIONS . Based on the above results, there seems to be heterogeneity (multiplicity) in the oligopeptide transport system which may depend on the structure of the N-terminal amino acid . S-1090 may be dominantly transported via a system that recognizes peptides having histidine as the N-terminal amino acid.

Bioconjug Chem, 1995 Sep-Oct, 6(5), 529 - 35
Competitive indirect ELISA for ceftiofur sodium and the effect of different immunizing and coating antigen conjugates; Rose BG et al.; Ceftiofur sodium is a broad spectrum, beta-lactamase-resistant cephalosporin . Ceftiofur and desfuroylceftiofur were used to develop competitive indirect enzyme-linked immunosorbent assays (CI-ELISA) for the determination of ceftiofur sodium . Hapten-protein conjugates were made using three different carrier proteins and three methods of conjugation . The first two methods use the free amine of ceftiofur as the site of conjugation, and coupling to bovine serum albumin and ovalbumin was achieved by using two different cross-linking reagents . The third conjugation procedure joins the hydrolyzed form of ceftiofur, desfuroylceftiofur, to the maleimide-activated carrier proteins, bovine serum albumin and keyhole limpet hemocyanin . A variety of immunization schedules is presented to show the effect of repeated immunizations on antibody maturation . Serum antibody levels were evaluated for each conjugation method using both homologous and heterologous conjugates as antigens . All of the immunogens resulted in the generation of anticeftiofur antibodies . The heterologous assay systems on average yielded more sensitive assays, but antisera obtained from all three immunogens were used successfully in developing enzyme-linked immunosorbent assays (ELISA's) for ceftiofur . Ceftiofur was detected in mouse sera in a concentration range of 3-500 ppb . The results illustrate that the method used to couple the hapten to a carrier protein as well as the site of coupling significantly influence the resulting enzyme-linked immunosorbent assays (ELISA's).

South Med J, 1995 Aug, 88(8), 809 - 12
Catfish stings in Mississippi; Das SK et al.; We reviewed a series of 83 catfish sting cases from inland hospitals (Belzoni and Indianola) and a coastal hospital (Pascagoula) to identify the type and severity of injury, as well as the type of treatment and its effectiveness . Oral cephalosporin was adequate in treating early infections.

Eur Respir J, 1995 Aug, 8(8), 1421 - 3
Occupational asthma due to ceftazidime; Stenton SC et al.; A worker employed in the manufacture of the new third generation cephalosporin antibiotic, ceftazidime, developed asthmatic symptoms, and a series of inhalation challenge tests was undertaken to investigate the problem . The inhalation of increasing daily doses of ceftazidime up to 3.2 mg, using a double-blind challenge protocol gave rise to symptoms, late asthmatic reactions, and increases in airway responsiveness to methacholine . A repeat challenge with the 3.2 mg dose additionally gave rise to a clear immediate reaction . Ceftazidime was, thus, shown to be capable of inducing occupational asthma.

J Chromatogr B Biomed Appl, 1995 Jul 21, 669(2), 265 - 9
On-line solid-phase extraction of ceftazidime in serum and determination by high-performance liquid chromatography; Bompadre S et al.; A column-switching high-performance liquid chromatographic assay is described for the determination of ceftazidime (a third-generation cephalosporin) in human serum . The method does not require prior sample pretreatment . Serum is directly injected in a first chromatographic column for sample clean-up and extraction . Thereafter, using an on-line column-switching system, the drug is quantitatively transferred and separated on a second, analytical column followed by determination using ultraviolet absorption at 258 nm . The technique allows direct, rapid, precise, and simple determination of ceftazidime in serum over the range of 1-250 micrograms/ml using 12.5 microliters of serum . This method was applied to study the pharmacokinetics of the drug in patients undergoing vascular surgery.

J Pharmacol Exp Ther, 1995 Jul, 274(1), 548 - 54
An inhibitor of leukocyte elastase prevents immune complex-mediated hemorrhage in the rat lung; Fletcher DS et al.; The typical reverse passive Arthus reaction (RPA) was attained in rats by the instillation of a rabbit antiovalbumin serum into the lungs and intravenous injection of ovalbumin . Instillation of antiserum alone caused accumulation of polymorphonuclear leukocytes (PMN) and increased vascular permeability, but did not cause hemorrhage . However, when an intravenous injection of ovalbumin was also given, the vascular permeability of the lungs increased dramatically and PMN, as well as hemoglobin, were measurable in the lung lavage fluids by 4 hr after initiation of the reaction . Various proteinase inhibitors were instilled into the lungs after the initial stages of the RPA had developed, specifically to investigate their effect on the development of the hemorrhage, which we chose to monitor as an indicator of severe vascular damage . A cephalosporin-based beta-lactam, L-658,758, which is a time-dependent inhibitor of human and rat PMN elastase, effectively prevented the lung hemorrhage associated with the RPA reaction (ED50 = 2 x 55 micrograms doses/animal when instilled at 1.5 and 2.5 hr after initiating the RPA) . The PMN elastase inhibitor, methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone, also inhibited hemorrhage in this model . Compounds of the same chemical class as these elastase inhibitors, but having no activity against PMN elastase in vitro, did not affect the hemorrhage associated with the RPA . Several specific inhibitors of proteinases other than PMN elastase (e.g., pepstatin and methoxysuccinyl-prolyl-glycyl-alanyl-lysine-chloromethylketone) were found to have little effect on the hemorrhage associated with the RPA reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioconjug Chem, 1995 Jul-Aug, 6(4), 440 - 6
Site-specific prodrug activation by antibody-beta-lactamase conjugates: preclinical investigation of the efficacy and toxicity of doxorubicin delivered by antibody directed catalysis; Meyer DL et al.; Antibody directed catalysis (ADC), the catalytic conversion of prodrugs to drugs by enzymes localized at disease targets by appropriate monoclonal antibodies, has shown promise in the treatment of cancer in nude mouse xenograft models . We investigated this concept using antibody enzyme conjugates constructed from beta-lactamase and Fab's reactive with carcinoembryonic antigen, CEA, and tumor associated glycoprotein, TAG-72, to convert prodrugs that are cephalosporin sulfoxide derivatives into oncolytic drugs . Previous work focused on ADC delivery of the potent vinca alkaloid derivative desacetylvinblastine carboxhydrazide (DAVLBHYD) . In the current study the ability of the system to deliver doxorubicin was tested in MCF7 breast carcinoma xenografts and OVCAR3 ovarian carcinoma xenografts, and in T380 and LS174T colon tumor xenografts for comparison with previous DAVLBHYD results . ADC enhanced the delivery of doxorubicin in the model systems investigated . Tumor growth suppression was equivalent to or greater than that observed with free doxorubicin at its maximum tolerated dose (MTD) . In contrast to the DAVLBHYD results, ADC delivery of doxorubicin did not regress tumors, but did result in a substantial increase in the MTD.

Ann Neurol, 1995 Jun, 37(6), 815 - 7
Cephalosporin-induced recurrent aseptic meningitis; Creel GB et al.; A 66-year-old woman had several episodes of aseptic meningitis associated with exposure to cephalexin, cefazolin, and ceftazidime . The cerebrospinal fluid IgG index was elevated, specific IgG-ceftazidime binding was shown, and skin allergy testing with cefazolin provoked a recurrence of meningitis . We postulate an acute hypersensitivity reaction involving an antigen-specific humoral immune response.

Biochem Pharmacol, 1995 May 17, 49(10), 1513 - 20
Formation of polymorphonuclear leukocyte elastase: alpha 1 proteinase inhibitor complex and A alpha (1-21) fibrinopeptide in human blood stimulated with the calcium ionophore A23187 . A model to characterize inhibitors of polymorphonuclear leukocyte elastase; Pacholok SG et al.; Incubation of human blood with the secretagogue A23187 resulted in the formation of increased plasma concentrations of polymorphonuclear leukocyte (PMN) elastase: alpha 1 proteinase inhibitor (PMNE:alpha 1 PI) complex as well as A alpha(1-21) fibrinopeptide {A alpha(1-21)} . The formation of these species was both time and A23187 concentration dependent . Using a sandwich ELISA and a radioimmunoassay, we determined the comparative potencies of several compounds to inhibit the formation of PMNE: alpha 1 PI complexes and A alpha(1-21), respectively . L-658,758, a substituted cephalosporin, essentially irreversible elastase inhibitor, inhibited the formation of PMNE: alpha 1 PI and A alpha(1-21) with IC50 values of 38 and 15 microM, respectively . L-683,845, a monocyclic beta-lactam, was much more potent against isolated PMNE than L-658,758 . However in this system it was approximately equivalent to L-658,758 with an IC50 of 15 microM against both species . ICI-200,880, a competitive slow-binding elastase inhibitor, was significantly less potent to inhibit A alpha(1-21), having an IC50 of 75 microM, while Declaben, a reversible noncompetitive inhibitor, was inactive at concentrations as great as 200 microM . We propose that evaluating inhibitors in the complex milieu of blood will provide a useful method to predict their therapeutic potential in vivo.

Biochem Mol Biol Int, 1995 May, 36(1), 177 - 84
Cephalosporin binding sites to human serum albumin and the relation with the N-B transition of this protein; Nerli B et al.; The binding of some cephalosporins to human serum albumin was studied using probes for the so-called I, II, bilirubin and fatty acids binding sites . The results showed that cephradine and cefsulodin bind to site II, cefaclor, cefamandole, cefsulodin, cephaloglycin and cefadroxil bind to the bilirubin binding site, while cefaclor does it to the fatty acid binding site . No binding of these cephalosporins to site I of albumin was found . The binding produced a perturbation on the N-B equilibrium of albumin, stabilizing the N conformational form, which suggests that the N form of albumin has more affinity with the cephalosporins than the B form . This finding gives support to the assumption that the binding of cephalosporins to site II, bilirubin and fatty acids binding sites affects the N-B transition of albumin.

Antimicrob Agents Chemother, 1995 May, 39(5), 1140 - 6
Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis . Meropenem Meningitis Study Group; Klugman KP et al.; Broad-spectrum cephalosporins are drugs of choice for the treatment of meningitis in communities which can afford them . The emergence of cephalosporin-resistant pneumococci demands the clinical trial of alternate agents . Carbapenems are active against the bacteria causing meningitis, but the use of imipenem-cilastatin was frustrated by drug-associated seizures . The safety and efficacy of meropenem, a new carbapenem, were compared to those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis . Seizures occurred within 24 h before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem and in 6 of 92 patients (7%) randomized to receive cefotaxime . In patients without seizures before therapy, seizures occurred during therapy in 5 of 82 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime (95% confidence interval: -0.7%, 10.6%) . None were thought to be drug related . Twenty-four meropenem-treated patients (24%) and 11 cefotaxime-treated patients (12%) had neurological abnormalities before therapy . In patients without pretherapy neurological abnormalities, these abnormalities were present after treatment in 4 of 74 meropenem-treated patients (5%) and in 2 of 81 cefotaxime-treated patients (2%) (95% confidence interval: -3.2%, 9.1%) . Of 75 meropenem-treated and 64 cefotaxime-treated patients with pretherapy positive cerebrospinal-fluid cultures, 68 and 59, respectively, had repeat lumbar punctures . Bacterial eradication was found to be 100% in both groups . Our data suggest that meropenem may be a carbapenem agent that is well tolerated and effective in the treatment of bacterial meningitis.

Diagn Microbiol Infect Dis, 1995 May-Jun, 22(1-2), 49 - 55
Pharmacokinetics of cefotaxime in healthy volunteers and patients; Patel KB et al.; Cefotaxime is a third-generation cephalosporin that has maintained good susceptibility pattern despite its extensive use . It is available for intravenous and intramuscular administration . Its pharmacokinetic property includes a small volume of distribution with low protein binding . Cefotaxime's half-life is approximately 1.1 h, and it is primarily eliminated by the kidney . It has an active metabolite desacetyl-cefotaxime that displays pharmacokinetic properties similar to cefotaxime . Desacetyl-cefotaxime has a half-life of 1.5 h and also is eliminated by the kidneys by both glomerular filtration and active secretion . The half-life of cefotaxime and its metabolite is altered in patients with severe renal dysfunction requiring dosage adjustment . Despite its relatively short half-life, cefotaxime may be dosed every 12 h based on its pharmacokinetic and pharmacodynamic properties.

Biochem Pharmacol, 1995 Mar 1, 49(5), 727 - 34
Toxicity of cephalosporins to fatty acid metabolism in rabbit renal cortical mitochondria; Tune BM et al.; Cephaloglycin (Cgl) and cephaloridine (Cld) are acutely toxic to the proximal renal tubule, in part because of their cellular uptake by a contraluminal anionic secretory carrier and in part through their intracellular attack on the mitochondrial transport and oxidation of tricarboxylic acid (TCA) cycle anionic substrates . Preliminary studies with Cgl have provided evidence of a role of fatty acid (FA) metabolism in its nephrotoxicity, and work with Cld has shown it to be a potent inhibitor of renal tubular cell and mitochondrial carnitine (Carn) transport . Studies were therefore done to examine the effects of Cgl and Cld on the mitochondrial metabolism of butyrate, the anion of a short-chain FA that does not require the Carn shuttle to enter the inner matrix, and the effects of Cgl on the metabolism of palmitoylcarnitine (PCarn), the Carn conjugate of a long-chain FA that does enter the mitochondrion by the Carn shuttle . The following was found: (1) Cgl reduced the oxidation and uptake of butyrate after in vitro (2000 micrograms/mL, immediate effect) and after in vivo (300 mg/kg body weight, 1 hr before killing) exposure; (2) Cld caused milder in vitro toxicity, and no significant in vivo toxicity, to mitochondrial butyrate metabolism; (3) like Cld, Cgl reduced PCarn-mediated respiration after in vivo exposure, but, unlike Cld, it did not inhibit respiration with PCarn in vitro; (4) the Carn carrier was stimulated slightly by in vitro Cgl but was unaffected by in vivo Cgl; (5) in vivo Cgl had no effect on mitochondrial free Carn or long-chain acylCarn concentrations in the in situ kidney; (6) Cgl increased the excretion of Carn minimally compared with the effect of Cld; and (7) cephalexin, a nontoxic cephalosporin, caused mild reductions of respiration with butyrate and PCarn during in vitro exposure, but stimulated respiration with both substrates after in vivo exposure . Conclusions: Cgl has essentially the same patterns of in vitro and in vivo toxicity against mitochondrial butyrate uptake and oxidation that both Cgl and Cld have against TCA-cycle substrates . Cld has little or no in vivo toxicity to mitochondrial butyrate metabolism, whereas in vivo Cgl is as toxic as Cld to respiration with PCarn . The greater overall in vivo toxicity of Cgl to mitochondrial FA metabolism, with lower cortical concentrations and AUCs than those of Cld, supports earlier evidence that Cld is less toxic than Cgl at the molecular level.

Am J Gastroenterol, 1995 Mar, 90(3), 439 - 48
Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo; McFarland LV et al.; OBJECTIVES: To determine the safety and efficacy of a new preventive agent for antibiotic-associated diarrhea (AAD) in patients receiving at least one beta-lactam antibiotic . METHODS: A double-blinded, placebo-controlled, parallel group study was performed in a high-risk group of hospitalized patients receiving a new prescription for a beta-lactam antibiotic and having no acute diarrhea on enrollment . Lyophilized Saccharomyces boulardii or placebo (1 g/day) was given within 72 h of the start of the antibiotic(s) and continued until 3 days after the antibiotic was discontinued, after which the patients were followed for 7 wk . RESULTS: Of the 193 eligible patients, significantly fewer, 7/97 (7.2%), patients receiving S . boulardii developed AAD compared with 14/96 (14.6%) on placebo (p = 0.02) . The efficacy of S . boulardii for the prevention of AAD was 51% . Using a multivariate model to adjust for two independent risk factors for AAD (age and days of cephalosporin use), the adjusted relative risk was significantly protective for S . boulardii (RR = 0.29, 95% CI = 0.08, 0.98) . CONCLUSION: The prophylactic use of S . boulardii given with a beta-lactam antibiotic resulted in a significant reduction of AAD with no serious adverse reactions.

Ann Pharmacother, 1995 Mar, 29(3), 240 - 5
Adverse drug reaction reporting in a multicenter surveillance study; Timm EG et al.; OBJECTIVE: To evaluate the performance of a multicenter, prospective surveillance program in identifying adverse events, and to seek explanations for misclassification bias . DESIGN: The design was a prospective observational study of patients with documented or suspected bacterial pneumonia . SETTING: Data were collected in 74 acute care hospitals across the US . PATIENTS: This evaluation was based on a consecutive sample of 1822 adult patients (> 18 years of age) with documented or suspected bacterial pneumonia who were being treated with a cephalosporin, a penicillin, or an aminoglycoside over a 3-month period . Patients were followed for the duration of antibiotic therapy and were excluded if antibiotic therapy was < 3 days or if the pneumonia was judged to be nonbacterial . INTERVENTIONS: Clinical pharmacists documented patient demographics, concurrent illnesses and medications, antibiotic administration, relevant laboratory data, and the occurrence of nephrotoxicity and neutropenia . MAIN OUTCOME MEASURES: Validity of investigators' identification of neutropenia and nephrotoxicity as compared with objective laboratory data was assessed by using sensitivity, specificity, and positive and negative predictive value measures . RESULTS: Among the 1502 patients with sufficient data to evaluate neutropenia, there was agreement in 1270 patients (84.6%); likewise, among 1291 patients with sufficient data to evaluate nephrotoxicity there was agreement in 1186 patients (91.9%) . Sensitivity of the researchers' assessments was 50.9% and 71.0% for neutropenia and nephrotoxicity, respectively . The negative predictive value was > 95% for both events . CONCLUSIONS: Overall, this evaluation demonstrated that the Drug Surveillance Network can successfully identify targeted adverse events . Moreover, this study highlights the importance of validation for all types of outcomes-oriented research studies.

Int J Clin Pharmacol Ther, 1995 Mar, 33(3), 149 - 55
Postmarketing surveillance on side-effects of cefminox sodium (Meicelin); Mayama T et al.; A postmarketing surveillance of cefminox sodium (Meicelin, CMNX) for intravenous injection was conducted for about 4 years from August 1987 through June 1991, and 13,431 patients were followed up to evaluate the safety of the drug . The incidence of side-effects was 1.76% . By organ, the most frequently observed were hepatic and of the bile duct system (0.87%) followed by those on leukocytes and reticuloendothelial system (0.24%), skin and adnexa (0.24%) and digestive tract (0.16%) indicating a tendency similar to that of other injectable cephalosporins . The incidence of the side-effects among elderly patients (65 years old or older) was 2.12%, whereas among patients 64 years old or younger it was 1.58% with no significant differences between the two groups . No side-effects specific to the elderly were observed . Among children 15 years old or younger the incidence was 0.59%, which was lower than that for patients 16 years old or older (1.90%) . Potential side-effects on pregnant women (n = 101) and their babies were also checked . No side-effects occurred among the 52 pregnant women evaluated and no abnormalities were detected in their babies who were followed up for up to 4 years . Cefminox is thus considered to be a highly safe cephalosporin antibiotic.

J Vet Pharmacol Ther, 1995 Feb, 18(1), 61 - 7
The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid; Whittem T et al.; Ceftiofur sodium is a third-generation cephalosporin antibiotic . It is possible that non-steroidal anti-inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle . Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin . In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter . The organic anion transporter substrate used in this evaluation was probenecid . Ten healthy, non-pregnant, non-lactating dairy cows were used in a randomized complete three-way crossover design . In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus . For treatment with ceftiofur sodium alone, the mean volume of distribution at steady-state Vd(ss) was 0.2 +/- 0.06 L/kg, the mean volume of distribution by the area method Vd(area) was 0.38 +/- 0.22 L/kg, mean residence time (MRT) was 6.5 +/- 1.8 h, mean residence time in peripheral tissues (MRTp) was 2.6 +/- 1.0 h, total body clearance (Cl) was 0.032 +/- 0.013 L/kg/h and elimination rate constant (beta) was 0.097 +/- 0.044 h-1 (mean +/- standard deviation) . No statistically significant changes were detected as a result of preceding treatment with aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

In Vitro Cell Dev Biol Anim, 1995 Feb, 31(2), 94 - 106
LLC-PK1 epithelia as a model for in vitro assessment of proximal tubular nephrotoxicity; Steinmassl D et al.; LLC-PK1 cells, an established epithelial cell line derived from pig kidney, were used as a model system for assessment of nephrotoxic side effects of three cephalosporin antibiotics: cephaloridine, ceftazidime, and cefotaxime . Toxic effects of these xenobiotics were monitored on confluent monolayers by light and electron microscopy and by the release of cellular marker enzyme activities into the culture medium . In addition, LLC-PK1 cells were grown on microporous supports, and cephalosporin-induced alteration of epithelial functional integrity was monitored by a novel electrophysiologic approach . For this purpose, an Ussing chamberlike experimental setup was used . The dose-dependent effects on transepithelial ionic permselectivity were monitored under conditions in which defined fractions of the apical culture medium NaCl contents were replaced iso-osmotically by mannitol . This method of determining the functional intactness of the epithelial barrier by measuring dilution potentials was found to be far more sensitive than monitoring cell injury by means of morphology or measurement of enzyme release . As expected from animal experimental data, a dose-dependent disruption of monolayer integrity was detected with all three methodologies applied . Cephaloridine was found the most toxic compound followed by ceftazidime, where a 3-fold, and cefotaxime, where a 10-fold dose of that of cephaloridine was needed to produce cell injury . Measurement of transepithelial dilution potentials was more sensitive as compared to the release of the apical plasma membrane marker enzyme activities alkaline phosphatase and gamma-glutamyltranspeptidase, the cytosolic lactate dehydrogenase, or the mitochondrial glutamate dehydrogenase . The data were compared to the effects of the aminoglycoside antibiotic gentamicin, which at least with respect to its effects on LLC-PK1 morphology and enzyme release, but not transepithelial electrical properties, was already investigated.

Antimicrob Agents Chemother, 1995 Feb, 39(2), 564 - 6
Low-level resistance to the cephalosporin 3'-quinolone ester Ro 23-9424 in Escherichia coli; Chapman JS et al.; Four spontaneous, single-step mutants of Escherichia coli K-12 resistant to low levels of the cephalosporin 3'-quinolone ester Ro 23-9424 were isolated at a frequency of 10(-10) to 10(-11) mutants per CFU plated . The mutants were cross-resistant to both cephalosporin (cefotaxime) and quinolone (fleroxacin) components . Accordingly, they had altered porins and replicative DNA biosynthesis resistant to fleroxacin . There was no increase in beta-lactamase activity when tested with nitrocephin, and the penicillin-binding protein profiles were normal.

Otolaryngol Head Neck Surg, 1995 Feb, 112(2), 210 - 4
Staging of chronic hyperplastic rhinosinusitis: treatment strategies; Friedman WH et al.; In 1990 we reported an initial prospective study of 100 patients using a four-stage system for classification of chronic rhinosinusitis . Between January 1988 and July 1992, we used this system in staging an additional 1814 patients, on whom 2980 intranasal sphenoethmoidectomies were performed . In this staging system a protocol trial of medication was given for 2 weeks, followed by axial and coronal computed tomography . Medication consisted of a second-generation cephalosporin antibiotic, usually cefuroxime; a 4-day burst of intraoral steroids, usually prednisone; and an antihistamine decongestant if not contraindicated . The stages of chronic hyperplastic rhinosinusitis included the stages described in the 1990 report (i.e., stage I, single-focus disease; stage II, discontiguous disease throughout the ethmoid labyrinth; stage III, diffuse disease responsive to medication; and stage IV, diffuse disease unresponsive to or poorly responsive to medication) . The results of this study have shown that the computed tomography staging system based on computed tomography extent of disease after medical therapy is a simple, easily remembered, and very effective modality for the classification of chronic sinusitis . This system provides a rationale for discussing and planning surgery with patients and physicians and is a convenient reference for the reporting of end results . More importantly, a linear relationship between disease stage and outcomes is demonstrated . This statistically highly significant feature of the staging system provides a firm basis for the production of outcomes after various treatment strategies, particularly ethmoidectomy and the treatment of sinusitis.

FEBS Lett, 1995 Jan 16, 358(1), 97 - 100
delta-L-(alpha-aminoadipoyl)-L-cysteinyl-D-valine synthetase: the order of peptide bond formation and timing of the epimerisation reaction; Shiau CY et al.; delta-L-(alpha-Aminoadipoyl)-L-cysteinyl-D-valine (ACV) synthetase catalyses the formation of the common precursor tripeptide of both the penicillin and cephalosporin antibiotics from the L-enantiomers of its constituent amino acids . Replacement of cysteine with L-O-methylserine in preparative-scale incubations led to the isolation of both L-O-methylserinyl-L-valine and L-O-methylserinyl-D-valine dipeptides . The dipeptides were characterized with the aid of authentic synthetic standards by both 1H NMR and electrospray ionization MS . A revised mechanism for ACV biosynthesis involving formation of the cysteinyl-valine peptide bond before the epimerisation of valine and subsequent condensation with the delta-carboxyl of L-alpha-aminoadipate is therefore proposed.

Microb Drug Resist, 1995 Winter, 1(4), 341 - 4
Cases of Lyme borreliosis resistant to conventional treatment: improved symptoms with cephalosporin plus specific beta-lactamase inhibition; Gasser R et al.; We present four cases of verified late Lyme borreliosis with persistent symptoms and positive serology despite repeated courses of high-dose intravenous penicillin G and/or cephalosporins (including cefoperazone) . The patients were now treated with cefoperazone 2 g plus sulbactam 1 g bid iv for 14 days . At the end of treatment, patients were symptom free and have remained so for the following 12 months . By then, IgG against Borrelia burgdorferi had decreased . It is concluded that the addition of beta-lactamase inhibitors to intravenous treatment could be beneficial in Lyme disease refractory to conventional treatment.

Orthop Clin North Am, 1995 Jan, 26(1), 191 - 7
Gunshot wounds to the foot; Boucree JB Jr et al.; One hundred and one patients who sustained gunshot wounds to their feet were retrospectively reviewed . All patients were treated at King/Drew Medical Center between 1982 and 1994 . From the authors' experience, they believe that patients with low-velocity gunshot wounds to the foot should be hospitalized and treated with at least a 3-day course of intravenous antibiotics of a first generation cephalosporin . Low-energy shotgun injuries should be treated the same as low-velocity injuries . Patients with high-velocity and high-energy shotgun wounds should be hospitalized and receive broad-spectrum intravenous antibiotics with multiple irrigation and debridements.

Cancer Res, 1995 Jan 1, 55(1), 63 - 70
Development of a humanized disulfide-stabilized anti-p185HER2 Fv-beta-lactamase fusion protein for activation of a cephalosporin doxorubicin prodrug; Rodrigues ML et al.; The humanized anti-p185HER2 antibody, humAb4D5-8, has completed Phase II clinical trials for p185HER2-overexpressing breast cancer . Here, this antibody is used as a building block to engineer a disulfide-linked Fv (dsFv) beta-lactamase fusion protein for use in antibody-dependent enzyme-mediated prodrug therapy using cephalosporin-based prodrugs . Three Fv variants were designed with an interchain disulfide bond buried at the VL/VH interface and secreted from Escherichia coli . One variant, dsFv3 (VL L46C VH D101C0, has similar affinity for antigen (Kd = 0.7 nM) as the wild-type Fv and was used to construct a fusion protein in which beta-lactamase, RTEM-1, is joined to the carboxy terminus of VH . The dsFv3-beta-lactamase fusion protein secreted from E . coli efficiently activates a cephalothin doxorubicin prodrug (PRODOX, kcat/km = 1.5 x 10(5) s-1 M-1) . PRODOX is approximately 20-fold less toxic than free doxorubicin against breast tumor cell lines SK-BR-3 and MCF7, which express p185HER2 at elevated and normal levels, respectively . Prebinding the dsFv3-beta-lactamase fusion protein specifically enhances the toxicity level of PRODOX to that of doxorubicin against SK-BR-3 but not MCF7 cells . The fusion protein retains both antigen-binding plus kinetic activity in murine serum and is cleared rapidly as judged by pharmacokinetic analysis in nude mice (initial and terminal half-lives of 0.23 and 1.27 h, respectively) . Development and characterization of the dsFv3-beta-lactamase fusion protein is an important step toward targeted prodrug therapy of p185HER2-overexpressing tumors.

Microbiology, 1994 Dec, 140 ( Pt 12), 3367 - 77
Possible involvement of the lysine epsilon-aminotransferase gene (lat) in the expression of the genes encoding ACV synthetase (pcbAB) and isopenicillin N synthase (pcbC) in Streptomyces clavuligerus; Yu H et al.; Streptomyces clavuligerus produces the beta-lactam antibiotics penicillin N, O-carbamoyldeacetylcephalosporin C and cephamycin C . We characterized a wild-type DNA region which restores antibiotic formation to a mutant strain named NP1, previously shown to exhibit depressed activities for two early enzymes of cephalosporin synthesis, delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) and isopenicillin N synthase (IPNS) . L-Lysine epsilon-aminotransferase (LAT) assays and alpha-AAA feeding experiments suggested that strain NP1 is a lat mutant . NP1 recovered LAT, ACVS and IPNS activities when transformed with the cloned region . DNA sequencing showed that this region encodes the entire LAT gene (lat), required for the conversion of L-lysine to the beta-lactam precursor L-alpha-aminoadipic acid (alpha-AAA), as well as the upstream half of the ACVS gene (pcbAB) . The activities of ACVS and IPNS appear to depend upon LAT expression . Gene fusions constructed to investigate promoter activities in the cloned region support a model of interdependence in the expression of the genes for LAT, ACVS and IPNS (pcbC).

Antimicrob Agents Chemother, 1994 Dec, 38(12), 2902 - 4
In vitro susceptibilities of 185 penicillin-susceptible and -resistant pneumococci to WY-49605 (SUN/SY 5555), a new oral penem, compared with those to penicillin G, amoxicillin, amoxicillin-clavulanate, cefixime, cefaclor, cefpodoxime, cefuroxime, and cefdinir; Spangler SK et al.; In vitro susceptibility of 185 penicillin-susceptible and -resistant pneumococci to WY-49605, a new oral penem, was compared with susceptibility to penicillin G, amoxicillin with and without clavulanate, cefixime, cefaclor, cefpodoxime, cefuroxime, and cefdinir . WY-49605 yielded MICs for 50 and 90% of the strains tested (MIC50 and MIC90, respectively) of 0.03 and 0.06, 0.125 and 0.5, and 0.5 and 1.0 micrograms/ml, respectively, against penicillin-susceptible, intermediately resistant, and fully resistant strains, respectively . The MIC50 and MIC90 for both amoxicillin and amoxicillin-clavulanate were identical and approximately 1 doubling dilution higher than those for WY-49605 and were < or = 0.06 and 0.125, 0.25 and 1.0, and 1.0 and 1.0 micrograms/ml, respectively . Cephalosporin MIC90s were all significantly higher than those of the latter three compounds for intermediately resistant and fully resistant strains.

Analyst, 1994 Nov, 119(11), 2411 - 6
Enzyme linked immunosorbent assay for ceftazidime in airborne samples; Farrell C et al.; A simple and rapid enzyme linked immunosorbent assay (ELISA) method for the cephalosporin, ceftazidime, has been developed for the quantification of this antibiotic in solutions that have been eluted from filters following the capture of air samples in the workplace . The assay has the specificity, sensitivity and precision necessary for its use in determining airborne concentrations of ceftazidime in the workplace as part of an occupational health and hygiene programme.

Toxicology, 1994 Nov-Dec, 94(1-3), 97 - 118
Renal cell type specificity of cephalosporin-induced cytotoxicity in suspensions of isolated proximal tubular and distal tubular cells; Lash LH et al.; We have developed an in vitro model for investigation of nephron heterogeneity and cell type-specific patterns of renal injury . To further validate our model and to study biochemical mechanisms of cephalosporin-induced injury, cytotoxicity of three cephalosporins was studied in freshly isolated proximal tubular (PT) and distal tubular (DT) cells from rat kidney . The three cephalosporins {cephaloridine (CPH), cephalexin (CXN), cephalothin (CTN)} were chosen because they exhibit varying degrees of nephrotoxicity in vivo and contain different functional groups . CPH produced greater amounts of lactate dehydrogenase release from PT cells than either CXN or CTN, indicating greater toxicity of CPH, which agrees with in vivo observations . DT cells were not affected by any of the cephalosporins . Thus, the cephem ring is sufficient to produce PT cell injury but the presence of other functional groups modifies toxicity . SKF-525A and alpha-tocopherol protected PT cells from both CPH and CTN, suggesting involvement of cytochrome P-450 metabolism and oxidative stress . Both PT and DT cells exhibited transport of CPH or CXN and transport of CPH into PT cells was inhibitable by probenecid, consistent with action of a specific carrier . Transport alone, therefore, cannot account for the cell type specificity pattern in vitro . Effects on intracellular glutathione status, malondaldehyde formation, and uncoupler-stimulated respiration were also investigated, and these generally correlated with cell type specificity patterns but not always with degree of cytotoxicity . These results validate further the isolated PT and DT cells as in vitro models to study cell type-specific renal injury and show a role for oxidative stress, cytochrome P-450 bioactivation, and mitochondrial dysfunction in cephalosporin-induced PT cell injury.

Minerva Stomatol, 1994 Nov, 43(11), 513 - 9
{The clinical evaluation of acetoxyethylcefuroxime in dentistry}; Scata E et al.; The study examines the use of an oral antibiotic with a wide spectrum of action tested in dentistry belonging to the cephalosporin class: acetoxyethylcefuroxime . The pharmaceutical industry has succeeded in synthesising a prodrug of parenteral cephalosporin "Metoxyrinic cefuroxime sodium", thus resolving the problems presented by earlier molecules such as: scarce bioavailability, poor palatability and collateral effects at a gastroenteric level . This is a 2nd generation cephalosporin whose mechanism of action consists in the capacity to selectively block the synthesis of the peptidoglycan, a fundamental component of the cell wall of both Gram+ and Gram- bacteria . The study, which was performed in the Division of Odontostomatology of the Mauriziano Hospital in Turin, examined 59 patients suffering from some of the most commonplace dental pathologies such as: apical periodontitis-alveolitis-odontogenic abscesses-eighth teeth in dysodontiasis-maxillary cysts . The following clinical parameters were evaluated in both outpatients and those undergoing surgery: swelling, pain, lymphoadenopathy at the start of treatment, and at days 3 and 5 of treatment . A 250 mg tablet was administered every 12 hours for 5 days . Owing to the rapid resolution of symptoms and the limited collateral effects observed, the authors conclude that the drug may be regarded as the elective form of treatment.

J Allergy Clin Immunol, 1994 Oct, 94(4), 725 - 31
Allergy to beta-lactams: a survey of current practices; Wickern GM et al.; Many issues related to the diagnosis and management of beta-lactam drug allergy still await definitive recommendations . To determine how practicing allergists deal with some of these dilemmas, a questionnaire was mailed to 3500 physician members and fellows of the American Academy of Allergy and Immunology . It was also sent to each of the allergy training program directors in the United States to determine what is currently taught to fellows in training . Benzylpenicilloyl-polylysine (Pre-Pen) and fresh penicillin G are used for skin testing by more than 86% of both respondent groups, whereas minor determinant mixtures are used by only 40% . Epicutaneous followed by intradermal injection was the skin test technique used by 86% of these allergists . More than 90% said they would skin test in cases of reaction history of urticaria, whereas only 1.5% would test in cases of family history of penicillin allergy . Practicing allergists and program directors differed slightly when queried about cephalosporin cross-reactivity . Program directors were more cautious in their use of cephalosporins with patients allergic to penicillin . Program directors were also more likely to repeat skin testing before future penicillin courses than were practicing allergists . Clearly, some individual approaches to the diagnosis and management of beta-lactam allergy are practiced . Development of practice guidelines by our professional organizations may be useful.

Neurosurgery, 1994 Oct, 35(4), 622 - 31
Nocardial brain abscess: treatment strategies and factors influencing outcome; Mamelak AN et al.; The successful management of nocardial brain abscess remains problematic . The authors report 11 cases of nocardial brain abscess treated between 1971 and 1993 and review 120 cases reported since 1950 . The clinical findings included focal deficits in 55 patients (42%), nonfocal findings in 36 (27%), and seizures in 39 (30%) . Extraneural nocardiae were present in 66% of the cases; pulmonary (38%) and cutaneous/subcutaneous (20%) locations were the most frequent . The abscesses were single in 54% of the patients, multiple in 38%, and of unknown number in 8% . Forty-four of 131 patients (34%) were immunocompromised; since 1975, 18 of 40 immunocompromised patients (45%) were transplant recipients and six (15%) had human immunodeficiency virus . The mortality rate was 24% after initial craniotomy and excision (11/45), 50% after aspiration/drainage (17/34), and 30% after nonoperative therapy (7/23); 29 cases (22%) were diagnosed at autopsy . The mortality rate was 33% in patients with single abscesses and 66% in those with multiple abscesses (P < 0.0003) . There was no difference in the mortality rates of immunocompromised and nonimmunocompromised patients treated before computed tomography (CT) was available; since the advent of CT, however, the mortality rate has been significantly higher in immunocompromised patients (55% vs . 20%, P < 0.05) . Although the mortality rate for nocardial brain abscesses has dropped almost 50% since the advent of CT, it has remained virtually unchanged in immunocompromised patients and is three times higher than that of other bacterial brain abscesses (30% vs . 10%) . The authors recommend image-directed stereotactic aspiration for diagnosis; however, craniotomy and total excision are necessary in most cases, because nocardial abscesses are usually multiloculated . Patients with minimal neurological deficits or small abscesses may be treated initially with antibiotics alone . Sulfonamides, alone or in combination with trimethoprim, are most effective and should be continued for at least 1 year . Minocycline, imipenem, or aminoglycoside in combination with a third-generation cephalosporin may be used with reasonably good success as second-line agents in cases of allergy or nonresponsiveness to sulfa agents.

Appl Microbiol Biotechnol, 1994 Oct, 42(1), 57 - 66
Expression studies with the bidirectional pcbAB-pcbC promoter region from Acremonium chrysogenum using reporter gene fusions; Menne S et al.; Two cephalosporin genes from Acremonium chrysogenum, pcbAB and pcbC encode the ACV (alpha-aminoadipyl-cysteinyl-valine) synthetase and isopenicillin N-synthetase, respectively . The two adjacent genes are orientated in opposite directions on the chromosomal DNA, separated by a 1.2-kb non-translated sequence, carrying the putative promoter sequences . Complete sequencing of this intergenic region revealed differences from homologous sequences from other strains . To assess the putative promoter strength, we constructed an expression vector carrying the beta-glucuronidase (gusA) and beta-galactosidase (lacZ) genes in opposite orientation . Fusion of the pcbAB-pcbC promoter region resulted in recombinant vector molecules, which were used for in-vivo expression studies . Using the co-transformation procedure, the reporter gene fusions were transferred into A . chrysogenum recipient strains together with vector pMW1 . Individual transformants were used for protein preparations to measure specific activities of the enzymes coded by the reporter genes . The data provide in-vivo evidence that the pcbC promoter is at least five times stronger than the pcbAB promoter . Our approach should prove useful in evaluating regulatory sequences that govern gene expression in A . chrysogenum.

Harefuah, 1994 Sep, 127(5-6), 163 - 5, 215
{Sonographic demonstration of pseudo-cholelithiasis after ceftriaxone}; Barzilai M; The term biliary pseudolithiasis was coined by Schaad (1988) to describe the appearance of gallbladder sludge following treatment with ceftriaxone . After cessation of the drug the condition resolves, hence the term "pseudolithiasis." The third generation cephalosporin, cefatriaxone, is a very potent, broad spectrum antibiotic indicated in meningitis, osteomyelitis, pyelonephritis, Lyme disease and many other severe infectious diseases . Up to 46% of those receiving this antibiotic develop gallbladder sludge . Most are asymptomatic, but a small proportion may develop right upper quadrant pain, nausea, vomiting and even cholecystitis . Ultrasonography may demonstrate many, small, echogenic particles within the gallbladder, as well as larger echogenic foci casting acoustic shadows . However, it can not differentiate these pseudostones from real stones . There are reports of surgical intervention in such cases . 2 boys, aged 5 and 10 years, respectively, treated with ceftriaxone for meningitis are presented . Both developed symptoms during treatment and in both gallbladder sludge was identified by ultrasonography . In 1 intraluminal gallbladder findings were identical with the appearance of surgical stones . Follow-up ultrasonography after the drug was stopped showed no evidence of pseudostones in either case . Awareness of this phenomena might save many unnecessary operations.

Chemotherapy, 1994 Sep-Oct, 40(5), 317 - 23
In vitro activity of two new oral cephalosporins, cefixime and cefdinir (CI 983), on human peripheral mononuclear and polymorphonuclear leukocyte functions; Fietta A et al.; The in vitro effects of cefixime and cefdinir (CI 983), two so-called third-generation oral cephalosporin derivatives, on human polymorphonuclear and mononuclear phagocyte functions (random migration and chemotaxis, specific and nonspecific phagocytosis, nitroblue tetrazolium reduction, superoxide production, microbicidal activity) were studied . Neither antibiotic, in the range of its attainable therapeutic concentration, exhibited any toxic effect on random migration, chemotaxis, metabolic activation and microbicidal mechanisms of phagocytic cells . Cefixime did not interfere in phagocytosis while cefdinir enhanced both phagocytosis frequency and index . The modulating effect on phagocytosis exerted by cefdinir was achieved at very low antibiotic concentrations (0.06 mg/l for polymorphonuclear leukocytes and 0.03 mg/l for monocytes) when non-opsonized zymosan particles were used as phagocytic challenge . Moreover, the effect was demonstrated both in the presence of cefdinir and after pretreatment of cells with the antibiotic and its removal by washings . As for specific phagocytosis, parameters were slightly increased by cefdinir but only the phagocytosis index was significantly improved in the presence of 2 mg/l of antibiotic.

J Pharm Sci, 1994 Sep, 83(9), 1204 - 8
Discrimination and direct determination of cephalosporins by circular dichroism; Gortazar P et al.; The circular dichroism and ultraviolet spectra of 15 commercial cephalosporins in common clinical use are analyzed . Distinguishing between the beta-lactam antibiotics (penicillins, cephalosporins, and cephamycins) on the basis of their CD spectral data has been found to be straightforward . Furthermore, sufficient CD spectral dissimilarities are observed to discriminate among the cephalosporin homologues and to classify these antibiotics in five spectroscopic groups, on the basis of the wavelengths of their Cotton effects . In addition, some chemical structural characteristics for these spectroscopic groups are discussed . Besides molar absorptivity and CD data, the slopes and the intercepts of the equations of the regression line are calculated for each of these antibiotics, the correlation coefficients being higher than 0.9993 . The validity of the proposed model is confirmed by analysis of the variance . The results demonstrated that the proposed method is accurate and precise . The method was successfully applied to the direct determination of these drugs in commercial oral suspensions, injections, and capsules . The principal advantages of this method are quickness and simplicity no derivatization or chromatographic separation steps being needed.

Am J Med, 1994 Aug 15, 97(2A), 14 - 22
Treatment of bone and joint infections utilizing a third-generation cephalosporin with an outpatient drug delivery device . HIAT Study Group; Mauceri AA; The purpose of this study was to determine the efficacy, safety, and cost effectiveness of a third-generation cephalosporin, cefotaxime, administered via an ambulatory delivery system (ADS) in the treatment of bone and joint infections (BJI) . A total of 27 BJI patients enrolled as a subgroup of a multicenter, prospective, open-label trial were administered 1-2 g of cefotaxime every 8 hours using ADS . Of these patients, 18 were evaluable, with the causative organisms identified and susceptible to cefotaxime . The evaluable group comprised 7 primary and 11 postsurgical BJI patients . Inpatient treatment followed by outpatient treatment with cefotaxime/ADS achieved a clinical success rate of 83.3%; however, the mean length of hospital stay for these patients was not substantially reduced . Administration via ADS permitted administration of several daily doses with minimal intervention by the patient . Both the drug and the delivery system were well tolerated . In conclusion, an intravenous antibiotic regimen such as cefotaxime administered via an ADS is an appropriate management option for patients with BJI . It is efficacious, well tolerated, and user friendly.

J Pharmacol Exp Ther, 1994 Aug, 270(2), 498 - 504
Transcellular transport of oral cephalosporins in human intestinal epithelial cells, Caco-2: interaction with dipeptide transport systems in apical and basolateral membranes; Matsumoto S et al.; The transport characteristics of p.o . cephalosporin antibiotics by monolayers of the human intestinal epithelial cell line Caco-2 were examined by measuring intracellular accumulation and transcellular transport . In the presence of an inward H+ gradient (at pH 6.0 of the apical medium), cephalosporins were accumulated by the monolayers in the following order: ceftibuten (anion) > cephradine (zwitterion) > cephalexin (zwitterion) > cefixime (anion) . The accumulation rate of ceftibuten was more rapid than that of cephradine, whereas both appeared at the same rate in the basolateral compartment . The efflux of ceftibuten from the monolayers to the basolateral compartment was lower than the efflux of cephradine . The accumulation rate of ceftibuten from the basolateral side was markedly lower than that of cephradine . The accumulation of ceftibuten from both the apical and basolateral compartment was significantly inhibited by excess dipeptides . The kinetic parameters indicated that ceftibuten has higher affinity for the apical dipeptide transport system in the presence of a pH gradient, whereas it has much lower affinity for the basolateral dipeptide transport system at physiological pH of 7.4 than cephradine . These results suggest that both cephradine and ceftibuten are transported via the H+/dipeptide cotransport system localized in the apical membranes, and that the flux of these drugs across the basolateral membranes is also mediated by the dipeptide transport system in an H+ gradient-independent manner, exhibiting a rate-limiting step for their transcellular transport in Caco-2 monolayers.

J Pediatr, 1994 Aug, 125(2), 325 - 8
Serum sickness-like reactions associated with cefprozil therapy; Lowery N et al.; Four patients had serum sickness-like reactions during treatment with cefprozil, a new cephalosporin . Two patients had had previous mild reactions associated with cephalosporin therapy . It remains uncertain whether cefprozil-associated serum sickness-like reaction represents a unique or a class-related adverse drug reaction.

J Pharm Pharmacol, 1994 Aug, 46(8), 680 - 4
The inhibitory effects of cephalosporin and dipeptide on ceftibuten uptake by human and rat intestinal brush-border membrane vesicles; Sugawara M et al.; The types of inhibitory effects caused by compound V (an analogue of ceftibuten) and alanylproline (dipeptide) on the uptake of ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed . In the presence of an inward H(+)-gradient, the initial uptake rate of ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent Km and Vmax values of 0.35 mM and 2.052 nmol (mg protein)-1 min-1 for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)-1 min-1 for rat BBMV, respectively . For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive . These results suggest that there is a stereospecific transport system which is common to ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.

Br J Obstet Gynaecol, 1994 Jul, 101(7), 610 - 4
A randomised controlled trial of prophylaxis of post-abortal infection: ceftriaxone versus placebo; Henriques CU et al.; OBJECTIVE: To investigate the incidence of post-operative infection after first trimester abortion in women treated with a long-acting cephalosporin (ceftriaxone) compared with low risk patients receiving no treatment and with high risk patients receiving our standard treatment of ampicillin/pivampicillin and metronidazole . DESIGN: A prospective, randomised controlled trial . SETTING: Department of Obstetrics and Gynaecology, Rigshospitalet, University of Copenhagen, Denmark . SUBJECTS: Nine hundred and ninety-six women, admitted on an outpatient basis for legal termination of pregnancy at 12 weeks or less of gestation, were included in the study after giving informed consent . The women were divided into high risk and low risk categories and allocated either to treatment with ceftriaxone or to standard treatment . For high risk patients the standard treatment was initiated by a peroperative injection of ampicillin and metronidazole, followed by oral doses of metronidazole and pivampicillin three times daily for four days . No prophylactic antibiotics were given to the women randomised to standard treatment in the low risk group . INTERVENTIONS: All women were kept under observation, and, between six and 14 days postoperatively, underwent pelvic examination . Clinical endpoints were noted . MAIN OUTCOME MEASURES: Post-operative pelvic inflammatory disease in women applying for legal first trimester abortion . RESULTS: Seven hundred and eighty-six women fulfilled the criteria for evaluation . A tendency toward a prophylactic effect of ceftriaxone was observed in most clinical findings . A significant prophylactic effect of ceftriaxone was found in the low risk group . CONCLUSIONS: This study demonstrated a significant reduction in post-operative pelvic inflammatory disease in low risk patients, who were applying for legal first trimester abortion, treated peroperatively with ceftriaxone . No significant difference was demonstrated between high risk patients treated with ceftriaxone or ampicillin/pivampicillin and metronidazole.

J Ind Microbiol, 1994 Jul, 13(4), 217 - 9
A role for alanine in the ammonium regulation of cephalosporin biosynthesis in Streptomyces clavuligerus; Kasarenini S et al.; It is known that excess ammonium supply decreases cephalosporin production and represses cephalosporin synthases . We wondered whether an additional important effect could be inhibition of synthase action by alanine . We had previously shown that ammonium addition induced alanine dehydrogenase and increased intracellular alanine and that alanine could inhibit resting cell synthesis of cephalosporins . In the present work we confirm the alanine inhibition of antibiotic production by resting cells . We found L-alanine inhibited three of the four synthases tested: ACV synthetase, cyclase and expandase; the epimerase was not inhibited . These data suggest that interference in cephalosporin production by growth in ammonium salts involves synthase inhibition by intracellular alanine, in addition to the known role of ammonium in synthase repression.

Clin Ter, 1994 Jun, 144(6), 517 - 20
{Safety of azithromycin in patients allergic to penicillin and cephalosporin}; Pacor ML et al.; We have evaluated the safety of a new antibiotic, azithromicin, in 48 patients with allergy to penicillin and/or to cephalosporin . Diagnosis of allergy was based on clinical history, skin test and detection of serum specific IgE . The most common symptoms were urticaria, oedema, pruritus, oral aphthosis . Azithromicin was administered at the increasing dosage of 100-200-300 and 400 mg every 2 days . Our patients did not show any reaction to azithromicin . This antibiotic is therefore a valid alternative to penicillin and/or cephalosporin in patients allergic to these two drugs.

Minerva Anestesiol, 1994 Jun, 60(6), 341 - 4
{Multiple organ failure in pre-term pregnancy: gestosis and/or typhoid fever?}; Iermano C et al.; The authors describe a clinical case of Multiple Organ Failure (MOF) . Such a pathology was reported, at admission in ICU, in a young woman aged 26 who was in the 30th week of amenorrhoea, formerly hospitalized in Obstetrics, where she had had a Caesarean section because of the met of eclamptic crisis, after a pregnancy substantially normal . At the moment of her admission to the ICU the examination highlighted the sense organ obnubilated, the breath dyspnoic, a systolic and diastolic hypotension and a tachycardia of medium seriousness . From laboratory examinations it was possible to maintain that there was a serious anemia with white cells raised, a coagulative imbalance and above all a serious alteration of hepatic and pancreatic function . The creatininemia had increased a bit, a clear contraction of diuresis was present and a considerable metabolic acidosis had become intelled . Therefore the patient was affected by multiple organ failure . In successive days it was possible to execute an EEG that proved substantially normal, then a Computer Tomography to abdomen showed the presence of vast areas of hepatic necrosis, ascitic hemorrhagic fluid and a volume increased pancreas . Hepatitis markers proved negative, while a positive response was achieved for a typhoid infection (this result was reconfirmed many times later.) Modifying the antibiotic therapy (substituting full dose ampicillin to the cephalosporin) the clinical case was solved . Moreover, also thanks to a very good answer to antibiotic therapy, it was possible to confirm the diagnosis of typhoid fever, not gestosis.

Diagn Microbiol Infect Dis, 1994 Jun, 19(2), 121 - 7
Cefetamet pivoxil in the treatment of uncomplicated gonorrhea; Lucena R et al.; We studied the efficacy and safety of cefetamet pivoxil (CAT), an oral aminothiazolyl cephalosporin, in a series of open, comparative multicenter studies in 207 women (four study centers) with uncomplicated gonorrhea, and summarized and pooled the results with those of earlier open dose-finding trials (360 men; six study centers) . We compared single-dose treatment regimen of CAT--over the range of 400-1500 mg--with spectinomycin, thiamphenicol, ampicillin, or amoxicillin plus probenecid . The overall cure rates were 100% in 88 women treated with 1500 mg CAT and in 137 men treated with 1200 or 1500 mg CAT, 98% (114 of 116 men) in those treated with 800 or 1000 mg CAT, and 93% (42 of 45 men) in those treated with 400 or 500 mg CAT; the composite cure rate of the comparators was 97% . The tolerability of CAT (n = 428) compared favorably (1.8% adverse events) with that of the standard drugs (n = 139) (4.3% adverse events) . Single-dose treatment with 1500 mg CAT is effective and safe in adults with uncomplicated gonorrhea.

Ann N Y Acad Sci, 1994 May 2, 721, 117 - 22
Interdependence of gene expression for early steps of cephalosporin synthesis in Streptomyces clavuligerus; Demain AL et al.; The early steps of cephamycin synthesis by S . clavuligerus are catalyzed sequentially by lysine epsilon-aminotransferase (LAT), delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) and isopenicillin N synthase (cyclase, IPNS) . The genes (lat, pcbAB, and pcbC, respectively) are closely linked in the same order as the enzymes act in the biosynthetic pathway and are transcribed in the same direction . Four cephamycin non- (or low-) producing mutants are pleiotropic in that they have undetectable or markedly diminished levels of ACVS and cyclase; two mutants almost completely lack LAT activity . All four mutants are complemented in cephamycin formation by transformation with pNBR1, a plasmid containing a 7.2-kb genomic region of S . clavuligerus in vector pIJ702 . The cloned DNA was found to possess no part of the cyclase gene, but instead it contained lat and the 5' upstream part of pcbAB . Doran et al . reported that the 31-bp region between pcbAB and pcbC contains no recognizable promoter or transcription termination sequences . We found that there are 153 bp between the lat ORF and the pcbAB start codon . A potential transcriptional terminator begins 4 to 6 bp downstream of the lat ORF . In the 111-bp segment between the end of the "terminator" and the pcbAB start codon, there are no Streptomyces-like or Escherichia coli-like promoter consensus sequences . However, upstream of the "terminator," that is, in the downstream portion of the lat ORF, are two regions resembling a Streptomyces consensus promoter . Promoter activity in gene fusion constructions was demonstrated in this region . A third potential promoter is upstream of the lat ORF, but only the--10 part is on the cloned DNA . The mechanism by which the cloned DNA (containing lat, the 5' part of pcbAB, and the intervening sequence) influences the expression of the downstream genes encoding ACVS and IPNS, even in strains that possess LAT activity, is an intriguing target of future investigation.

FEMS Microbiol Lett, 1994 Apr 15, 117(3), 333 - 9
Val-237 for Ala substitution in the TEM-2 beta-lactamase dramatically alters the catalytic efficiencies towards carbenicillin and ticarcillin; Barthelemy M et al.; The mutant 554 of TEM-2 beta-lactamase was selected for a decrease in the resistance to carbenicillin of an Escherichia coli K12 carrier . The amino acid sequence of the mutant beta-lactamase was determined by manual Edman degradation analysis of proteolytic peptides . A single substitution Val for Ala was localized at position 237 . The mutant exhibited only 2% of the catalytic efficiency of the wild-type enzyme towards carbenicillin and ticarcillin, whereas it retained 30-60% of the hydrolytic activity towards other penicillin and cephalosporin substrates . Carfecillin, the phenyl ester of the side-chain carboxyl group of carbenicillin, was hydrolysed as a good substrate . This suggests that the behaviour of the mutant enzyme towards carbenicillin may result from ionic rather than steric constraints . A molecular model of the Val-237 TEM-2 mutant suggests possible electrostatic interaction between Glu-171 and the carboxylic group of the side chain of carbenicillin.

Ann Allergy, 1994 Apr, 72(4), 341 - 2
Delayed allergic reaction to cefonicid; Martin JA et al.; We report a case of delayed cutaneous reaction to intramuscular treatment with cefonicid, a second generation cephalosporin . An isolated late skin test response was observed to cefonicid only and not to other beta-lactams . A patch test with cefonicid 1% was positive after 48 and 96 hours.

J Pharm Biomed Anal, 1994 Apr, 12(4), 533 - 41
The chromatographic behaviour of cephalosporins in gel filtration chromatography, a novel method to separate high molecular weight impurities; Hu C et al.; The interaction between cephalosporins and the dextran matrix of Sephadex gel in gel filtration chromatography has been thoroughly studied . Twelve cephalosporins with specific structures were examined under different chromatographic conditions, including 12 different mobile phases comprising inorganic or organic compounds of different charge or/and density of electrons on their negative ions, different types of Sephadex gel (Sephadex G-10 and Sephadex G-50) and different flow rates . It was found that the more negative the charge or/and density of electrons on the negative ions of buffer components, the more was the adsorption of cephalosporins on the solid phase; this indicated tht the mobile phase played an important role in gel filtration chromatography for cephalosporins . By choice of suitable chromatographic conditions, optimum separation of high molecular weight impurities from cephalosporins could be achieved . The novel method could be used as a routine method for the quality control of cephalosporin preparations.

Arerugi, 1994 Mar, 43(3), 511 - 4
A case report of drug-induced allergic hepatitis probably due to the N-methyltetrazolethiol group cephalosporin; Kojima N et al.; Drug-induced allergic hepatitis occurred in a patient being treated with cefpiramide sodium . A lymphocyte blast transformation test suggested that the N-methyltetrazolethiol group of the drug was responsible for the induction of acute hepatitis . A detailed case report and discussion of the relevant literature are presented in this paper.

Biophys Chem, 1994 Mar, 49(2), 163 - 74
Thermodynamics of the hydrolysis of penicillin G and ampicillin; Kishore N et al.; Apparent equilibrium constants and calorimetric enthalpies of reaction have been measured for the beta-lactamase catalyzed hydrolysis of penicillin G(aq) and ampicillin(aq) to penicillinoic acid(aq) and to ampicillinoic acid(aq), respectively . High-pressure liquid-chromatography and microcalorimetry were used to perform these measurements . The results for the reference reactions at T = 298.15 K and Im = 0 are: Ko = (9.4 +/- 3.1) x 10(-7), delta rGo = (34.4 +/- 1.0)kJ mol-1, delta rHo = -(73.7 +/- 0.4)kJ mol-1, and delta rSo = -(363 +/- 4) J K-1 mol-1 for penicillin G-(aq) + H2O(1) = penicillinoic acid2-(aq) + H+(aq); Ko = (6.0 +/- 3.0) x 10(-6), delta rGo = (29.8 +/- 1.7) kJ mol-1, delta rHo = -(70.0 +/- 7.5) kJ mol-1, and delta rSo = -(335 +/- 26) J K-1 mol-1 for ampicillin-(aq)+ H2O(1) = ampicillinoic acid2-(aq)+H+(aq) . Calorimetric enthalpies of reaction for the beta-lactamase catalyzed hydrolysis of cephalosporin C have also been measured but the reaction products have not been identified and the measured enthalpies cannot be assigned to a specific reaction . Acidity constants for ampicillin, penicillin G, ampicillinoic acid, and penicillinoic acid are also reported . A strain energy of 116 kJ mol-1 for the beta-lactam ring is obtained from thermochemical data.

Toxicol Lett, 1994 Mar, 71(1), 63 - 7
Effect of the cephalosporin cefepime on hepatic drug metabolising enzyme activity in rats; Jordan MC et al.; Oral doses of the new cephalosporin cefepime administered to rats for 14 days (40 mg/kg/day) did not affect the activities of the hepatic drug metabolising enzymes measured . By contrast there were highly statistically significant increases in all measured parameters in rats treated with phenobarbitone (80 mg/kg/day), the positive control . Control activities in male rats exceeded those in females by about 2-3 fold.

Mol Immunol, 1994 Mar, 31(4), 261 - 7
A bifunctional murine::human chimeric antibody with one antigen-binding arm replaced by bacterial beta-lactamase; De Sutter K et al.; We here report the genetic engineering of a murine::human chimeric antibody--directed against the tumor marker human placental alkaline phosphatase--in which one antigen-binding arm (Fab) has been replaced by Escherichia coli beta-lactamase (Bla) . A mutated Bla gene in which the termination codon had been replaced by GAG, was fused in-phase to the cDNA sequence encoding the hinge region, CH2 and CH3 of the human IgG3 heavy chain . The resulting BlaHG3f fusion gene was placed under control of the Simian Virus 40 late promoter, and transiently expressed in COS-1 cells together with the genes encoding the murine light and murine::human chimeric heavy chains . Approximately 200 ng/ml of correctly assembled bifunctional antibody-Bla immunoconjugates were detected in the culture supernatant . This observation indicates that Bla (with its own leader peptide) can efficiently direct secretion into the culture medium of adventitious sequences fused at its C-terminus . Furthermore, the assembly in the Fc region was not affected by steric hindrance due to a Bla moiety and an Fab arm in close proximity . The antibody-Bla immunoconjugate could be of therapeutic value for the activation of cephalosporin-based anti-cancer prodrugs at the tumor site . Moreover, the expression strategy adopted here is particularly suitable for a quick and convenient analysis of newly designed gene products in which the Bla moiety has been replaced by other enzymes or by antigen-binding fragments in order to engineer bispecific antibodies.

J Immunol, 1994 Mar 1, 152(5), 2447 - 55
Cefdinir (CI-983), a new oral amino-2-thiazolyl cephalosporin, inhibits human neutrophil myeloperoxidase in the extracellular medium but not the phagolysosome; Labro MT et al.; Cefdinir, a new oral 2-amino-5-thiazolyl cephalosporin, inhibited the luminol-amplified chemiluminescence (LACL) response of human neutrophils stimulated by PMA but not opsonized zymosan, in a concentration-dependent but not time-dependent manner . The LACL response to opsonized zymosan in cytochalasin B-treated neutrophils was, however, inhibited by cefdinir . Various cephalosporins, regardless of the presence of a 2-amino-5-thiazolyl moiety, did not significantly alter the neutrophil LACL response triggered by PMA and zymosan . The LACL response induced by the calcium ionophore A23187 and FMLP was also impaired by cefdinir, and this impairment was increased in cytochalasin B-treated neutrophils . Superoxide anion generation by neutrophils, measured in terms of lucigenin-amplified chemiluminescence and cytochrome c reduction, was not altered . Spontaneous and FMLP-induced neutrophil degranulation, assessed by lysozyme and beta-glucuronidase release, were not modified by cefdinir . Furthermore, cefdinir inhibited LACL generation in cell-free systems consisting of H2O2, NaI, and either horseradish peroxidase or a myeloperoxidase-containing neutrophil extract . Orthodianisidine oxidation in these two acellular systems was inhibited by cefdinir . Cefdinir did not alter neutrophil bacterial killing at concentrations that inhibited myeloperoxidase-containing neutrophil extract-dependent reactions induced by soluble stimuli . Taken together, these data strongly suggest that cefdinir directly inhibits the activity of myeloperoxidase-containing neutrophil extract released into the extracellular medium during neutrophil stimulation by soluble mediators, but has no effect on that released into the phagolysosome during phagocytosis . This unusual property of a member of the beta-lactam family could be of interest in modulating the exaggerated inflammatory process often associated with infectious diseases.

Biochem Mol Biol Int, 1994 Mar, 32(4), 789 - 95
Evidence of human serum albumin beta-lactamase activity; Nerli B et al.; The beta lactamase activity of serum albumin was measured using a chromogenic cephalosporin: 3-(2,4 dinitrostyryl) -(6 R, 7R) - 7 -(2 thienacetamido) ceph 3 - em 4 carboxylic acid) (nitrocefin) . It was found that albumin of different species and purity, obtained from a variety of sources, showed a significant beta lactamase activity . The reaction presented a saturation kinetics, with a KM of 1.42 10(-5) M . Oleic acid and ibuprofen inhibited the reaction, suggesting that the cephalosporin and these ligands are bound to the same site in albumin . The tertiary structure of albumin is necessary for the catalytic activity to be present probably unprotoned lysine residues in the catalytic site of albumin are related with this activity.

Gastroenterology, 1994 Mar, 106(3), 782 - 6
Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime; Cooper GS et al.; The central nervous system (CNS) is frequently involved in patients with Whipple's disease and is the most common site of disease relapse . Antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMX) that have reliable CNS penetration, are therefore recommended as first-line therapy . We report a patient with Whipple's disease who was treated with TMP-SMX and presented 14 months after initiation of therapy with visual decline and severe headaches . The patient was also treated concurrently with low-dose weekly methotrexate for severe psoriasis . Evaluation by magnetic resonance imaging revealed bilateral posterior white matter abnormalities that pathologically were consistent with Whipple's disease . He was ultimately treated with cefixime, an orally administered third-generation cephalosporin . Visual function improved on this regimen and follow-up magnetic resonance imaging showed regression of the lesions . This case represents the first report of both CNS relapse during therapy with TMP-SMX and successful treatment with cefixime . We also speculate that methotrexate, which impairs cell-mediated immunity, may have contributed to the relapse.

Dig Dis Sci, 1994 Feb, 39(2), 418 - 22
Eosinophilic cholecystitis, appendiceal inflammation, pericarditis, and cephalosporin-associated eosinophilia; Felman RH et al.; A patient with eosinophilic cholecystitis and accompanying eosinophilic appendiceal inflammation, eosinophilic pericarditis, and peripheral eosinophilia is described . Review of the nine previously reported cases of eosinophilic cholecystitis suggests that this is the first case with closely associated eosinophilic appendiceal inflammation and pericarditis as manifestations of a systemic hypereosinophilic syndrome . The possible etiologic role of cephalosporin hypersensitivity is discussed.

J Vet Pharmacol Ther, 1994 Feb, 17(1), 24 - 30
Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment; Jaglan PS et al.; Ceftiofur sodium, a broad spectrum cephalosporin antibiotic approved for veterinary use, is metabolized to desfuroylceftiofur which is conjugated to micro as well as macromolecules . Twelve horses, weighting 442-618 kg, were injected intramuscularly with a single dose of 2.2 mg ceftiofur/kg (1.0 mg/lb) body weight . Blood was collected at various intervals over 24 h after treatment . Three groups of four horses each were euthanized and lungs were collected at 1, 12, and 24 h after treatment . The concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the plasma and lungs was determined by converting them to desfuroylceftiofur acetamide (DCA) and measured DCA by high performance liquid chromatography with UV detection . The average maximum concentration (Cmax) of desfuroylceftiofur and related metabolites in plasma expressed as ceftiofur equivalents was 4.46 +/- 0.93 micrograms/ml occurred at 1.25 +/- 0.46 h after treatment . These concentrations declined to 0.99 +/- 0.16, 0.47 +/- 0.15 and 0.17 +/- 0.02 microgram/ml at 8, 12, and 24 h, respectively . The mean residence time of ceftiofur metabolites was 6.10 +/- 1.27 h . Concentrations of desfuroylceftiofur and desfuroylceftiofur conjugates in the lungs of horses expressed as ceftiofur equivalents were 1.40 +/- 0.36, 0.27 +/- 0.07, and 0.15 +/- 0.08 micrograms/ml at 1, 12, and 24 h, respectively . These concentrations of the drug at 12 and 24 h in lung homogenate were similar but slightly lower than plasma concentrations in the same horses, and the plasma pharmacokinetic values including half-life were similar to those observed at the approved dose of 1.1-2.2 mg ceftiofur/kg body weight administered intramuscularly once daily for 3-5 days in cattle.

Br J Clin Pharmacol, 1994 Feb, 37(2), 193 - 7
The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion; Verhagen CA et al.; 1 . The renal tubular excretion of cefuroxime and ceftazidime in relation to the coadministration of probenecid was investigated in eight and two healthy subjects, respectively . 2 . Cefuroxime or ceftazidime were administered by i.v . infusion and 1 g probenecid was administered orally after steady state plasma concentrations of the cephalosporin were reached . 3 . In a second session the same antibiotic was administered at increasing infusion rates such that three different levels of plasma drug concentration were achieved . 4 . The renal clearance of antibiotic was calculated based upon unbound plasma concentration, and tubular clearance was estimated by subtracting inulin clearance from the renal clearance of the antibiotic . 5 . Non-linear regression analysis was used to estimate parameters describing the saturability of tubular excretion and the effect of probenecid inhibition, i.e . EC50 and Rtub,max, could be established for cefuroxime: EC50 was 248 (s.d . 130) mg l-1 and Rtub,max was 1.852 (s.d . 0.577) mg h-1 . Tubular excretion of ceftazidime was practically zero . The EC50 of probenecid for inhibition of the tubular excretion of cefuroxime was 0.80 (s.d . 0.31) mg l-1 . 6 . The results indicate that in the therapeutic plasma concentration range of cefuroxime its renal clearance is not saturated . Probenecid at therapeutic doses will block tubular excretion of cefuroxime almost completely.

Allergy, 1994 Feb, 49(2), 108 - 13
Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin; Audicana M et al.; A group of 34 penicillin-allergic patients was studied to determine skin test reactivity to the different penicillins involved in inducing the allergic reaction and the cross-reactivity with side-chain-related and side-chain-unrelated cephalosporins . All the subjects selected for the study had to be skin test positive to at least one of the following determinants: benzyl-penicilloyl-polylysine (BPO-PLL), minor-determinant mixture (MDM), amoxicillin (AX), or ampicillin (AMP), or to possess in vitro IgE to the following conjugates: benzyl-penicilloyl-human-serum albumin (BPO-HSA), ampicilloyl-human-serum albumin (AMP-HSA), and amoxicilloyl-human-serum albumin (AX-HSA) . Cephalexin (CE) and ceftazidime (CEF) were used to assess cross-reactivity . If skin tests to any of these compounds were positive, the patient was considered to be allergic; if negative, a challenge test was performed . Sixteen patients (47%) were skin test positive to BPO and/or MDM, and nine (26%) exclusively to AX and/or AMP . In three cases (8%), the RAST was positive although the skin test was negative; one to BPO-HSA and two to AX-HSA and AMP-HSA . Six patients (17%) needed to be challenged with the penicillin involved to establish the diagnosis . In five patients (14%), the skin tests were positive to CE and in none to CEF . In all the others, the skin tests were negative to both cephalosporins, and the patients tolerated the drugs when challenged . These results indicate the relevance of side-chain-specific minor determinants in betalactams allergy and provide support for the role of this chemical structure in the evaluation of cross-reactivity between penicillins and cephalosporins.

J Bacteriol, 1994 Feb, 176(4), 985 - 91
Exogenous methionine increases levels of mRNAs transcribed from pcbAB, pcbC, and cefEF genes, encoding enzymes of the cephalosporin biosynthetic pathway, in Acremonium chrysogenum; Velasco J et al.; Methionine stimulated cephalosporin production in cultures of three different strains of Acremonium chrysogenum when added either at inoculation time or at 72 h to cells grown previously in the absence of methionine . When methionine was added at 72 h, the stimulation of cephalosporin biosynthesis was observed only 12 h later and required de novo protein synthesis . Methionine increased the levels of enzymes (isopenicillin N synthase and deacetylcephalosporin C acetyltransferase) expressed from genes (pcbC and cefG, respectively) located in the two clusters of cephalosporin biosynthesis genes in the wild-type A . chrysogenum strain and also in the two improved strains, CW19 and C10 . Methionine-supplemented cells showed higher levels of transcripts of the four known genes (pcbAB, pcbC, cefEF and, to a slight extent, cefG) of the cephalosporin biosynthetic pathway than cells grown in the absence of methionine . The levels of the cefG transcript were much lower than those of the pcbAB, pcbC, and cefEF transcripts . The induction by methionine of transcription of the four cephalosporin biosynthesis genes and the known effect of this amino acid on the differentiation of A . chrysogenum indicate that methionine exerts a pleiotropic effect that coordinately regulates cephalosporin biosynthesis and differentiation.

Ned Tijdschr Geneeskd, 1994 Jan 1, 138(1), 41 - 2
{Vietnam back in perspective; reforms also concern health care}; Kager PA; PIP: Vietnam has a population of 71 million people with a per capita income of $205 per year . In recent years the economy has become liberalized, and development has accelerated, as foreign investments have poured in . The changes have their drawback, as the gap between the rich and the poor has widened, health care is no longer free in practice, the number of admissions into hospitals has decreased, and hospitals and health posts are ill-maintained . There is an extensive network of basic health care with district hospitals and health posts in the villages . In most district hospitals, there are essential drugs available (penicillin, ampicillin, co-trimoxazole, and chloramphenicol), but no cephalosporin or chinolone, which are too expensive . There are X-ray facilities in 50% of hospitals, but there is no echo apparatus . Six medical schools graduate 2000 doctors per year, but the quality of education was mediocre for many years . Malaria, diarrhea, and respiratory infections are the greatest problems . In 1992, there were 20% more malaria cases than in 1991 . There were 29,000 cases of serious malaria in 1992 and 3300 deaths, compared to 4561 serious cases and 1070 deaths in 1987 . The increase is attributable to socioeconomic factors: the dwindling of aid from the Soviet Union and less DDT spraying, people who are not immune to malaria settle in new economic zones for rice cultivation, diminished effectiveness of the antimalarial network because of scant resources, the chloroquine- and sulfadoxine-pyrimethamine-resistant parasites since mefloquine and halofantrine are too expensive, and the resistance of certain mosquitos against insecticides . Severe malaria has a mortality rate of 20-30% in spite of treatment . Vietnam produces hundreds of kilos of artemisinine annually, and derivatives are experimented with that could be used parenterally . The country needs help because its resources are limited, and unless the US economic embargo is lifted, it is parcelled out only piecemeal .

Neurologia, 1994 Jan, 9(1), 29 - 31
{Failure of empirical treatment with ceftriaxone in motor neuron disease}; Carod Artal FJ et al.; We describe two patients with lateral amyotrophic sclerosis who, after informed consent, received empirical treatment with intravenous cephtriaxone at a dose of 2 g/24 hours for three weeks, with no positive results . The pharmacokinetics of this cephalosporin is analyzed, along with the relationship between motor neuron disease, neuroborreliosis and immunoreactivity to Borrelia burgdorferi.

Therapie, 1994 Jan-Feb, 49(1), 35 - 9
{Kinetics of cefixime biliary clearance in cholecystectomized patients}; Westphal JF et al.; Cefixime is an orally administered cephalosporin with physicochemical properties able to account for a possibly significant biliary excretion . In addition, over 50% of total clearance of the drug has been shown to operate through extra renal pathways in healthy volunteers . The aim of the study was to quantify and to delineate the kinetics of cefixime biliary elimination in ten patients provided with external drainage . Following a single 200 mg oral dose of cefixime, biliary clearance of the drug appears to vary from 0.85 to 27.3 ml/min . Contribution of the latter to the apparent total clearance is relatively low since ranging from 0.8 to 18.6% (mean 5%) . Additionally, biliary clearance kinetics of the drug proves non linear and well described according to a sigmoidal model . On account of these results, and given the dianionic charge of the molecule as well as the absence of any metabolite reported so far, an intrahepatic binding and accumulating process, mediated by ligandin, seems to underlie the hepatobiliary excretion of cefixime, as previously reported for other anionic beta-lactam antibiotics.

Pediatr Radiol, 1994, 24(3), 218 - 9
Biliary pseudolithiasis in a child associated with 2 days of ceftriaxone therapy; Blais C et al.; Ceftriaxone, a third-generation cephalosporin, is known to induce reversible precipitations in the gallbladder of children . In general, radiologic signs and symptoms will develop after 9-11 days of treatment . The authors report a case where 48 h of therapy were sufficient to develop a biliary pseudolithiasis . Clinicians and radiologists should be aware of this complication which mimics true cholelithiasis.

Antonie Van Leeuwenhoek, 1994, 65(3), 227 - 43
Expression of genes and processing of enzymes for the biosynthesis of penicillins and cephalosporins; Martin JF et al.; The genes pcbAB, pcbC and penDE encoding the enzymes (alpha-aminoadipyl-cysteinyl-valine synthetase, isopenicillin N synthase and isopenicillin N acyltransferase, respectively) involved in the biosynthesis of penicillin have been cloned from Penicillin chrysogenum and Aspergillus nidulans . They are clustered in chromosome I (10.4 Mb) of P . chrysogenum, in chromosome II of Penicillium notatum (9.6 Mb) and in chromosome VI (3.0 Mb) of A . nidulans . Each gene is expressed as a single transcript from separate promoters . Enzyme regulation studies and gene expression analysis have provided useful information to understand the control of genes involved in penicillin biosynthesis . The enzyme isopenicillin N acyltransferase encoded by the penDE gene is synthesized as a 40 kDa protein that is (self)processed into two subunits of 29 and 11 kDa . Both subunits appear to be required for acyl-CoA 6-APA acyltransferase activity . The isopenicillin N acyltransferase was shown to be located in microbodies, whereas the isopenicillin N synthase has been reported to be present in vesicles of the Golgi body and in the cell wall . A mutant in the carboxyl-terminal region of the isopenicillin N acyltransferase lacking the three final amino acids of the enzymes was not properly located in the microbodies and failed to synthesize penicillin in vivo . In C . acremonium the genes involved in cephalosporin biosynthesis are separated in at least two clusters . Cluster I (pcbAB-pcbC) encodes the first two enzymes (alpha-aminoadipyl-cysteinyl) valine synthetase and isopenicillin N synthase) of the cephalosporin pathway which are very similar to those involved in penicillin biosynthesis . Cluster II (cefEF-cefG), encodes the last three enzymatic activities (deacetoxycephalosporin C synthetase/hydroxylase and deacetylcephalosporin C acetyltransferase) of the cephalosporin pathway . It is unknown, at this time, if the cefD gene encoding isopenicillin epimerase is linked to any of these two clusters . Methionine stimulates cephalosporin biosynthesis in cultures of three different strains of A . chrysogenum . Methionine increases the levels of enzymes (isopenicillin N synthase and deacetylcephalosporin C acetyltransferase) expressed from genes (pcbC and cefG respectively) which are separated in the two different clusters of cephalosporin biosynthesis genes . This result suggests that both clusters of genes have regulatory elements which are activated by methionine . Methionine-supplemented cells showed higher levels of transcripts of the pcbAB, pcbC, cefEF genes and to a lesser extent of cefG than cells grown in absence of methionine . The levels of the cefG transcript were very low as compared to those of pcbAB, pcbC and cefEF.(ABSTRACT TRUNCATED AT 400 WORDS)

Ann Otolaryngol Chir Cervicofac, 1994, 111(4), 217 - 22
{Efficacy and tolerance of cefotiam hexetil in the super-infected chronic sinusitis . A randomized, double-blind study in comparison with cefixime}; Dellamonica P et al.; Efficacy and safety of a new oral third generation Cephalosporin, Cefotiam Hexetil (CTM) 200 mg bid were compared with those of Cefixime (CX) 200 mg bid over 10 day duration of treatment . One hundred and twenty two ambulatory adults suffering from chronic sinusitis were randomized by ENT specialists in this multicentre prospective double blind, doubled dummy study . Sinusitis diagnosis evocated in front of fascial pain, purulent nasal discharge and/or obstruction was confirmed with sinus X-ray . Use of antibiotics or corticosteroids concomitantly or 15 days prior inclusion represented one of the major exclusion criterion . One hundred and seventy one patients were evaluated for efficacy analysis (62 and 59 respectively in CTM and CX groups) . Regarding demographic data, clinical and radiological signs, the two populations were comparable at inclusion excepted for sex and weight (female: 73% in CTM group versus 47% in CX group) . The overall clinical success rate at the end of treatment (cure+improvement) was not significantly different between the two groups (CTM: 82% versus CX: 80%) . The incidence of adverse events was less frequent in the CTM group (14.5% versus 19%) . In conclusion, CTM 200 mg bid is as efficacious and as well tolerated as CX 200 mg bid in the treatment of chronic sinusitis in adults.

Drugs, 1994, 47 Suppl 3, 21 - 6
Cefetamet pivoxil vs cefaclor in the treatment of acute otitis media in children; Furman S et al.; 74 children with acute otitis media (AOM) were entered into an observer-blind randomised multicentre general practice study to compare the efficacy and safety of the new third generation oral cephalosporin, cefetamet pivoxil, at a dose of 10 mg/kg twice daily with the efficacy and safety of cefaclor 10 mg/kg twice daily administered for 10 days . Of 36 evaluable patients in the cefaclor treatment group, 28 (78%) were cured, and a further 4 were improved, giving an overall efficacy rate (cure/improvement) of 89% . Of 36 evaluable patients in the cefetamet pivoxil treatment group, 31 (86%) were cured, and a further 4 were improved, giving an overall efficacy rate of 97% . Adverse events were reported in 4 patients: 1 cefaclor recipient and 3 patients in the cefetamet pivoxil treatment group . Diarrhoea, the most frequently observed adverse event, occurred in both treatment groups . The study results indicate that cefetamet pivoxil and cefaclor appear to have similar efficacy and safety in the treatment of AOM in children.

Pharmacoeconomics, 1994, 5(Suppl 2), 27 - 33
Third generation cephalosporins in the parenteral to oral switch; Rimmer D; In the present economic climate, it is increasingly necessary to ensure the cost-effectiveness of all aspects of healthcare . The expenditure on medications in a hospital is largely determined by the workload and throughput, but efforts to rationalise the use of medications will result in benefits both in patient care and overall costs . The purpose of this report is to discuss the advantages of switching from parenteral to oral cephalosporin therapy after the initial stage of infection treatment, the potential of presently available oral cephalosporins for use in a parenteral-to-oral switch regimen, and the outcome of a parenteral-to-oral switch programme, which used parenteral cefotaxime and oral cefixime, implemented at Hillingdon Hospital.

Pharmacoeconomics, 1994, 5(Suppl 2), 11 - 9
Defining criteria for the pharmacoeconomic evaluation of new oral cephalosporins; Davey PG et al.; Economic analysis is founded on the assumption that resources are limited and that they should be used in a way that maximises the benefits gained . It should be clear that economic analysis must be based on a consideration of choices for resource utilisation . Pharmacoeconomics extends these assumptions to drug treatment . Therefore, a full pharmacoeconomic analysis must consider two or more alternative treatments and should be founded on measurement of incremental cost, incremental efficacy, and the value of successful outcome . Most doctors would agree that it is easy to choose between two treatments if the least expensive drug is also the most effective . Economic analysis is required whenever the more expensive of two options is also the more effective . In this instance, the decision maker must believe that the value of one additional successful outcome is greater than the investment made in the more effective treatment . This approach would be a suitable model for comparing new oral third generation cephalosporins with cheaper oral drugs such as amoxicillin . Another decision requiring economic analysis is the choice between a new, oral third generation cephalosporin and an older intravenous formulation of a third generation cephalosporin . In this case, the new treatment is cheaper than the old treatment and the decision maker must be convinced that the oral treatment is as effective as the intravenous treatment . Statistically, it is only possible to exclude a difference of a given magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Hua Xi Yi Ke Da Xue Xue Bao, 1993 Dec, 24(4), 439 - 41
{Determination of ceftizoxime in serum by high performance liquid chromatography}; Huang Y et al.; This paper reports the determination of ceftizoxime, a new cephalosporin antibiotic, in serum by RP-HPLC . The technique for serum protein precipitation by adding perchloric acid is adapted for sample preparations . After centrifugation, a 100 microliters portion of aqueous phase is injected into chromatographic column of ultrasphere CN, the mobile phase being a mixture of methanol and 1% acetic acid (15:85) . The standard curve is linear within the range of 2.5-120 mg/L in serum . The detection limit of ceftizoxime in serum stands at 0.1 mg/L . The recoveries from serum samples after protein precipitation reach 95.4-96.3% . The within day CVs and interday CVs are 2.7-3.3% and 4.8-7.6%, respectively . This method is rapid, reliable and reproducible . It has been utilized to measure the concentration of ceftizoxime in patient serum for clinical research and pharmacokinetic studies.

Pharmacol Toxicol, 1993 Dec, 73(6), 297 - 300
Identification of the cephalosporin human serum albumin binding sites; Nerli B et al.; We have demonstrated that the cephalosporins which possess heterozyclic pentagonal group substituents bind to the bilirubin binding site on albumin, while the cephalosporins which possess hexagonal hydrocarbon cycle substituents bind to the benzodizepine binding sites (site II) on albumin . No binding of cephalosporins to the so-called site I and fatty acids binding site on human albumin was demonstrated.

Pflugers Arch, 1993 Nov, 425(3-4), 300 - 12
Bisubstrates: substances that interact with both, renal contraluminal organic anion and organic cation transport systems . II . Zwitterionic substrates: dipeptides, cephalosporins, quinolone-carboxylate gyrase inhibitors and phosphamide thiazine carboxylates; nonionizable substrates: steroid hormones and cyclophosphamides; Ullrich KJ et al.; In order to test what chemical structure is required for a substrate to interact not only with the contraluminal organic anion (p-aminohippurate, PAH) transporter, but also with the organic cation (N1-methylnicotinamide, NMeN, or tetraethylammonium, TEA) transporter, the stop-flow peritubular capillary perfusion method was applied and app . Ki values were evaluated . Zwitterionic hydrophobic dipeptides not only interact with PAH but also with NMeN transport although with lower inhibitory potency (Ki,PAH = 0.2-1.4; Ki,NMeN 6-14 mmol/l) . Amongst the zwitterionic cephalosporins, which all inhibit PAH transport, the amino cephalosporin analogue cefadroxil was identified to interact also with NMeN transport (Ki,PAH = 3.0, Ki,NMeN = 11.2 mmol/l) . All zwitterionic naphthyridine and oxochinoline gyrase inhibitors tested inhibit NMeN transport with app . Ki,NMeN values between 1.2 mmol/l and 4.7 mmol/l; the naphthyridine analogues show a good inhibitory potency against PAH transport (Ki,PAH approximately 0.4 mmol/l), the piperazine-containing quinolone analogues have a moderate inhibitory potency (Ki,PAH = 1.1-2.5 mmol/l) and the piperazine-containing pipemidic acid did not inhibit PAH transport at all . Zwitterionic thiazolidine carboxylate phosphamides also interact with both transporters (app . Ki,PAH approximately 3.0; app . Ki,NMeN approximately 18.0 mmol/l) . The nonionizable oxo- and hydroxy-group-containing corticosteroid hormones also interact with the two transporters . (a) An OH group in position 21 is necessary for interaction with the PAH transporter, but not for interaction with the TEA transporter . (b) Introduction of an OH group in position 17 alpha abolishes interaction with the TEA transporter, but has different effects with the PAH transporter . (c) Introduction of an OH group in position 6 abolishes interaction with both, the PAH and the TEA transporter . (d) A change of the side-group in position 11 of corticosterone from -OH to -H to = O enhances interaction with the PAH transporter but has no effect on the interaction with the TEA transporter . Nonionizable 4- or 5-androstene analogues inhibit both transporters with app . Ki between 0.16 mmol/l and 0.64 mmol/l, if the steroids are soluble in a concentration greater than 1 mmol/l . Nonionizable oxazaphosphorins with more than one chloroethyl group interact with the PAH transporter with app . Ki between 0.84 mmol/l and 4.9 mmol/l and with the NMeN transporter with app . Ki between 3.2 mmol/l and 18.7 mmol/l . Thus a substrate interacts with both transporters if it is sufficiently hydrophobic, possesses acidic and/or electron-attracting plus basic and/or electron-donating groups, or possesses several electron-attracting nonionizable groups (O, OH, Cl) . A certain spatial arrangement of the interacting groups seems to be necessary.

Curr Genet, 1993 Nov, 24(5), 421 - 7
Targeted integration into the Acremonium chrysogenum genome: disruption of the pcbC gene; Walz M et al.; The cephalosporin C-producing fungus Acremonium chrysogenum was transformed to hygromycin B resistance using different vector constructs . These constructs contain sequences of the pcbC gene from A . chrysogenum, encoding isopenicillin N synthetase . Detailed analysis of transformants, including pulsed-field gel electrophoresis (PFGE), suggests that integration of multiple vector copies takes place predominantly via non-homologous integration . By increasing the length of vector-DNA homologous to genomic DNA, integration occurs more frequently into chromosome VI, carrying the endogenous pcbC gene copy . In gene disruption experiments, the length of vector homology required to obtain cephalosporin C-minus transformants was investigated . Inactivation of the pcbC gene was observed only when homologous fragments of more than 3.0 kb were used on both sites of the resistance cassette . Southern analysis indicated homologous, as well as heterologous, integration of recombinant DNA . The integration of multiple vector copies leads to the appearance of truncated pcbC transcripts.

Drug Saf, 1993 Nov, 9(5), 340 - 5
A review of the adverse events profile of cefpirome; Rubinstein E et al.; Cefpirome is a new fourth generation injectable cephalosporin antibiotic . Its tolerability profile was established in a programme of 16 clinical studies involving 3103 patients in Europe and the US . The overall incidence of clinical adverse events with cefpirome was 21.9% compared with 27.1% with comparators (ceftazidime, imipenem, ceftriaxone) . Adverse events thought possibly related to treatment occurred in 12.5% of patients receiving cefpirome and 13.7% of recipients of comparator agents . Withdrawals from treatment due to adverse events occurred in 5.1 and 5.0% of patients receiving cefpirome and comparators, respectively . The commonest adverse events thought possibly related to treatment were gastrointestinal symptoms (mainly diarrhoea in 1.6 and 1.7%, respectively) and rash (1.4 and 1.4%, respectively) . Comparison with data obtained from the literature for ceftazidime, ceftriaxone and the third generation cephalosporins in general shows that the adverse event profile of cefpirome is similar to that of other broad-spectrum injectable cephalosporins.

Isr J Med Sci, 1993 Nov, 29(11), 673 - 6
Cefuroxime prophylaxis in biliary surgery: single versus triple dose; Katz S et al.; The standard regimen for prophylaxis in bilary surgery consists of three doses of a first- or second-generation cephalosporin (one pre- and two postoperatively) . The purpose of our study was to compare a single dose of cefuroxime (1.5 gi.v . on call to surgery) with the standard regimen (1.5 gi.v . on call to surgery followed by two additional doses of 750 mg i.v . each, 8 and 16 h after surgery) . One hundred patients participated in the study, 44 in the single-dose group and 56 in the triple-dose group . These two groups did not differ with regard to sex, risk factors, duration of surgery, etc . The incidence of infection was 9% in the single-dose group and 7% in the triple-dose group . We conclude that one dose of cefuroxime is as effective as three for biliary surgery . This regimen would reduce the risk of side effects and/or suprainfections and the emergence of resistant strains of bacteria . It is also more convenient for the nursing staff and reduces the cost by one-half.

Chemotherapy, 1993 Nov-Dec, 39(6), 374 - 85
Effects of food, ceruletide and ranitidine on the pharmacokinetics of the oral cephalosporin S-1108 in humans; Saito A; The pharmacokinetics of S-1108, an ester-type oral cephalosporin antibiotic, were studied in healthy male volunteers in a crossover study . This study focused especially on the effects on S-1108 absorption of (1) a meal, (2) concomitant administration of ceruletide diethylamine (a drug which promotes the secretion of bile) in the fasting state, and (3) concomitant administration of ranitidine hydrochloride (a drug which adjusts the acidity of the gastric juice) in the fasting state . The results show that the absorption of S-1108 after oral administration may be affected by factors such as food and ranitidine hydrochloride.

Clin Pharmacol Ther, 1993 Nov, 54(5), 473 - 5
Impairment of cefdinir absorption by iron ion; Ueno K et al.; The effect of iron ion on the absorption of cefdinir, a new oral cephalosporin derivative, was evaluated in healthy male volunteers in a randomized three-way crossover study . The subjects received 200 mg cefdinir alone, 200 mg cefdinir and two tablets of iron ion concomitantly, and two tablets of iron ion preparation 3 hours after 200 mg cefdinir administration . The area under the concentration curve {AUC(0-12)} of cefdinir with concurrent iron was significantly smaller than that with cefdinir alone (mean +/- SD, 0.78 +/- 0.38 versus 10.3 +/- 1.35 micrograms.hr/ml) . While there were no differences in AUC(0-3) between drug alone and drug with iron 3 hours later, the AUC(3-12) with delayed iron was significantly smaller than that of cefdinir alone (4.60 +/- 1.54 versus 8.03 +/- 1.72 micrograms.hr/ml) . These findings suggest that the mechanism of interaction between cefdinir and iron ion preparation is the formation of a chelation complex and that this complex probably restricts gastrointestinal absorption.

J Pharm Biomed Anal, 1993 Oct, 11(10), 897 - 902
Raised transaminase activity of blood plasma from rats with experimentally-induced kidney damage detected by spin-echo 1H-NMR spectroscopy; Anthony ML et al.; We report the application of spin-echo 1H-NMR spectroscopy to the detection of raised plasma transaminase activity in rats treated with the nephrotoxic cephalosporin antibiotic cephaloridine (CPH) . Spin-echo 1H-NMR analysis of lyophilized plasma, reconstituted in H2O reveals a doublet at delta 1.48 for alanine . However when samples were reconstituted with 2H2O we noted that in samples from CPH-treated rats (but not in control samples) there was a variable degree of appearance of a singlet at delta 1.47 together with a reduction in the doublet at delta 1.48 . We suggest that this is due to the release of transaminases from damaged tissue which, via a reversible conversion of alanine to pyruvate, causes selective deuteration of alanine at the alpha-hydrogen (alpha-CH) position . This observation suggests that these 1H-NMR spectral patterns are dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.

Md Med J, 1993 Oct, 42(10), 1001 - 4; discussion 1005
Infection in major sickle hemoglobinopathies: should management strategies change?
Freeman D, Luddy RE, Schwartz AD.
Four children with major sickle hemoglobinopathies developed severe pneumococcal infection . Three had sickle cell hemoglobin C (Hb SC) disease and one had sickle cell anemia (Hb SS) . In three instances, there was a fatal outcome . The authors' experience with these cases leads them to question whether any patient with a major sickle hemoglobinopathy should be excluded from receiving prophylactic penicillin or if outpatient management with long-acting cephalosporin treatment in the sickle cell patient with suspected sepsis is appropriate therapy.

Chemotherapy, 1993 Sep-Oct, 39(5), 331 - 5
Efficacy of ceftizoxime in the treatment of incubating syphilis in rabbits; Korting HC et al.; While ceftizoxime given as a single intramuscular shot cures uncomplicated gonorrhoea in almost every case, its efficacy against Treponema pallidum in cases of concomitant incubating syphilis is less clear . To analyse this question, the rabbit orchitis model was used . After initial experiments defining appropriate inocula and doses, ceftizoxime was compared to penicillin G with its well-known activity against the organism in vitro and in vivo . According to the final experiment, ceftizoxime applied in doses corresponding to the ones used in humans for uncomplicated gonorrhoea cures rabbit orchitis due to T . pallidum about as effectively as penicillin . Hence there seems to be no need to refrain from using the third-generation cephalosporin ceftizoxime to cure gonorrhoea for fear of masking concomitant syphilis.

Cancer Res, 1993 Sep 1, 53(17), 3956 - 63
Site-specific prodrug activation by antibody-beta-lactamase conjugates: regression and long-term growth inhibition of human colon carcinoma xenograft models; Meyer DL et al.; Antibody-directed catalysis (ADC) is a two-step method for the delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug . An ADC system consisting of F(ab')-beta-lactamase conjugates and a cephalosporin derivative of the oncolytic agent 4-desacetylvinblastine-3-carboxhydrazide was investigated . The ability of the system to mediate antitumor activity was compared with that of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice . Efficacy increased from moderate tumor growth inhibition by using free 4-desacetylvinblastine-3-carboxhydrazide to tumor regression and long-term stabilization with the ADC system . Labile covalent drug-antibody conjugates prepared from the same antibodies were less effective than ADC and required much higher antibody doses . The antigens KS1/4, carcinoembryonic antigen, and tumor-associated glycoprotein-72, TAG-72, present on the model cell lines, were chosen to investigate the effect of differences in subcellular location and expression heterogeneity on the efficacy of ADC delivery . Response was equivalent with the three tumor antigens . Hence, heterogeneous expression and membrane shedding of carcinoembryonic antigen and TAG-72, did not diminish the suitability of these antigens as targets for ADC therapy . In contrast, drug-antibody conjugate efficacy was more sensitive to subcellular location and heterogeneity . Thus, ADC is a highly effective form of immunochemotherapy in preclinical models, with applicability toward a variety of antigen targets.

Antimicrob Agents Chemother, 1993 Sep, 37(9), 1850 - 5
Partial characterization of Nocardia farcinica beta-lactamases; Steingrube VA et al.; The beta-lactamases obtained from culture supernatants and cell extracts of 26 clinical strains and 5 reference strains of Nocardia farcinica were partially characterized . The enzymes exhibited two patterns on isoelectric focusing (IEF) . beta-Lactamases from the majority of the 31 strains (87%) including the 5 reference strains exhibited two major bands with pIs of 4.56 and 4.49 . The remaining strains had two similar major bands but with slightly higher pIs . Culture supernatants and cell extracts exhibited identical patterns . The two sets of enzymes were functionally indistinguishable by substrate and inhibitor profiles and lack of inducibility . By disk testing, ampicillin, amoxicillin, ticarcillin, amoxicillin-clavulanic acid, and imipenem were highly synergistic with cefotaxime . The enzymes were primarily penicillinases and hydrolyzed cephalosporins at rates of < or = 12% of those for penicillins . N . farcinica beta-lactamases were susceptible to inhibition by clavulanic acid and BRL 42715, exhibiting 50% inhibitory concentrations of 0.025 to 0.045 micrograms/ml (0.12 to 0.22 microM) and 0.05 to 0.1 micrograms/ml (0.31 to 0.63 microM), respectively, less susceptible to tazobactam, and least susceptible to sulbactam, cloxacillin, and imipenem . The beta-lactamases of N . farcinica are believed to mediate penicillin resistance and may play a secondary role in extended-spectrum cephalosporin resistance . The close similarity among N . farcinica beta-lactamases and their distinct differences from beta-lactamases of other Nocardia species support the taxonomic identity of this species.

J Cardiothorac Vasc Anesth, 1993 Aug, 7(4), 422 - 4
An assessment of the duration of cephapirin-induced coagulation abnormalities as measured by thromboelastography; Baeuerle JJ et al.; Cephalosporin antibiotics are used prophylactically in cardiothoracic surgery to prevent postoperative infection . In 30 patients undergoing primary elective coronary artery bypass grafting, the whole blood coagulation system was prospectively evaluated before, and 10 and 30 minutes after administration of 1 g of cephapirin (Cefadyl, Bristol Laboratory, Evansville, IN) . All patients had normal preoperative coagulation studies and had not received anticoagulant or antiplatelet therapy within 7 days of surgery . At 10 minutes after cephapirin administration, 23 of 30 patients had a significant change in all phases of whole blood coagulation as monitored by thromboelastography (TEG) . Thirty minutes after cephapirin administration there was no statistical difference compared with the baseline TEG . It is concluded that cephapirin can cause a significant but transient change in the viscoelastic properties of blood . Coagulation parameters of the TEG should be measured prior to cephapirin administration to prevent errors in establishing baseline values prior to cardiopulmonary bypass.

Biotechnology (N Y), 1993 Aug, 11(8), 926 - 9
The production of cephalosporin C by Acremonium chrysogenum is improved by the intracellular expression of a bacterial hemoglobin; DeModena JA et al.; A DNA vector for expressing an oxygen-binding heme protein (Vitreoscilla hemoglobin, or VHb) in filamentous fungi was constructed and introduced into a cephalosporin C-producing strain of Acremonium chrysogenum . Expression of VHb in transformants was demonstrated by Western immunoblot analysis and by increased carbon monoxide binding activity of cell extracts . Several VHb-expressing transformants produced significantly higher yields of cephalosporin C than control strains in batch culture experiments . Using the same vector system, VHb was also expressed in the related fungus Penicillium chrysogenum.

Klin Padiatr, 1993 Jul-Aug, 205(4), 295 - 9
Ceftriaxone alone or in Combination with Teicoplanin in the Management of Febrile Episodes in Neutropenic Children and Adolescents with Cancer on an Outpatient Base; Preis S et al.; STUDY OBJECTIVE: This study prospectively investigated the outpatient once daily therapy with ceftriaxone alone or if necessary in combination with teicoplanin, in the treatment of infections in children and adolescents with chemotherapy-induced neutropenia or aplastic anemia . PATIENTS: 42 patients 1-22 years of age suffering from solid tumors, hematological and oncological diseases, with clinical signs of infection, increased serum CRP (> 1 mg/dl) and/or fever above 38.5 degrees C and neutropenia (WBC count and/or ANC < 1 x 10(9)/l) were included in this outpatient based study . One important exclusion criterion was poor clinical condition with symptoms of septic shock . METHODS: After bacterial, fungal and viral cultures had been obtained, single agent broad spectrum cephalosporin treatment was initiated with ceftriaxone applied once daily in a dose of 80 mg/kg body weight as short infusion over 30 min . Daily examinations included WBC, CRP, physical inspection and reassessment . In case of persistence or increase of fever and CRP, either outpatient management was carried on with teicoplanin added or patients were hospitalized and switched to combination antibiotic regimen . RESULTS: There were 64 febrile episodes in 42 patients . Single agent once daily broad spectrum cephalosporin was adequate in 43/64 (67%) of infectious episodes in neutropenic patients . For persisting or increased fever or CRP elevation, 9 patients were treated with ceftriaxone and teicoplanin successfully . Thus hospitalized was avoided in 52/64 (81%) of infectious episodes.

Ann Pharmacother, 1993 Jul-Aug, 27(7-8), 881 - 2
Cefuroxime-induced fever; Mevorach D et al.; OBJECTIVE: To report on three patients with cefuroxime-induced fever . CASE SUMMARIES: Recurrence of fever was noted in three patients after five to seven days of cefuroxime sodium therapy for acute exacerbation of chronic obstructive pulmonary disease . No source of infection was found and the fevers resolved within 30 hours of drug discontinuation . One patient was rechallenged; the same pattern of fever resulted . DISCUSSION: Fever secondary to cephalosporin administration is reviewed and the place of cephalosporins in the differential diagnosis of fever is postulated . CONCLUSIONS: Cefuroxime should be added to the list of cephalosporins that induce fever.

Chemotherapy, 1993 Jul-Aug, 39(4), 278 - 85
Immunotoxicity of cephalosporins in mice; Furuhama K et al.; This study was performed in female B6C3F1 mice to confirm previously observed effects of selected cephalosporin antibiotics on nonspecific immunity, and to determine possible effects on specific acquired immunity and host resistance . Mice were treated intravenously with DQ-2556, ceftizoxime or ceftezole at 800 mg/kg/day for 3, 5, or 7 consecutive days . All three compounds increased total serum IgM levels from day 3, but had no effects on total serum IgG levels and the thymus weight . All three cephalosporin antibiotics caused a slight increase in spleen weight and splenic germinal centers were enlarged after 5- or 7-day treatments . Antibody responses to type III pneumococcal polysaccharide (S3), a T-cell-independent immunogen, and sheep red blood cells (SRBC), a T-cell-dependent immunogen, were slightly decreased after 5-day dosings with each compound, and reached significance in DQ-2556 (response to S3) and ceftizoxime (response to S3 and SRBC) . None of the tested cephalosporin antibiotics altered delayed-type hypersensitivity to oxazolone or host resistance to Plasmodium yoelii, indicating that the antibiotic-treated mice retained the capacity to mount a multicomponent and sustained protective immune response . These data suggest that although cephalosporins may cause polyclonal expansion of B cells with associated increases in total serum IgM, they do not affect the tested measures of cell-mediated immunity or host resistance . The decreased IgM antibody responses to S3 and SRBC are associated with but not known to be causally related to the concurrent IgM hypergammaglobulinemia.

Allergol Immunopathol (Madr), 1993 Jul-Aug, 21(4), 131 - 5
Cefadroxil reduces the production of IgE in a 3 year old asthmatic with juvenile rheumatoid arthritis; Tang AT et al.; Cefadroxil, a cephalosporin, had been prescribed to children with superinfected atopic dermatitis, and was shown to improve both the infection, the clinical status and induced a dramatic lowering of the serum total IgE levels . Further studies have confirmed the IgE immunomodulating properties of cefadroxil . We report the case of a 3 year old asthmatic child who was hospitalized for superimposed pneumonia and was included in a study evaluating cefadroxil . The child was also suffering of juvenile rheumatoid arthritis . After treatment with cefadroxil and oral salbutamol, the child fully recovered . The initially elevated serum IgE (day 1:556 IU/ml) dropped to normal values (day 21: 52 IU/ml), while the production of IgE in vitro by peripheral blood B cells was normalized . We suggest that one mechanism of action of cefadroxil is the stimulation of production of gamma interferon in patients with atopic disorders; this mechanism interferes with the IL-4 primary signal, as well as with other second signals recognized for the synthesis of IgE . Gamma interferon may also prove beneficial for the control of juvenile rheumatoid arthritis.

Bioorg Med Chem, 1993 Jul, 1(1), 1 - 17
The enzymes involved in biosynthesis of penicillin and cephalosporin; their structure and function; Cooper RD; The biosynthetic pathway resulting in the penicillins and cephalosporins contains two Fe2+ oxidase enzymes which are responsible for the conversion of alpha-aminoadipoyl-L-cysteinyl-D-valine into isopenicillin N and penicillin N into deacetoxycephalosporin C . We will discuss the studies delineating the ligand binding of these enzymes and present a possible secondary structure.

Clin Exp Pharmacol Physiol, 1993 Jun, 20(6), 399 - 404
Effects of diabetes on disposition and hepatic handling of cefmetazole in rats; Barrientos C et al.; 1 . The effects of streptozotocin-induced diabetes on disposition and hepatic handling of cefmetazole, a broad-spectrum cephalosporin, were investigated in rats . 2 . Male Wistar rats were pretreated with streptozotocin (60 mg/kg, i.p.) to induce uncontrolled diabetes . Fourteen days later bile flow was significantly reduced (12%) and bile acid secretion was significantly enhanced (87%) when compared with control animals . 3 . Following intravenous injection of cefmetazole at a dose of 200 mumol/kg, maximal and cumulative biliary excretion of the antibiotic were significantly impaired in streptozotocin-treated animals (27 and 22%, respectively) . 4 . Cefmetazole excretion into bile was accompanied by marked choleresis . The magnitude of bile flow increase was larger in control animals . 5 . Total systemic clearance of the antibiotic was reduced (36%) and mean half-life for the fast and slow phases of disposition increased (136 and 48%, respectively) in diabetic rats . 6 . These changes were probably due to the diabetic condition of the animals because insulin treatment resulted in almost complete correction.

J Pharm Sci, 1993 Jun, 82(6), 622 - 6
Isolation and structure elucidation of a novel product of the acidic degradation of cefaclor; Baertschi SW et al.; The acidic aqueous degradation of cefaclor, an orally administered cephalosporin antibiotic, has been investigated . The most prominent peak in the high-performance liquid chromatography profile of a degraded solution of cefaclor was isolated by preparative high-performance liquid chromatography . Mechanistically, the formation of this degradent from cefaclor involves a condensation of two cefaclor degradation products in which both products have undergone contraction from a six-membered cephem ring to a five-membered thiazole ring, presumably via a common episulfonium ion intermediate.

Antimicrob Agents Chemother, 1993 May, 37(5), 1043 - 9
Carnitine status and safety after administration of S-1108, a new oral cephem, to patients; Shimizu K et al.; The metabolism and clinical safety of the pivalic acid-containing antibiotic S-1108, an orally active pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of carnitine consumption in 15 patients with various infectious diseases receiving S-1108 three times a day at a 300- or 600-mg total daily dose for 3 to 7 days . The free carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma pivaloylcarnitine (the main metabolite of pivaloyloxymethyl ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the cessation of treatment . In three elderly patients with declining renal function (creatinine clearance rate, 31 to 50 ml/min), the acylcarnitine/free carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug . The degree of free carnitine reduction and increase of the acylcarnitine/free carnitine ratio depended mostly on the dose and the duration of S-1108 treatment . The increased acylcarnitine/free carnitine ratio in elderly patients was due to reduction of the free carnitine concentration in plasma and mainly to the retardation of nontoxic pivaloylcarnitine excretion . This study indicated that there was a decrease in free carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with carnitine reduction in patients during the 7-day multiple administration of S-1108.

Unfallchirurg, 1993 May, 96(5), 253 - 8
{Open joint fractures of the distal lower leg}; Hendrich V et al.; Ninety-five open fractures of the joint at the distal end of the lower leg (73 ankle fractures, 22 fractures of the pylon tibia) were treated between 1970 and 1987 . For different reasons (death, amputation, etc.) only 63 could be followed up . The clinical and radiological assessments of 60 patients are presented in this paper . The Weber evaluation (only 18% good-to-excellent results) seemed to be inadequate for grading these cases . Fifty-six percent of the patients rated the results as very good, 37% as good . Radiological signs of post-traumatic arthritis were found in 48% of the cases . Different arthritis rates were found in a subgroup followed up after 1.5 to 6 years, and another subgroup treated earlier (maximum 18 years) . In the first subgroup post-traumatic arthritis was found in 20%; in the second group-treated more than 6 years ago-it was 79% . The fact that the outcome of these late results was worse may be because of the severe traumatization 6-18 years ago, but it is more likely that the results were better in the other subgroup as a result of improved procedures . Nowadays a broad-spectrum cephalosporin is administered in the emergency room . All open fractures are operated on as emergency cases as quickly as possible . All bandages applied at the accident site are removed in the operation theater, not before . There the wounds are carefully irrigated and debrided . Rigid internal fixation with a minimum apparatus is applied . Exceptions are made in the case of severe trauma: external fixation is applied to bridge the joint in the correct position.(ABSTRACT TRUNCATED AT 250 WORDS)

Presse Med, 1993 May 1-8, 22(16), 779 - 82
{Moraxella (Branhamella) catarrhalis . A common pathogenic agent}; Prost J et al.; Moraxella (Branhamella) catarrhalis, a commensal organism of the oropharyngeal flora, has been considered a potential pathogen since the early 1970s, mainly causing otitis in infants and exacerbations of chronic bronchitis in the elderly or in immunosuppressed adults . This view was initially based on the isolation of M . catarrhalis during infections: a density of at least 10(7)/ml of sputum, particularly when it exceeds that of other organisms by at least 100-fold, is considered to indicate the responsibility of M . catarrhalis . The pathogenic potential of M . catarrhalis was proven by the increase in specific serum antibodies (total, IgG, IgA) in patients infected by this organism . Given the large proportion (60 percent) of strains that produce beta-lactamase, antibiotic therapy is based on a combination of amoxycillin and clavulanic acid (or another penicillin/beta-lactamase inhibitor combination) or a third-generation cephalosporin; tetracyclines or macrolides can also be used.

Enzyme Microb Technol, 1993 Apr, 15(4), 281 - 5
Enzymatic oxidation of cephalosporin C using whole cells of the yeast Triginopsis variabilis within a "cross-flow filter-reactor"; Vicenzi JT et al.; An economical process for the enzymatic oxidation of cephalosporin C to glutaryl-7-ACA was developed at a pilot plant scale . The process utilized nonviable whole cells of the yeast Triginopsis variabilis containing high levels of D-amino acid oxidase . Prior to use, the whole cells were permeabilized with a 25% acetone/water solution which enhanced their apparent activity by 20- to 50-fold . After permeabilization, the whole cells were incubated at pH 11, which served to selectively deactivate catalase which was present in very large quantities . Deactivation of catalase was critical to achieving high reaction yields . The whole cells were utilized within a "cross-flow filter-reactor" which allowed easy and economical recycle of the cells for repeated use . The overall yield of glutaryl-7-ACA from cephalosporin C was 90-95% . The overall productivity of the yeast was 13 kg cephalosporin C oxidized per kilogram yeast (dry basis) . The reaction was run at a concentration of 40 g cephalosporin CL-1 and the overall reactor productivity was 11 g glutaryl-7-ACA l-1 h-1 . The process has been thoroughly demonstrated on a 35-l scale, and it should be directly scaleable to 10,000 l or more.

J Biotechnol, 1993 Apr, 28(2-3), 165 - 77
Cephalosporin C production by a highly productive Cephalosporium acremonium strain in an airlift tower loop reactor with static mixers; Zhou W et al.; The production of cephalosporin C (CPC) and its precursors penicillin N (PEN N), deacetoxycephalosporin C (DAOC) and deacetylcephalosporin C (DAC), with a highly productive strain of Cephalosporin acremonium, was investigated in an 80-1 airlift tower loop reactor with four static mixer modules (Type SMV, Sulzer) (ATLRM) on a complex medium containing 50 g l-1 peanut flour (PF) . The most important key parameters such as glucose concentration and cell mass concentration were monitored during a fed-batch cultivation process . The concentrations of products CPC, PEN N, DAOC an DAC were determined on line by HPLC . The influences of four motionless mixers on the dissolved oxygen concentration (DOC), oxygen transfer rate, the cell growth and the CPC production, as well as the reactor performance, were evaluated . The results were compared with the performance of an airlift tower loop reactor (ATLR) without static mixers as well as with a stirred tank reactor (STR) . A comparison of cultivations in the ATLRM and ATLR with 50 g l-1 PF indicates that the obtained maximal CPC concentration and the (CPC + DAC + DAOC) concentration were 7% and 22% higher in the ATLRM (4.96 and 7.46 g l-1) than in the ATLR (4.63 and 6.13 g l-1) respectively . The maximal CPC volumetric productivity in the ATLRM (55.1 mg l-1 h-1) was also considerably higher than that in the ATLR (48.5 mg l-1 h-1) . The specific power input was reduced from 2.36 to 1.5 kW m-3, the specific productivity pertaining to the power input was improved from 1.96 to 3.31 g W-1 . On the other hand, cultivation in the ATLRM had a lower maximum CPC concentration and volumetric productivity than those in STR (7.2 g l-1 and 71.2 mg l-1 h-1) with the same medium due to the lower shear stress levels and the lower specific power input (1.5 vs . 3.0 kW m-3); but the specific power imput-based yield coefficient was in the ATLRM (3.31 g W-1) higher than in the STR (2.40 g W-1) . By increasing the amount of PF, it was possible to enhance the CPC concentration and volumetric productivity in the STR . However, the performance of the ATLRM was limited to using a medium containing maximal 50 g l-1 PF because of the high viscosity of the medium, the limited energy input and thus the limited oxygen supply.

Hindustan Antibiot Bull, 1993 Feb-May, 35(1-2), 111 - 25
Cephalosporin acylases: enzyme production, structure and application in the production of 7-ACA; Kumar KK et al.; Cephalosporin acylases have application in the production of 7-aminocephalosporanic acid which forms a key raw material for the preparation of semisynthetic injectable cephalosporins . The enzymes are of industrial importance and hyperproducing genetically engineered strains have been constructed . Different aspects of these enzymes such as subunit structure, post translational modification, primary structure, substrate specificity and their importance in pharmaceutical industry are discussed.

Arch Microbiol, 1993, 159(4), 392 - 5
Morphological, physiological and enzymatic characteristics of cephalosporin acylase-producing Arthrobacter strain 45-8A; Zhang QJ et al.; A bacterial strain producing cephalosporin acylases was isolated from soil . The morphological and physiological properties of this strain suggest that it belongs to the genus Arthrobacter, and the isolate was therefore designated Arthrobacter strain 45-8A . Substrate specificity of the enzyme was examined . The enzyme can convert both cephalosporin acid to 7-aminocephalosporanic acid . An interesting feature of the acylases is their temperature-dependent regulation . Activity of acylases was detected in strain 45-8A grown at temperature below 30 degrees C, but was not observed at higher temperature . Arthrobacter strain 45-8A did not exhibit beta-lactamase activity, even though its resistance to cephalosporin C was very strong (> 2000 micrograms/ml) . This is quite beneficial for its application in the manufacture of 7-aminocephalosporanic acid.

J Gastroenterol Hepatol, 1993 Jan-Feb, 8(1), 52 - 9
Protective effect of a cephalosporin, Shiomarin, plus a new potent protease inhibitor, E3123, on rat taurocholate-induced pancreatitis; Hirano T et al.; The role of infectious factors in the pathogenesis of acute pancreatitis and the protective effect of combined therapy with a new potent synthetic protease inhibitor, E3123, and a new potent synthetic cephalosporin, Shiomarin were examined in rat acute pancreatitis . Sodium taurocholate injection into the pancreatico-biliary duct of rats caused severe pancreatitis with a high mortality rate, characterized by hyperamylasaemia, high amylase activity in ascitic fluid, hyperendotoxaemia and a high serum level of fibrin degradation products (FDP) and redistribution of cathepsin B from the lysosomal fraction to the zymogen fraction . Sodium taurocholate injection into the pancreatico-biliary duct also caused the bacterial growth in the pancreas . In rats with E3123 infusion almost all parameters were improved, including mortality rate, serum and ascitic fluid amylase levels, plasma endotoxin and serum FDP levels, and distribution of lysosomal enzyme . But combination therapy with E3123 and Shiomarin was significantly more protective than E3123 therapy alone . These results indicate that infection plays an important role in the development of severe pancreatitis and that combination therapy with a new synthetic protease inhibitor and a new potent antibiotic may be useful in the treatment of severe pancreatitis.

Antimicrob Agents Chemother, 1993 Jan, 37(1), 84 - 8
Cloning of a Streptomyces clavuligerus DNA fragment encoding the cephalosporin 7 alpha-hydroxylase and its expression in Streptomyces lividans; Xiao X et al.; A 26-mer DNA probe was designed from N-terminal sequence data for the cephalosporin 7 alpha-hydroxylase (CH) of Streptomyces clavuligerus NRRL 3585 and used to screen a DNA library from this organism . The library was constructed in the lambda GEM-11 phage system . After plaque purification and reprobing, positive recombinant phages were chosen for further analysis . Characterization of the cloned DNA by restriction mapping and Southern hybridization showed that a 1.5-kb SalI fragment hybridized to the probe . Polymerase chain reaction assays using this fragment as a template and the probe as a primer indicated that the fragment carries the entire putative CH gene (cmcI) . This was confirmed through the expression of CH enzymatic activity when the fragment was introduced into Streptomyces lividans . A putative beta-lactamase activity was detected in S . lividans.

J Pharm Sci, 1993 Jan, 82(1), 52 - 5
Determination of ceftibuten in sputum by column-switching high-performance liquid chromatography on-line with thermospray mass spectrometry; Pan HT et al.; A column-switching high-performance liquid chromatographic assay on-line with thermospray mass spectrometric detection is described for the determination of ceftibuten, an oral cephalosporin antibiotic, in human sputum . The method does not require sample pretreatment and provides increased selectivity not available from the previously reported method with UV detection . The thermospray mass spectrometric detection conditions were optimized for ceftibuten . The technique has a detection limit of 0.50 micrograms/mL and allows precise, simple, and accurate determination of ceftibuten in sputum over the range 0.50-10.00 micrograms/mL.

Curr Genet, 1993 Jan, 23(1), 33 - 41
Cloning, characterization, and use in strain improvement of the Cephalosporium acremonium gene cefG encoding acetyl transferase; Mathison L et al.; A long open reading frame (ORF) closely linked to the Cephalosporium acremonium gene cefEF was identified by DNA sequencing . The cefEF gene encodes the enzyme involved in cephalosporin C (CPC) biosynthesis known as expandase/hydroxylase . Complementation of a C . acremonium cefG mutant, as well as expression of the gene in Aspergillus niger, showed this ORF to be the cefG gene, encoding cephalosporin C acetyltransferase, which catalyzes the last step in CPC biosynthesis . Analysis of transformants containing additional copies of this gene showed that a direct relationship exists between cefG copy number, cefG message levels, and CPC titers . This gene encodes an enzyme for what may be a rate-limiting step in CPC production.

Arch Ophthalmol, 1993 Jan, 111(1), 121 - 5
Pharmacokinetics of newer cephalosporins after subconjunctival and intravitreal injection in rabbits; Barza M et al.; Pharmacologic considerations suggest that third-generation cephalosporins might penetrate the vitreous humor better after periocular injection and might be eliminated less readily after intravitreous injection than older agents . We studied the sodium salts of ceftizoxime, ceftriaxone, and ceftazidime, and of an investigational cephalosporin, cefepime, in rabbits . After a single subconjunctival injection in animals with normal eyes, vitreous levels ranged from 3 to 13 mg/L . After five subconjunctival injections in rabbits with infected eyes, vitreous concentrations ranged from 12 to 34 mg/L . These concentrations are not appreciably greater than those found with older beta-lactams . The vitreous half-life of the four drugs after intravitreous injection varied from 5.7 to 20 hours in rabbits with uninflamed eyes and from 9.4 to 21.5 hours in rabbits with infected eyes . Except for ceftizoxime, the half-lives were substantially longer than those for older beta-lactams and suggest predominantly anterior route elimination . Vitreous penetration of these new agents after subconjunctival injection does not appear to be sufficient to overcome the need for intravitreous injections in the treatment of endophthalmitis . However, the longer vitreous half-lives of some of the newer agents may be useful if the drugs are to be given intravitreally.

Arch Surg, 1993 Jan, 128(1), 55 - 63; discussion 63-4
Prospective alterations in therapy for penetrating abdominal trauma; Nichols RL et al.; In a double-blind, randomized study, 170 patients with traumatic perforation of the gastrointestinal tract were administered an advanced-generation cephalosporin . Patients were divided into infection risk groups (< or = 40%, low; 40% to 70%, mid; and > 70%, high) at surgical closure using a logistic regression formula based on four proved risk factors--age, blood replacement, ostomy, and the number of organs injured . Patients in the low group received 2 days of antibiotic therapy; those in the mid to high group received 5 days of antibiotic therapy . Those patients in the low to mid group had primary wound closure; those in the high group had their wounds packed open and closed later . Most of the patients (144 {85%}) were in the low group . Their major and minor infection rates (10% and 12%, respectively) were not significantly different from 145 historic control subjects receiving 5 days of antibiotic therapy (9% major; 14% minor) . Patients in the mid to high group showed a greater incidence of major infections (46%) but a similar incidence of minor infections (12%) . The results indicate that risk factors can be used to identify low-risk patients who require only short-term antibiotic therapy and primary wound closure . The remaining patients are at greater risk for infection despite prolonged antibiotic therapy and delayed wound closure.

J Infect Dis, 1993 Jan, 167(1), 173 - 9
Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring; Bertino JS Jr et al.; Incidence of and risk factors for aminoglycoside-associated nephrotoxicity (AAN) were evaluated in 1489 patients prospectively monitored with individualized pharmacokinetic monitoring (IPM) . Incidence of AAN was 7.9% with individual (univariate) risk factors including advanced age, decreased albumin, poor nutritional status, pneumonia, concurrent furosemide, amphotericin B, vancomycin, cephalosporin, or piperacillin, intensive care unit treatment, leukemia, rapidly fatal illness, liver or renal disease, reduced aminoglycoside clearance, elevated initial steady-state trough concentration (Cminss), volume of distribution or half-life, duration of therapy, total dose, fever, male gender, shock, pleural effusion, and ascites . Multiple logistic regression revealed that Cminss, concurrent clindamycin, vancomycin, piperacillin, or cephalosporin, ascites, advanced age, male gender, decreased albumin, duration of therapy, and leukemia were significant independent risk factors for AAN . Positive predictive value of the model was 30.8%; negative predictive value was 91.7% . No identifiable risk factor alone or in combination was of sufficient sensitivity to reliably predict AAN, but use of IPM may lower the incidence of AAN.

Int Arch Allergy Immunol, 1993, 102(1), 87 - 93
Effect of cefadroxil on antigen-induced bronchial hyperresponsiveness and eosinophil accumulation in lung from sensitized guinea pigs; Boichot E et al.; The effect of a semi-synthetic cephalosporin, Cefadroxil, on antigen-induced bronchial hyperresponsiveness and eosinophil accumulation in lungs from sensitized guinea pigs was investigated and compared to the effects of Cetirizine and Ketotifen . When aerosol-sensitized guinea pigs were pretreated 1 h before the antigen challenge with Cefadroxil (100 mg/kg i.p.) a partial but significant inhibition of the bronchial hyperresponsiveness to aerosolized acetylcholine chloride was observed . Furthermore, the treatment of guinea pigs (115 mg/kg, per os) 24 and 1 h before ovalbumin challenge also significantly reduced bronchial hyperresponsiveness . In contrast, no significant inhibition was noted when the guinea pigs were treated by a single dose of Cefadroxil (115 mg/kg per os) 1 h before challenge . Pretreatment of the guinea pigs with Cetirizine (1 mg/kg per os) or Ketotifen (0.1 mg/kg per os) completely inhibited the antigen-induced bronchial hyperresponsiveness . Cefadroxil (100 mg/kg i.p.) slightly inhibited the accumulation of eosinophils in the peribronchial area induced by antigen challenge . In contrast, no significant reduction was noted when the guinea pigs were treated per os with Cefadroxil (115 mg/kg), Cetirizine (1 or 10 mg/kg) or Ketotifen (0.1 mg/kg) . These results show that Cefadroxil is effective in reducing antigen-induced bronchial hyperresponsiveness, an effect independent of a reduction in the pulmonary inflammation, namely eosinophil accumulation in lung.

Pediatr Radiol, 1993, 23(7), 541 - 2
Multifocal thoracic actinomycosis simulating lymphoma; Wu CY et al.; Thoracic actinomycosis is rare in the pediatric age group . We report the unusual case of a 10-year-old girl who presented with prolonged fever and weight loss with a neck mass and multiple pulmonary nodules resembling lymphoma . Open lung biopsy confirmed the diagnosis of actinomycosis and the symptoms and signs improved after treatment with cephalosporin . The pathogenesis and radiographic manifestations are briefly discussed.

Acta Med Austriaca, 1993, 20(5), 124 - 6
{Community-acquired pneumonia}; Mayer KH et al.; Pneumonias are inflammatory diseases of the lung parenchyma, infection is one of possible causes . With regard to the causes of community acquired pneumonias it is possible to distinguish those typical ones (caused by pneumococcus, legionella and other bacteria) and atypical ones (caused by mycoplasma, chlamydiae and others) . Contrary to the atypical ones, typical pneumonias are characterized by sudden onset, high fever, chills, sometimes bloody expectoration and pains, as well as segmental or lobar changes and high leukocyte counts . Patients with tachycardia, diastolic blood pressure below 60 mm Hg and a blood urea nitrogen (BUN) of more than 7 mmol/l, as well as those with chronic basic diseases and a severe course should be hospitalized, further also those, who do not improve after 2 or 3 days therapy, in all cases of suspected pneumonia, with smokers and with patients aged over 40 years, a thorax X-ray should be executed . Typical pneumonias should be treated with penicillin or macrolide antibiotics, atypical ones with macrolide antibiotics, pneumonias with severe course additionally with a second generation cephalosporin . Where these simple rules are observed, a reduction of the still high mortality due to externally acquired pneumonias might be expected.

Enzyme Microb Technol, 1993 Jan, 15(1), 50 - 6
Direct determination of the cephalosporin transforming activity of immobilized cells with use of an enzyme thermistor . 1 . Verification of the mathematical model; Gemeiner P et al.; A simple method for the direct measurement of the catalytic properties of immobilized cells in the flow minicalorimeter, the enzyme thermistor (ET), is presented . A Trigonopsis variabilis strain with cephalosporin C-transforming activity was used as the model system . The yeast cells were immobilized either by crosslinking with a homobifunctional reagent or by entrapment in gels . The actual activity of the immobilized cells used in the ET was estimated by means of a stirred-batch reactor measurement in conjunction with HPLC analysis of substrate and products . Similar results were also obtained using D-amino acid oxidase (EC 1.4.3.3) isolated from T . variabilis cells and immobilized by gel entrapment . This calibration procedure was found to be appropriate for all biocatalyst systems used . The thermometric signal was proportional to the amount of biocatalyst immobilized in the ET minicolumn . It was shown that the rate of reaction catalyzed by T . variabilis entrapped in calcium pectate gel was limited by internal diffusion to an extent depending on the cell concentration in the biocatalyst particle . This approach offers a direct method for studying the kinetic properties of immobilized cells.

Dakar Med, 1993, 38(2), 159 - 64
{Broad spectrum beta-lactamases: results in Principal Hospital of Dakar (February 1st 1992 - February 1st 1993)}; N'Doye B et al.; The intensive, unreasonable use of antibiotics makes resistant strains growing particularly in hospital areas where the selection pressure is important . During the last years, the outstanding event was the emergence of resistant strains against 3rd generation of cephalosporin . In many cases this resistance is linked with Extended broad spectrum Beta-lactamase . After the description of a simple method to detect these particular strains, the authors report the epidemiologic situation in Hopital Principal of Dakar from February 1992 to January 1993 . The emergence of these resistant strains creates heavy problems in intensive care services and Pediatrics . As conclusion, principal measures to prevent this phenomen are exposed.

Biochemistry, 1992 Dec 22, 31(50), 12648 - 57
Two isozymes of clavaminate synthase central to clavulanic acid formation: cloning and sequencing of both genes from Streptomyces clavuligerus; Marsh EN et al.; Clavaminate synthase (CS) is an alpha-ketoglutarate-dependent oxygenase central to the biosynthesis of clavulanic acid, a potent inhibitor of beta-lactamases . CS catalyzes the oxidative cyclization/desaturation of proclavaminic acid to clavaminic acid in a two-step process involving the intermediacy of dihydroclavaminic acid {Salowe, S . P., Krol, W . J., Iwata-Reuyl, D., & Townsend, C . A . (1991) Biochemistry 30, 2281-2292} . During the purification of CS to homogeneity from Streptomyces clavuligerus {Salowe, S . P., Marsh, E . N., & Townsend, C . A . (1990) Biochemistry 29, 6499-6508}, two forms of the enzyme capable of carrying out the complete reaction having very similar molecular weights and kinetic properties were isolated by Mono-Q chromatography . The gene for each has been cloned, sequenced, and found to be significantly homologous (87% identity) . The two genes so isolated, cs1 and cs2, have open reading frames of 975 and 978 nucleotides, respectively, encoding proteins of M(r) 35,347 and 35,774 . These genes are located in different loci of the genome separated by > 20 kbp . This separation is large for a natural product biosynthetic pathway in bacteria where gene duplication and limited divergence are typically observed to occur within narrower confines of a gene cluster . Sequence comparisons made between cs1/cs2 and other genes encoding iron-dependent proteins involved in penicillin and cephalosporin biosynthesis in the same organism show minimal homology . Further sequence alignments made to other non-heme iron oxygenases reveal unexpected dissimilarity within the alpha-ketoglutarate-dependent class itself . The limited data available suggests evolutionary convergence among these proteins.

Biochim Biophys Acta, 1992 Dec 9, 1112(2), 167 - 73
Cefaclor uptake by the proton-dependent dipeptide transport carrier of human intestinal Caco-2 cells and comparison to cephalexin uptake; Dantzig AH et al.; The human Caco-2 cell line spontaneously differentiates in culture to epithelial cells possessing intestinal enterocytic-like properties . These cells possess a proton-dependent dipeptide transport carrier that mediates the uptake of the cephalosporin antibiotic cephalexin (Dantzig, A.H . and Bergin, L . (1990) Biochim . Biophys . Acta 1027, 211-217) . In the present study, the uptake of cefaclor was examined and found to be sodium-independent, proton-dependent, and energy-dependent . The initial rate of D-{3-phenyl-3H}cefaclor uptake was measured over a wide concentration range; uptake was mediated by a single saturable transport carrier with a Km of 7.6 mM and a Vmax of 7.6 nmol/min per mg protein and by a non-saturable component . Uptake was inhibited by dipeptides but not amino acids . The carrier showed a preference for the L-isomer . The effect of the presence of a 5-fold excess of other beta-lactam antibiotics was examined on the initial rates of 1 mM cefaclor and 1 mM cephalexin uptake . Uptake rates were inhibited by the orally absorbed antibiotics, cefadroxil, cefaclor, loracarbef, and cephradine and less so by the parenteral agents tested . The initial uptake rates of both D-{9-14C}cephalexin and D-{3-phenyl-3H}cefaclor were competitively inhibited by cephalexin, cefaclor, and loracarbef with Ki values of 9.2-13.2, 10.7-6.2, and 7.7-6.4 mM, respectively . Taken together, these data suggest that a single proton-dependent dipeptide transport carrier mediates the uptake of these orally absorbed antibiotics into Caco-2 cells, and provide further support for the use of Caco-2 cells as a cellular model for the study of the intestinal proton-dependent dipeptide transporter.

Clin Orthop, 1992 Dec, (285), 223 - 8
Fractures of the femur treated by intramedullary nailing using the fluted rod . A report of 193 consecutive cases; Groh GI et al.; One hundred ninety-three of 196 acute nonpathologic femoral shaft fractures were treated consecutively with intramedullary nailing using the fluted rod . Closed intramedullary nailing was used in 126 fractures, and an open technique was used in 67 . This series includes 58 open fractures and 104 comminuted fractures . All fractures treated with the fluted rod united . Complications included three superficial infections (1.5%) . Malrotation greater than 20 degrees was noted in six patients (3.1%) . Significant shortening (5 cm), which required treatment, occurred in one patient . After initial resuscitation and evaluation, routine treatment included preoperative traction and a first-generation cephalosporin followed by accurate reduction and nailing of the fracture . The results of this series suggest that the fluted rod may be ideal for the treatment of most femoral shaft fractures.

Am J Vet Res, 1992 Nov, 53(11), 2201 - 5
Safety of ceftiofur sodium administered intramuscularly in horses; Mahrt CR; Ceftiofur sodium, a broad-spectrum cephalosporin antibiotic, was evaluated for safe use in horses . Male or female horses were allotted to groups and were given either saline solution (control), or 2.2, 6.6, or 11 mg of an aqueous solution of ceftiofur sodium/kg of body weight/d, IM, for 30 or 31 days . These dosages are expressed in terms of the ceftiofur free acid, and represent 1 to 5 times the proposed therapeutic dosage (2.2 mg/kg/d) administered for 3 times the maximal recommended duration of 10 days . Some of the horses were euthanatized and necropsied on day 31 or 32 . The other horses were evaluated for an additional 30 days, and some were euthanatized and necropsied on day 60 . The following types of data were collected: clinical observation; physical examination; pelleted food consumption; body weight; hematologic, serum biochemical, and urinalysis findings; organ weight; gross necropsy observations; and histopathologic findings . Ceftiofur sodium was generally well tolerated at the exaggerated doses and treatment durations used in these safety studies . Slight to mild decrease in pelleted food consumption was detected in horses given 6.6 or 11 mg of ceftiofur sodium/kg/d . Decreased food consumption began on day 2 and lasted for approximately 9 to 12 days . Generally, mild skeletal muscle irritation was detected by gross and microscopic examination of the injection sites of horses given ceftiofur sodium . Prevalence and severity of the muscle irritation tended to increase with increasing concentration of the dosing solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Nippon Geka Hokan, 1992 Nov 1, 61(6), 423 - 32
Combined therapy of a cephalosporin, Shiomarin and a new potent protease inhibitor, E3123 in rat taurocholate-induced pancreatitis; Hirano T et al.; The role of infectious factors in the pathogenesis of acute pancreatitis and the protective effect of combined therapy with a new potent synthetic protease inhibitor, E3123, and a new potent synthetic cephalosporin, Shiomarin (SM) were examined in rat acute pancreatitis . Sodium taurocholate injection into the pancreatico-biliary duct of rats caused severe pancreatitis with a high mortality rate, characterized by hyperamylasemia, high amylase activity in ascitic fluid, and hyperendotoxemia and a high serum level of fibrin degradation products (FDP), redistribution of cathepsin B from the lysosomal fraction to the zymogen fraction . In rats with E3123 infusion almost all parameters were improved, including mortality rate, serum and ascitic fluid amylase levels, plasma endotoxin and serum FDP levels, and distribution of lysosomal enzyme . But combination therapy with E3123 and SM was significantly more protective than E3123 therapy alone . These results indicate that infection plays an important role in the development of severe pancreatitis and that combination therapy with a new synthetic protease inhibitor and a new potent antibiotic may be useful in the treatment of severe pancreatitis.

J Med Chem, 1992 Oct 16, 35(21), 3731 - 44
Inhibition of human leukocyte elastase . 4 . Selection of a substituted cephalosporin (L-658,758) as a topical aerosol; Finke PE et al.; Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases . The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical activity in an in vivo hamster lung hemorrhage model . While the most potent in vitro HLE inhibition had previously been obtained with lipophilic ester derivatives, it was found that the less active, but more polar and stable, amide derivatives were much more effective in vivo . The development of the structure--activity relations for optimization of these activities is discussed . These results led to the selection of 3-(acetoxymethyl)-2-{(2(S)-carboxypyrrolidino)carbonyl}-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo{4.2.0}oct-2-ene, 5,5-dioxide (3, L-658,758) as a selective, potent, time-dependent HLE inhibitor suitable for formulation as a topical aerosol drug for possible clinical use.

Obstet Gynecol, 1992 Oct, 80(4), 650 - 4
Abdominal wound closure using a running, looped monofilament polybutester suture: comparison to Smead-Jones closure in historic controls; Sutton G et al.; OBJECTIVE: To determine whether abdominal wound closure with a running, looped monofilament polybutester suture was as effective, inexpensive, and rapid as Smead-Jones closure using the same material . METHODS: Between April 19, 1990 and August 29, 1991, 154 patients undergoing major gynecologic surgery had wound closure using a running, looped monofilament polybutester suture . Controls were 154 patients undergoing similar surgical procedures in the 15 months immediately preceding the study period (January 5, 1989 to April 18, 1990) whose wounds were closed with 0 polybutester using the Smead-Jones technique . All patients received prophylactic cephalosporin antibiotic therapy and external pneumatic leg compression perioperatively . The subcutaneous tissues were not sutured after fascial closure, and the skin was closed with stainless-steel staples . There was no difference between the groups when compared by mean weight, mean ponderal index, number of previous abdominal operations, operative blood loss, or the use of chemotherapy or radiotherapy in the pre- or postoperative period . Both groups had similar rates of complicating medical conditions including insulin-dependent and non-insulin-dependent diabetes mellitus, hypertension, obstructive pulmonary disease, atherosclerotic coronary disease, or peripheral vascular disease . RESULTS: The use of a running closure with looped monofilament polybutester suture in the study patients resulted in a reduction in operating time when compared with controls . The rates of superficial separation and wound infection were similar in both groups . In the study group, there was one minor fascial separation and one wound dehiscence, which occurred when the running suture was inadvertently snipped during debridement of a superficial infection . CONCLUSION: Running closure with looped polybutester is an acceptable, inexpensive, and expeditious method of abdominal wound closure.

J Lab Clin Med, 1992 Oct, 120(4), 604 - 13
In vivo studies of biliary ceftriaxone excretion and solubility in guinea pig hepatic bile; Purdum PP 3rd et al.; Ceftriaxone (CFTX), a third-generation cephalosporin, has occasionally been reported to produce biliary sludge composed of its calcium salt . We performed studies in guinea pigs to (1) investigate the hepatic route of CFTX excretion, (2) determine ceftriaione's effects on bile flow and composition, and (3) quantify the solubility and metastability of the calcium salt as a function of administered dose . Our results show that even at high doses ceftriaxone has only minimal effects on bile flow and biliary electrolyte secretion, either alone or in combination with bile salt (taurocholate) infusion . A significant increase in total calcium concentration was observed without change in free Ca2+ concentration, this is compatible with formation of a soluble calcium salt of ceftriaxone, as previously demonstrated in vitro . Ion products of Ca2+ and ceftriaxone as high as 3.5 times the solubility product constant without crystal formation were observed, confirming the presence of a metastable state for the calcium salt of ceftriaxone in the living animal . Biliary excretion of ceftriaxone inhibited excretion of indocyanine green, suggesting that ceftriaxone and indocyanine green share a common anionic excretory pathway in this species.

Appl Microbiol Biotechnol, 1992 Oct, 38(1), 122 - 8
Identification of rate-limiting steps in cephalosporin C biosynthesis in Cephalosporium acremonium: a theoretical analysis; Malmberg LH et al.; A kinetic model describing the biosynthesis of cephalosporin C in Cephalosporium acremonium has been developed to identify the rate-limiting step(s) . Using this model and in-vitro kinetic data of the biosynthetic enzymes, the production kinetics of cephalosporin C were examined theoretically . The predicted time profile of the specific production rate during batch culture is in good agreement with that of experimental results published previously . Sensitivity analysis indicates that delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase is the rate-limiting enzyme . Our analysis also predicts that increasing ACV synthetase enhances the production rate initially until expandase/hydroxylase becomes rate-limiting . Furthermore, increasing expandase/hydroxylase reduces the accumulation of penicillin N, and thus, enhances the production of cephalosporin C . Based on our analysis, amplifying both ACV synthetase and expandase/hydroxylase concurrently should enhance the production rate to a great extent.

Enzyme Microb Technol, 1992 Oct, 14(10), 848 - 54
Influence of dissolved oxygen concentration on the biosynthesis of cephalosporin C; Zhou W et al.; Cephalosporin C was produced by a highly productive strain of Cephalosporium acremonium under industrial production conditions by fed-batch cultivation in a 40-l stirred-tank reactor using a complex medium containing 50 g l-1 peanut flour . The influence of dissolved oxygen concentration (pO2, DOC), which was maintained at different constant levels between 5 and 40% of its saturation value, during the production phase by means of a parameter-adaptive pO2-controller, on the cephalosporin C biosynthesis, was investigated . The concentrations of cephalosporin C (CPC) and its precursors penicillin N (PEN N), deacetoxycephalosporin C (DAOC), and deacetylcephalosporin C (DAC) were monitored by on-line HPLC . The concentrations of amino acids, valine (VAL), cysteine (CYS), alpha-amino-adipic acid (alpha-AAA), the dipeptide alpha-amino-adipyl-cysteine (AC), and the tripeptide alpha-amino-adipyl-cysteinyl-valine (ACV) were determined by off-line HPLC . By reducing the pO2 in the production phase from 40 to 5% of its saturation value, the CPC concentration diminished from 7.2 to 1.1 g l-1 and the PEN N concentration increased from 2.57 to 7.65 g l-1 . The DAC concentration also dropped from 3.13 to 0.42 g l-1; however, the DAOC concentration was less influenced . The concentrations of AC and ACV were also less affected . The small DOC did not lead to an accumulation of the intermediate AC and ACV during the production phase . With increasing DOC in the range of 5-20%, the maximal specific production rate, the cell mass concentration-based and the substrate-based yield coefficients for CPC increased almost linearly, and fell back for PEN N.(ABSTRACT TRUNCATED AT 250 WORDS)

J Chromatogr, 1992 Sep 11, 608(1-2), 275 - 87
Chiral separation by capillary electrophoresis with oligosaccharides; D'Hulst A et al.; Maltodextrins, i.e., mixtures of linear alpha-(1-4)-linked D-glucose polymers, were found to be effective as chiral electrolyte modifiers to perform direct, rapid separations by capillary electrophoresis of racemic mixtures of 2-arylpropionic acid non-steroidal anti-inflammatory compounds and coumarinic anticoagulant drugs, and also diastereomeric cephalosporin antibiotics . Enantioselectivity seemed to be dependent on an as yet unidentified combination of variables.

Rev Med Panama, 1992 Sep, 17(3), 194 - 8
{Acute epiglottitis in adults}; Castillo A; The author presents the clinical history of 14 patients, from 21 to 48 years of age, 10 men and 4 women, with a final diagnosis of acute epiglottitis who were hospitalized at Gorgas Army Hospital or at the San Fernando Clinic . All the patients had pharyngitis and dysphagia, a few with nasal voice, stridor and difficulty breathing, as the chief complaint . All the patients were initially intubated orally for diagnostic purposes and immediately after nasotracheal intubation was done until the patient improved in 2 or 3 days (one patient remained intubated for 5 days) . All patients were kept in the Intensive Care Unit and were treated with Ampicillin and Chloramphenicol IV and lately with a second generation cephalosporin (Cefamandole) . The patients allergic to Penicillin were treated with Clindamycin and Chloramphenicol . Corticosteroids were not used in any of the patients . There were no sequelae and none of the patients expired.

Biosci Biotechnol Biochem, 1992 Sep, 56(9), 1410 - 2
Purification of acetyl coenzyme A: deacetylacephalosporin C O-acetyltransferase from Acremonium chrysogenum; Matsuyama K et al.; Acetyl CoA: deacetylcephalosporin C O-acetyltransferase, which catalyzes the final step of the biosynthetic pathway to cephalosporin C, was stabilized by a buffer solution containing 7-aminocephalosporanic acid and purified over 1300-fold from Acremonium chrysogenum . The purified enzyme has a molecular weight of 55,000 as measured by gel filtration . SDS-polyacrylamide gel electrophoresis showed two subunit bands corresponding to molecular weights of 27,000 and 14,000 . The enzyme has an isoelectoric point at pH 4.0 and optimum activity at pH 7.5.

J Ind Microbiol, 1992 Sep, 10(3-4), 157 - 63
Determination of the rate-limiting step(s) in the biosynthetic pathways leading to penicillin and cephalosporin; Usher JJ et al.; This paper is a review of strategies that have been used, or that could be used, to determine the rate-limiting step(s) in the biosynthetic pathways leading to penicillin or cephalosporin . Information is summarized from published material that involves studies with low-producing strains of Penicillium chrysogenum and Cephalosporium acremonium . We also summarize information derived from some high-producing production strains . Identification of the rate-limiting step(s) was of great interest to us as the first step in a rational program to further improve antibiotic titers of these highly developed strains . A number of approaches that could be used to elucidate the rate-limiting step(s) are described herein.

J Antibiot (Tokyo), 1992 Aug, 45(8), 1346 - 57
Structure-binding relationship and binding sites of cephalosporins in human serum albumin; Tawara S et al.; The binding of some cephalosporins to human serum albumin (HSA) was studied by an ultrafiltration technique . Changes in C-3 side chain resulted in marked changes in the binding to HSA, but changes in C-7 side chain did not . Cephalosporins were classified into three groups by C-3 side chain: (i) Cationic side chain with low affinity for HSA; (ii) anionic side chain with high affinity for HSA; (iii) non ionized side chain, in which binding to HSA was dependent on lipophilicity . These findings suggest that electrostatic and hydrophobic forces play a role in the binding affinity of cephalosporins for HSA . The binding of cephalosporins with high HSA affinity was displaced significantly by warfarin but not by phenylbutazone, L-tryptophan, or diazepam . The interaction of the cephalosporins with high affinity for HSA with chemically modified HSA was investigated to clarify the amino acid residues of HSA involved in the cephalosporin binding sites . The binding of the cephalosporins decreased remarkably with the modification of the tyrosine residues . These results suggest that the binding site of cephalosporins is located in the vicinity of warfarin binding site rather than benzodiazepine binding site and that tyrosine residues are involved in the cephalosporin binding site.

Biochem Biophys Res Commun, 1992 Jul 15, 186(1), 40 - 6
Cloning and disruption of the cefG gene encoding acetyl coenzyme A: deacetylcephalosporin C o-acetyltransferase from Acremonium chrysogenum; Matsuda A et al.; Acetyl CoA: deacetylcephalosporin C o-acetyltransferase(DCPC-ATF) catalyses the final step in the biosynthesis of cephalosporin C (CPC) in Acremonium chrysogenum . The gene encoding DCPC-ATF, cefG, has been isolated from an A . chrysogenum genomic library using a DCPC-ATF cDNA probe . Nucleotide sequence analysis revealed that cefG contains two short introns of 79bp and 65bp . The gene was found to be closely linked to the cefEF gene encoding deacetoxycephalosporin C synthetase/deacetylcephalosporin C synthetase, which catalyses the preceding two steps in the pathway . The two genes are separated by a 1114 bp segment from which they are divergently transcribed . Introduction of the cloned cefG gene to A.chrysogenum resulted in an increased level of DCPC-ATF activity . A plasmid carrying a cefG gene interrupted in the coding region by a selectable marker for resistance to hygromycin B was constructed and used to disrupt the cefG locus in A.chrysogenum . The cefG-disrupted strains were found to lack the ability to produce CPC, and accumulated its precursor, deacetylcephalosporin C in the culture broth . Southern hybridization analysis confirmed that the disruption resulted from a gene replacement event at the cefG locus.

Am J Pathol, 1992 Jul, 141(1), 153 - 60
Detection of extracellular neutrophil elastase in hamster lungs after intratracheal instillation of E . coli lipopolysaccharide using a fluorogenic, elastase-specific, synthetic substrate; Rudolphus A et al.; Repeated intratracheal instillations of E . coli lipopolysaccharide (LPS) in hamster lungs cause an influx of polymorphonuclear leukocytes (PMNs) into the alveolar walls, with concomitant development of severe emphysema . It has been suggested that elastase, released by these PMNs, is involved in the development of emphysema . This study demonstrates the release of elastase from recruited PMNs in cryostat sections of hamster lungs, after being treated once, twice, or thrice with LPS, intratracheally . Elastase activity was visualized using two elastase-specific synthetic substrates, to which a methoxynaphthylamine (MNA) group had been bound covalently . Liberated MNA, when made insoluble by coupling with 5-nitrosalicylaldehyde, fluoresces strongly . The authors observed that the interval between start of incubation and appearance of fluorescence and the intensity of fluorescence correlated with the number of LPS administrations . Fluorescence was observed to be located in or in close vicinity to alveolar walls . No fluorescence was observed in sections of untreated hamsters . Liberation of MNA from synthetic substrates was delayed strongly by the addition of a recombinant secretory leukocyte proteinase inhibitor or a substituted cephalosporin neutrophil elastase inhibitor . The authors conclude that LPS-mediated PMN influx into the lung is accompanied by release of elastase from these cells and speculate that this PMN-elastase is involved in the development of LPS-mediated emphysema.

Biochemistry, 1992 Jun 2, 31(21), 4980 - 6
Mechanism of inhibition of human leukocyte elastase by two cephalosporin derivatives; Knight WB et al.; The cephalosporin derivatives L 658758 {1-{{3-(acetoxymethyl)-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo {4.2.0}oct-2-en-2-yl}carbonyl}proline S,S-dioxide} and L 659286 {1-{{7 alpha-methoxy-8-oxo-3-{{(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- 1,2,4-triazin-3-yl)thio}methyl}-5-thia-1-aza-(6R)-bicyclo{4.2.0}-o ct-2-en-2-yl}carbonyl}pyrrolidine S,S-dioxide} are mechanism based inhibitors of human leukocyte elastase (HLE) . The mechanism involves initial formation of a Michaelis complex followed by acylation of the active site serine . The group on the 3'-methylene is liberated during the course of these reactions, followed by partitioning of an intermediate between hydrolysis to regenerate active enzyme and further modification to produce a stable HLE-inhibitor complex . The partition ratio of 2.0 obtained for the reaction with L 658758 approaches that of an optimal inhibitor . These compounds are functionally irreversible inhibitors as the recovery of activity after inactivation is slow . The half-lives at 37 degrees C of the L 658758 and L 659286 derived HLE-I complexes were 9 and 6.5 h, respectively . The complexes produced by both inhibitors are similar chemically since the thermodynamic parameters for activation to regenerate active enzyme are essentially identical . The free energy of activation for this process is dominated primarily by the enthalpy term . The stability of the final complexes likely arises from Michael addition on the active site histidine to the 3'-methylene.

J Bone Joint Surg Am, 1992 Jun, 74(5), 766 - 9
Shrapnel wounds in children; Hoffer MM et al.; Nineteen children who had open fractures and skin wounds of at least two centimeters due to shrapnel were followed for one to five weeks after they had been injured . All of the patients were managed with debridement at twenty-four to forty-eight-hour intervals and were given cephalosporin antibiotics . Fourteen patients did well . The wounds in the three patients who had the least severe soft-tissue injury were healing well at two weeks, and ten other patients were progressing to soft-tissue and osseous healing at five weeks . One patient had progressive but slower healing, and plastic reconstructive procedures would be advisable . Five patients had major problems . In one of these children, a wound continued to drain after six weeks . Three children had an amputation, and another child died due to a vascular injury.

Pediatr Infect Dis J, 1992 Jun, 11(6), 456 - 60
Thrombocytosis and thrombocytopenia in childhood bacterial meningitis; Kilpi T et al.; To assess factors affecting the development of reactive thrombocytosis during bacterial meningitis, thrombocyte counts of 311 children with cerebrospinal fluid culture-positive bacterial meningitis were followed during hospitalization . Thrombocytosis (platelet counts greater than 500 x 10(9)/liter) was seen in 49% of the patients after the first week of treatment . Thrombocyte counts were higher in infants and in patients with long duration of illness before admission . Subdural effusion and cephalosporin therapy were associated with more pronounced thrombocytosis We found no relation between thrombocytosis and neurologic complications, but the patients who died developed thrombocytopenia instead of thrombocytosis . The difference between the thrombocyte curves of the surviving and dying patients might be utilized in predicting the final outcome in the severest cases of bacterial meningitis . We speculate that inflammatory cytokines, especially interleukin 1-beta, induce reactive thrombocytosis in bacterial meningitis.

Am J Hematol, 1992 Jun, 40(2), 121 - 5
Cephalosporin-induced hemolysis: a case report and review of the literature; Ehmann WC; Cephalosporins are commonly used drugs that interact with red blood cell membranes . They frequently cause a positive direct antiglobulin test but rarely cause hemolysis . A case of cefotetan-induced hemolytic anemia is described in which two types of antibodies were detected . One reacted with red blood cells by a hapten mechanism, the other reacted with drug to form immune complexes . This case is compared with the 13 cases of cephalosporin-induced hemolytic anemia reported to date . Understanding the interactions of red blood cells and cephalosporins is critical to the safe use of these commonly prescribed drugs.

Jpn J Antibiot, 1992 Jun, 45(6), 681 - 6
{Clinical efficacy of ceftriaxone when administered once daily for respiratory tract infections in patients with advanced ages}; Takizawa S et al.; Ceftriaxone (CTRX), a new third generation cephalosporin, was investigated upon once daily administration for its clinical efficacy and safety on respiratory tract infections in patients with advanced ages . The results are summarized as follows: 1 . Clinical responses to CTRX of 48 cases of advanced age patients with respiratory tract infections were good with an efficacy rate of 89.6% . 2 . Adverse reactions to CTRX were mainly exanthema in 7 cases (14.6%) . 3 . Serum levels of CTRX were determined in 4 cases after intravenous drip infusion of 2 g CTRX . Serum levels were analyzed by one-compartment model . There was no evidence of accumulation of CTRX in the patients with advanced ages.

Jpn J Antibiot, 1992 Jun, 45(6), 661 - 80
{General pharmacology of cefepime}; Goto A et al.; General pharmacological properties of cefepime (CFPM), a new injectable semisynthetic cephalosporin and its metabolite N-methylpyrrolidine-N-oxide (NMP-N-oxide) were studied in laboratory animals . The results obtained are summarized as follows: 1 . CFPM reduced spontaneous locomotor activity but potentiate the anesthesia at the highest dose in mice . Furthermore, significant hypothermia and analgesia were observed at the same dose in mice . No effects were found on the other CNS function in mice and rats or on EEG activities in rabbits . 2 . Muscle relaxant activity was not observed in mice treated with CFPM even at the highest dose . 3 . CFPM had no effect on the intestinal smooth muscle and did not show any antagonism against some smooth muscle contracting drugs . 4 . The respiration, blood pressure, heart rate and ECG were affected by CFPM . Those changes, however, might have been principally caused by L-arginine blended with CFPM product . 5 . No effect of CFPM on the intestinal movement or gastric secretion was found even at the highest dose of CFPM . 6 . The pH neutralizer L-arginine caused alterations in the renal function and electrolyte metabolism but CFPM did not . 7 . Whole blood clotting time tended to be lengthened by CFPM at the highest concentration but this effect seemed to have been caused by L-arginine . Other parameters of the coagulation system or red blood cell resistance were not affected by CFPM . 8 . NMP-N-oxide, a metabolite of CFPM, had almost no effect on any of the tested parameters except for its slight effect on the circulatory system . These findings indicate that CFPM has scarcely any pharmacological properties which might be leading to severe adverse reactions in clinical use.

Arch Intern Med, 1992 May, 152(5), 930 - 7
A perspective on penicillin allergy; Lin RY; Clinical situations for which penicillin is indicated as the sole effective treatment are not infrequent and may be increasing in incidence . Penicillin allergy in these circumstances complicates their medical management . The proper evaluation of penicillin allergy is thus crucial to making decisions about alternative antibiotic therapy vs penicillin and the need for desensitization in allergic individuals . The combination of skin testing and assessment of the type of previous penicillin allergic reaction allows designation of patients into those at high risk and those at low risk for subsequent reactions . Penicillin allergy may also complicate the management of infections in which a cephalosporin is the preferred treatment . The available data on cross-reactivity and concurrent hypersensitivity involving these antibiotics and penicillin are incomplete . The current and past literature were reviewed in an attempt to develop practical treatment approaches and to identify clinical questions that need further investigation related to penicillin allergy.

J Bacteriol, 1992 May, 174(9), 3056 - 64
The cefG gene of Cephalosporium acremonium is linked to the cefEF gene and encodes a deacetylcephalosporin C acetyltransferase closely related to homoserine O-acetyltransferase; Gutierrez S et al.; The gene (cefG) encoding the acetyl coenzyme A:deacetylcephalosporin C acetyltransferase of Cephalosporium acremonium (synonym Acremonium chrysogenum) C10 has been cloned . It contains two introns and encodes a protein of 444 amino acids with an M(r) of 49,269 that correlates well with the M(r) deduced by gel filtration . The cefG gene is linked to the cefEF gene (encoding the bifunctional deacetoxycephalosporin C synthase/hydroxylase), but it is expressed in an orientation opposite that of the cefEF gene . Two transcripts of 1.2 and 1.4 kb were found in C . acremonium that correspond to the cefEF and cefG genes, respectively; the degree of expression of the cefG gene was clearly lower than that of the cefEF gene in 48-h cultures . The cloned cefG complemented the deficiency of deacetylcephalosporin acetyltransferase in the nonproducer mutant C . acremonium ATCC 20371 and restored cephalosporin biosynthesis in this strain . Heterologous expression of the cefG genes took place in Penicillium chrysogenum . The deacetylcephalosporin acetyltransferase showed a much higher degree of homology with the O-acetylhomoserine acetyltransferases of Saccharomyces cerevisiae and Ascobolus immersus than with other O-acetyltransferases . The cefEF-cefG cluster of genes encodes the enzymes that carry out the three late steps of the cephalosporin biosynthetic pathway and is not linked to the pcbAB-pcbC gene cluster that encodes the first two steps of the pathway.

Fundam Appl Toxicol, 1992 May, 18(4), 532 - 9
Nephrotoxicity of a new cephalosporin, DQ-2556, in rats; Kato M et al.; A single intravenous administration of a new cephalosporin, DQ-2556, at 1200 mg/kg to Sprague-Dawley rats induced proximal tubular necrosis . The histological lesions were not closely correlated with renal cortical concentrations of DQ-2556 . Development of renal injuries was examined histologically . The arcuate and cortical radial arteries of the kidneys were constricted immediately after the injection, but then became dilated and showed histological changes: penetration by erythrocytes, edematous thickening, and necrosis in the media . In addition to congestion in the outer medulla, the proximal convoluted and straight tubules exhibited the earliest changes 30 min after the injection, namely, enlargement and rounding of the mitochondria and swelling and irregular arrangement of the microvilli in the epithelial cells . Small necrotic foci of epithelium were observed from 4 hr . They were mainly distributed in the outer cortex and the outer stripe of the outer medulla 24 hr later . In the examination of hemodynamics, DQ-2556 significantly decreased the blood flow with increased vascular resistance in the renal artery during and after a single injection . These changes had disappeared wholly or partially 60 min after dosing commenced . Furthermore, Ca2+ channel blockers markedly inhibited increases in the serum urea nitrogen and creatinine concentrations and development of the tubular necrosis and the lesions of the arterial walls, which were induced by DQ-2556 . These results suggest a possible contribution of the constriction of renal artery to the tubular necrosis.

Z Rheumatol, 1992 May-Jun, 51(3), 136 - 41
{Bacterial sacroiliitis}; Nagler P et al.; We saw two cases of infectious sacroiliitis in young patients . The multi-various clinical symptoms, the predispositions, as well as the alteration of laboratory analyses are described . Further, we discuss problems of early diagnosis, diagnostic measures like x-ray, sonography, bone-scan, computerized tomography scan, magnetic resonance imaging, and their particular significance . Computerized tomography scan of iliosacral joints determined the further therapeutic procedure . In both cases, we prescribed cephalosporin-antibiotic cefotaxime-sodium.

Pathol Biol (Paris), 1992 May, 40(5), 538 - 44
{Biliary excretion and hepatic disposal of cefixime: experimental and clinical study}; Westphal JF et al.; Cefixime is a new oral cephalosporin with in vitro activity similar to that of third-generation cephalosporins . Renal excretion accounts for only 40% of systemic clearance of cefixime, suggesting that biliary excretion of the drug may be significant . This study was designed to determine to what extent nonrenal clearance of cefixime is due to biliary excretion of the parent compound . In an isolated perfused rabbit liver model, biliary excretion of cefixime was very low, with only 0.28 +/- 0.15% of a single 10 mg dose injected in the system being recovered in the bile after three hours perfusion . The liver biotransformation rate for cefixime was found to be 16.2% . These results are in striking contrast with those obtained in human studies . Cefixime levels in duodenal juice aspirates collected over four hours following an intravenous injection of 200 mg cefixime in six healthy volunteers were at least fivefold concomitant serum levels . Studies of bile collected by external biliary drainage during 24 hours following an oral dose of 200 mg cefixime in ten cholecystectomized patients showed that the Cmax was 56.9 +/- 70 mg/l, i.e., 25-fold the serum Cmax (2.3 +/- 0.85 mg/l) . The bile AUC/serum AUC ratio was 20.4 +/- 20.3 . Mean bile level of cefixime was still as high as 4.3 +/- 3.7 mg/l 20 hours after dosing . The amount of cefixime excreted in the bile over 24 hours was 10.0 +/- 12.3 mg i.e., 5% of the dose administered . Twenty-four hour renal excretion of cefixime was 53.3 +/- 26.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

J Biotechnol, 1992 May, 23(3), 315 - 29
Influence of medium composition on the cephalosporin C production with a highly productive strain Cephalosporium acremonium; Zhou W et al.; Cephalosporin production by a highly productive Cephalosporium acremonium strain was carried out and optimized by fed-batch operation in a 40 l stirred tank reactor using a complex medium containing 30-120 g l-1 peanut flour . The concentrations of cephalosporin C (CPC) and its precursors: penicillin N (PEN N), deacetoxy cephalosporin C (DAOC), and deacetyl cephalosporin C (DAC) were monitored with an on-line HPLC . The concentrations of amino acids valine (VAL), cysteine (CYS), alpha-amino adipic acid (alpha-AAA), the dipeptide alpha-amino-adipyl-cysteine (AC), and the tripeptide alpha-amino-adipyl-cysteinyl-valine (ACV), were determined off-line by HPLC . The RNA content and dry weight of the sediment as well as the oxygen transfer rate (OTR) and the CO2 production rate (CPR) were used to calculate the cell mass concentration (X) . The influences of peanut flour (PF) and the on-line monitored and controlled medium components: glucose (GLU), phosphate, methionine (MET) as well as the dissolved oxygen (DOC) on the cell growth, the product formation, and the pathway of cephalosporin C biosynthesis were investigated and evaluated . When the glucose fed-batch cycle was optimized and oxygen transfer limitation was avoided (DOC greater than 20% of the saturation value), high process performance (103.5 g l-1 X, 11.84 g l-1 CPC, a maximum CPC productivity of 118 mg l-1 h-1, and the whole concentration of the beta-lactam antibiotics CPC, DAC, DAOC, PEN N 17.34 g l-1) was achieved by using 100 g l-1 PF in the medium with the optimum concentration of phosphate (260-270 mg l-1) and a low glucose concentration (less than 0.5 g l-1) . The cultivations with different medium concentrations demonstrated that the product formation was directly proportional to the cell mass concentration . On the average, the cell mass-based yield coefficient of CPC: YCPC/X amounted to 0.115 g CPC per g cell mass.

Arzneimittelforschung, 1992 Apr, 42(4), 567 - 70
Effect of cefodizime on parameters of cell-mediated immunity in vitro; Mallmann P et al.; A positive effect of cefodizime (CAS 69739-16-8), a new aminothiazolyl cephalosporin, on a number of immunological variables, and in particular phagocytosis, was demonstrated in several test systems . The aim of the present investigation was to establish whether clinically relevant concentrations of cefodizime affect cell-mediated immune variables . Peripheral lymphocytes from healthy subjects were isolated and incubated with cefodizime in increasing concentrations from 0 to 200 mg/l . The effects of cefodizime on membrane-bound antigenic determinants of the lymphocytes were determined in the rosette inhibition test, and its effects on the proliferative capacity of lymphocytes after stimulation with phytohaemagglutinin, concanavalin A and pokeweed mitogen were determined in the lymphocyte transformation test . Cefodizime inhibited rosette formation in a concentration dependent manner . A direct inhibitory effect on proliferation was not, however, demonstrated in the lymphocyte transformation test . Indeed, stimulation of mitogen-induced lymphocyte transformation, particularly of concanavalin A-sensitive cells was observed at concentrations higher than 100 mg/l . The findings in healthy volunteers were reproduced in samples from three female patients with impaired host-defence . These results may suggest a positive effect of cefodizime on the proliferative capacity of the cellular immune system . However, no conclusions can be drawn on the clinical relevance of these findings until the results of in vivo investigations are available.

J Antimicrob Chemother, 1992 Apr, 29 Suppl A, 51 - 7
Cerebrospinal fluid penetration of cefpirome in patients with non-inflamed meninges; Nix DE et al.; Twenty patients (mean age 52 +/- 12 years, mean weight 75 +/- 15 kg) scheduled for elective myelogram or spinal anaesthesia were enrolled to determine the cerebrospinal fluid (CSF) penetration of a new expanded spectrum cephalosporin antibiotic, cefpirome (HR-810) . A single 2 g intravenous dose of cefpirome was administered as a bolus between 1 and 8 h before lumbar puncture . Blood samples were collected at 15 pre-determined times and a single CSF sample was obtained at the time of lumbar puncture . Serum and CSF cefpirome concentrations were determined by high performance liquid chromatography . The mean maximal serum concentration of cefpirome was 264 +/- 76 mg/L . A mean steady-state volume of distribution of 20 +/- 4 L, clearance of 7.4 +/- 1.3 L/h, and half-life of 2.5 +/- 0.5 h were determined . Mean CSF concentrations were 0.50 +/- 0.11 mg/L at 1-2 h post dose (n = 4), 0.57 +/- 0.13 mg/L at 2-4 h post dose (n = 4), 0.76 +/- 0.34 mg/L at 4-6 h post dose (n = 7), and 0.83 +/- 0.29 mg/L at 6-8.3 h post dose (n = 5) . Blood:brain barrier permeability to cefpirome may not be a limiting factor as CSF concentrations were rapidly attained . Further studies are required to determine the mechanism of cefpirome transport between plasma and CSF.

Antimicrob Agents Chemother, 1992 Mar, 36(3), 616 - 9
Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys; Rodriguez CA et al.; The effects of variations in renal perfusate flow on the excretion of cefonicid was examined in isolated perfused rat kidneys . Cefonicid, an expanded-spectrum cephalosporin, is primarily eliminated by active tubular secretion and is neither metabolized nor reabsorbed in the isolated kidney . We used angiotensin II (AII), a strong vasoconstrictor hormone of the afferent and the efferent arterioles in the kidney, to determine whether the renal and secretion clearances, as well as the excretion ratio (ER = CLR/{fu x GFR}, where CLR is renal clearance, fu is the unbound fraction, and GFR is glomerular filtration rate), of this low-extraction compound can be altered by a decreased perfusion flow . Control studies were performed in the absence (n = 5) and presence (n = 4) of AII; cefonicid studies were performed in the absence (n = 4) and presence (n = 5) of AII . AII (1 to 4 ng/min) and cefonicid (5 to 10 micrograms/min) were infused into the perfusate . Cefonicid was assayed by high-performance liquid chromatography, and its protein binding was determined by ultrafiltration . AII decreased the perfusate flow rate and increased the renal vascular resistance and filtration fraction of the isolated kidney in the presence and absence of cefonicid . The glomerular filtration rate remained unchanged among the groups . The fractional excretion of glucose was low and steady, indicating a well-preserved tubular function . Although the unbound fraction was unchanged between treatments, the renal and secretion clearances and the excretion ratio of cefonicid were reduced by about 40% in the presence of AII (excretion ratios, 10.3 without AII versus 6.03 with AII) . These results suggest that the altered clearance parameters of cefonicid are the result of a flow-induced change in the intrinsic secretory transport of the drug.

Biochem J, 1992 Mar 1, 282 ( Pt 2), 495 - 500
Importance of the His-298 residue in the catalytic mechanism of the Streptomyces R61 extracellular DD-peptidase; Hadonou AM et al.; Among the active-site-serine penicillin-recognizing proteins, the Streptomyces R61 extracellular DD-peptidase is the only one to have a His-Thr-Gly sequence {instead of Lys-Thr(Ser)-Gly} in 'box' VII . The His residue was replaced by Gln or Lys . Both mutations induced a marked decrease in the rates of both tripeptide substrate hydrolysis and acylation by benzylpenicillin and cephalosporin C . The rate of hydrolysis of the thioester hippuryl thioglycollate was less affected . The most striking result was the disproportionate loss of transpeptidation properties by both mutants, indicating an important role of His-298 in this reaction . We believe that this result represents the first modification of a DD-peptidase leading to a specific decrease of the transpeptidation-to-hydrolysis ratio.

Biochem Biophys Res Commun, 1992 Feb 14, 182(3), 995 - 1001
Molecular cloning of acetyl coenzyme A: deacetylcephalosporin C o-acetyltransferase cDNA from Acremonium chrysogenum: sequence and expression of catalytic activity in yeast; Matsuda A et al.; Acetyl CoA: deacetylcephalosporin C o-acetyltransferase(DCPC-ATF) catalyses the final step in the biosynthesis of cephalosporin C, the conversion of deacetylcephalosporin C to cephalosporin C . A cDNA encoding DCPC-ATF has been isolated from a cDNA library of a cephalosporin C producing fungus Acremonium chrysogenum using oligonucleotide probes based on N-terminal amino acid sequences of the enzyme . The cDNA contains a single large open reading frame for a putative precursor consisting of 12 amino acid(AA) leader peptide of unknown function, 274 AA large subunit and 126 AA small subunit at the carboxyl end . The cDNA was expressed in yeast exhibiting a functional DCPC-ATF activity . It was also indicated that the leader peptide was not essential for expression of the enzyme activity . The primary structure of DCPC-ATF shows significant homology with those of acetyl CoA: homoserine o-acetyltransferase in Saccharomyces cerevisiae and Ascobolas immersus.

Postgrad Med, 1992 Feb 1, 91(2), 301 - 4, 307-8, 311-2 passim
Sorting out the cephalosporins; Brogan JC; How can you choose the best cephalosporin to prescribe out of an array that is vast and quickly growing? Dr Brogan simplifies the process by describing the specific advantages as well as the shortcomings of individual agents . He also makes general recommendations based on his experience.

J Bacteriol, 1992 Jan, 174(2), 441 - 6
Purification of a nocardicin A-sensitive LD-carboxypeptidase from Escherichia coli by affinity chromatography; Ursinus A et al.; An LD-carboxypeptidase releasing the terminal D-Ala from UDP-MurNAc-L-Ala-D-Glu-m-A2pm-D-Ala (UDP-MurNAc-tetrapeptide) was purified from Escherichia coli to biochemical homogeneity and characterized biochemically . Final purification was achieved by nocardicin A-Sepharose affinity chromatography . An apparent molecular weight of 32,000 was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the enzyme, which seems to be a monomeric protein as indicated by gel filtration . The optimum pH of the enzyme was 8.4, and the pI was 5.5 . The Km for UDP-MurNAc-tetrapeptide was 1.5 x 10(-4) M, and the Vmax was 0.4 nmol/min . Nocardicin A inhibited the enzyme competitively, with a Ki of 5 x 10(-5) M . Benzylpenicillin, cephalosporin C, thienamycin, and D-alanyl-D-alanine did not affect the enzyme activity . Possible functions of the enzyme for growth and division of the murein sacculus are discussed.

Bioconjug Chem, 1992 Jan-Feb, 3(1), 42 - 8
Preparation and characterization of a beta-lactamase-Fab' conjugate for the site-specific activation of oncolytic agents; Meyer DL et al.; Antibody-directed catalysis (ADC) is a two-step method for the targeted delivery of chemotherapeutic agents in which enzyme-antibody conjugates, prelocalized to antigen-bearing cells, activate prodrugs designed to be substrates for the enzyme . An enzyme-Fab' conjugate exhibiting both native beta-lactamase activity and immunoreactivity toward carcinoembryonic antigen (CEA) was constructed . Treatment of CEA-expressing LS174T cells with this conjugate imparted beta-lactamase activity to the cells; beta-lactamase activity was not imparted by treatment with unconjugated beta-lactamase and not to CEA negative cells treated with conjugate . Cephalosporin-based prodrugs, and other substrates synthesized as model compounds, were found to have wide variations in their kinetic parameters toward the conjugate, with kcat values ranging from 16 to 3300 s-1 and KM values ranging from 5 to 160 microM . The prodrug derived from desacetylvinblastine-3-carboxylic acid hydrazide (DAVLBHYD) was studied in vitro and found to be 5-fold less cytotoxic to LS174T cells than the parent DAVLBHYD . For antigen-positive cells preincubated with conjugate, however, the prodrug showed the same potency as the parent drug . Thus, the combination of conjugate and prodrug appears to provide antigen-dependent toxicity to tumor cells.

Drug Saf, 1992 Jan-Feb, 7(1), 32 - 45
Drug-induced gallbladder disease . Incidence, aetiology and management; Michielsen PP et al.; A great variety of drugs is reported to induce gallbladder disease by various pathogenetic mechanisms . Early epidemiological studies indicated a doubled risk of gallbladder disease in women taking oral contraceptives . More recent studies, however, have failed to confirm those findings; these conflicting results might be explained by the different methods used to define gallbladder disease . It was shown that the lithogenic index of the bile is increased during intake of oral contraceptives . Estrogens cause hypersecretion of cholesterol in bile, due to increase in lipoprotein uptake by the hepatocyte . Progesterone inhibits acyl coenzyme A-cholesterol acyl transferase (ACAT) activity, causing delayed conversion of cholesterol to cholesterol esters . Of the lipid lowering drugs, only clofibrate has been shown to increase the risk for gallstone formation . The other fibric acid derivatives have similar properties, but clinical experience is not as extensive . They seem to be inhibitors of the ACAT enzyme system, thereby rendering bile more lithogenic . Conflicting epidemiological data exist regarding the induction of acute cholecystitis by thiazide diuretics . Ceftriaxone, a third-generation cephalosporin, is reported to induce biliary sludge in 25 to 45% of patients, an effect which is reversible after discontinuing the drug . The sludge is occasionally a clinical problem . It was clearly demonstrated that this sludge is caused by precipitation of the calcium salt of ceftriaxone excreted in the bile . Long term use of octreotide is complicated by gallstone formation in approximately 50% of patients after 1 year of therapy, due to gallbladder stasis . Hepatic artery infusion chemotherapy by implanted pump is shown to be associated with a very high risk of chemically induced cholecystitis . Prophylactic cholecystectomy at the time of pump implantation is therefore advocated . Some drugs, such as erythromcyin or ampicillin, are reported to cause hypersensitivity-induced cholecystitis . Furthermore, there are reports on the influence of cyclosporin, dapsone, anticoagulant treatment, and narcotic and anticholinergic medication in causing gallbladder disease.

Infection, 1992, 20 Suppl 1, S41 - 4
Effects of cefodizime and cefotaxime on cellular and humoral immune responses; Pulverer G; Cefodizime is a new cephalosporin antibiotic which has shown some remarkable immunomodulating activities . To mimic possible immunopharmacological effects of prolonged chemotherapy in vivo, we investigated the influence of a seven-day treatment with cefodizime on cellular and humoral parameters of the immune system in BALB/c mice . The dosages (0.4, 0.8 and 1.8 mg cefodizime per day) were calculated on a per kg bodyweight basis according to therapy recommendations for humans . Delayed type hypersensitivity (oxazolone test) as well as the production of IgM and IgG antibodies (direct and indirect plaque forming test) were investigated in BALB/c mice . Leukocyte and monocyte activities were measured using human cells . The results are discussed using cefotaxime as comparable reference drug.

Toxicol Pathol, 1992, 20(2), 155 - 68
Cephaloridine-induced renal pathological and biochemical changes in female rabbits and isolated proximal tubules in suspension; Rush GF et al.; Cephaloridine (Cld) is a nephrotoxic cephalosporin antibiotic . The intracellular biochemical changes that occur leading to Cld-induced nephrotoxicity may involve lipid peroxidation and/or mitochondrial injury . The purpose of this report was to examine and correlate the biochemical changes induced by Cld in vivo and in vitro with the observed pathological changes in an attempt to understand better the mechanisms of beta-lactam-induced nephrotoxicity . Cld treatment (500 mg/kg sc) caused elevations in blood urea nitrogen and decreases in the accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices . Histopathological alterations, characterized by individual cell necrosis of tubular epithelial cells, were first seen 6 hr after treatment in the pars recta of the outer stripe of the medulla . Ultrastructural alterations involved the straight (S2 and S3) segments of the proximal tubules . Mitochondrial morphology was, for the most part, unaffected by Cld exposure . Cld did not cause any significant changes in tissue malondialdehyde (MDA) content in vivo at any of the time points examined, but it did cause a depletion of GSH to approximately 40% of control by 1 hr after dosing that recovered toward control by 6 hr . Significant changes were observed in renal ATP content beginning at 6 hr after treatment; however, this change mirrored the onset of histological evidence of necrosis . In isolated tubules in vitro, the onset of glutathione (GSH) depletion and MDA formation clearly preceded lactate dehydrogenase (LDH) leakage, whereas ATP depletion was a mirror image of cell death . These data demonstrate that isolated proximal tubules in vitro are a reasonable model for Cld nephrotoxicity in vivo . Cld-induced mitochondrial alterations leading to ATP depletion and cell injury were not observed in this study.

Acta Derm Venereol, 1992, 72(1), 48 - 9
Drug-triggered pemphigus in a predisposed woman; Ruocco V et al.; A 31-year-old woman with three pemphigus-prone antigens in her HLA haplotype (B7, DR4, DQw7) developed the disease soon after taking a pyrazolone derivative, viz . feprazone . The pemphigus lesions persisted despite withdrawal of the drug and worsened appreciably when she used ceftriaxone (a new cephalosporin with three sulphur atoms) for a bout of acute pharyngitis . Thiol groups formed from the metabolic breakdown of ceftriaxone are thought to have promoted acantholysis via a biochemical route . Genetic predisposition alone ('the soil') may be essential, though not per se sufficient for outbreak of pemphigus; the intervention of exogenous, heterogeneous factors ('the seed') often seems decisive in triggering full-blown disease.

Polim Med, 1992, 22(3), 45 - 58
{Septopal from E . Merck in the prevention and treatment of bone and soft tissue infections}; Misterka S; On the basis of the many years usage of Gentamycin-Septopal in treatment of blood-derived and traumatic inflammation of bones we can say that in both forms of inflammation fully satisfying results were achieved . In chronic traumatic inflammations of bones with active stomias where the inflammatory process lasted many weeks, and from the purulent matter two or more tribes with various sensitiveness to antibiotics, associated treatment was also used with application of large doses cephalosporin antibiotics of Glaxo-Zinacef of Fortum firms . It should be stressed that in treatment of a patient with that disease correct radioisotopic diagnostic of the focus of inflammation and the evaluation of the immunity state of the organism of the patient, especially during long-lasting disease, is, among others, important.

Pharm Res, 1991 Dec, 8(12), 1525 - 7
Determination of cefsulodin, cefmenoxime, and cefadroxil as residues on surfaces; Gorski RJ et al.; Cefsulodin, cefmenoxime, and cefadroxil are degraded instantaneously in aqueous sodium hypochlorite, sodium hypochlorite-detergent, or alkaline detergent solutions . These alkaline solutions are used to clean surfaces that have been exposed to the cephalosporins . The cleaned surfaces are monitored for residual drug levels (microgram) using a wet swab-dry swab technique . After extraction from the swabs, the content of the respective cephalosporin is determined in the solution by high-performance liquid chromatography . The limit of detection for each of the compounds is 0.1 microgram/ml . Recoveries from nonporous surfaces ranged from 56 to 102%.

Biochem J, 1991 Dec 1, 280 ( Pt 2), 471 - 4
Purification and characterization of cephalosporin 7 alpha-hydroxylase from Streptomyces clavuligerus; Xiao XF et al.; Cephalosporin 7 alpha-hydroxylase, which catalyses the conversion of cephalosporins into their 7 alpha-hydroxy derivatives, was purified nearly 390-fold from Streptomyces clavuligerus through ion-exchange chromatography, (NH4)2SO4 fractionation, gel filtration and dye chromatography, with the use of h.p.l.c . to monitor enzyme activity . The nearly pure enzyme migrates as a single major band, with an Mr of 32,000 in SDS/PAGE . Its optimum pH is in the range 7.3-7.7 . Under our conditions the reaction was fastest at temperatures in the range 20-30 degrees C . The Km for cephalosporin C is 0.72 mM, and the Vmax . is 15.4 mumol of cephalosporin C hydroxylated/min per mg . Cephalosporin 7 alpha-hydroxylase did not show any deacetoxycephalosporin C synthase or deacetoxycephalosporin C hydroxylase activity.

Biochemistry, 1991 Nov 5, 30(44), 10783 - 7
Site-directed mutagenesis of beta-lactamase leading to accumulation of a catalytic intermediate; Escobar WA et al.; Site-specific mutation of Glu-166 to Ala in beta-lactamase causes a millionfold reduction in catalytic activity toward both penicillin and cephalosporin substrates and results in the stoichiometric accumulation of a normally transient acyl-enzyme intermediate . Kinetic analysis indicated that substitution of Glu-166 by Ala leads to negligible effect on the acylation half of the reaction but effectively eliminates the deacylation reaction . Such differential effects on the rates of formation and breakdown of an enzyme-substrate intermediate have not been previously reported . Thus, unlike the situation for most transfer enzymes, e.g., the serine proteases, acylation and deacylation in beta-lactamase catalysis are not "mirror" images and must involve different mechanisms . The results suggest an explanation for the different catalytic activities between the beta-lactamases and the penicillin-binding proteins involved in bacterial cell-wall synthesis.

Antimicrob Agents Chemother, 1991 Nov, 35(11), 2267 - 74
Pharmacokinetics of ceftibuten-cis and its trans metabolite in healthy volunteers and in patients with chronic renal insufficiency; Kelloway JS et al.; The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects . Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CLCR) . The apparent total body clearance (CLP/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CLCR, 5 to 29 ml/min; group IV) and moderate (CLCR, 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CLCR, 50 to 80 ml/min; group II) or normal renal function (CLCR, greater than 80 ml/min; group I) . A significant correlation was observed between CLCR and ceftibuten-cis CLP/F . The mean apparent steady-state volume of distribution (V beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV . V beta/F was significantly greater in the group V subjects with end-stage renal disease (V beta/F, 0.39 +/- 0.27 liters/kg) . These changes in V beta/F cannot be separated from possible changes in bioavailability . The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

J Am Acad Dermatol, 1991 Nov, 25(5 Pt 1), 805 - 8
Serum sickness-like reactions from cefaclor in children; Hebert AA et al.; Cefaclor is an oral semisynthetic cephalosporin that is popular in the treatment of infections in children . This drug has been associated with a serum sickness--like reaction characterized by an urticarial eruption, pruritus, arthritis, and/or arthralgias . We report 12 additional cases of cefaclor-related serum sickness--like reactions in children . All patients improved after discontinuation of the drug and no long-term complications resulted.

Jpn J Antibiot, 1991 Sep, 44(9), 987 - 92
{Clinical studies on cefuzonam for acute peritonitis due to perforated appendicitis . Tissue concentration and clinical efficacy}; Hirayama T et al.; A clinical study on cefuzonam (CZON), a new parenteral cephalosporin antibiotic, was performed in 22 patients with acute appendicitis . CZON in a dose of 1 g was administered by intravenous bolus injection or intravenous drip infusion for 60 minutes . In the appendices, concentrations of CZON were 0.066-21.7 micrograms/g in normal or slight catarrhal cases, 0.173-11.7 micrograms/g in moderate phlegmous cases and 0.116-12.1 micrograms/g in serious gangrenous perforated cases . The concentration of CZON in appendixes was not directly proportional to the degree of pathological change of inflammation . 6 patients with acute peritonitis due to perforated appendicitis were treated with CZON of 2 g/day for 5-10 days . The clinical effect was good in 5 cases, fair in 1 case of the above 6 . The clinical efficacy rate was 83% . Side effects were not notable in the patients.

Am J Gastroenterol, 1991 Sep, 86(9), 1251 - 4
Reversible symptomatic biliary obstruction associated with ceftriaxone pseudolithiasis; Zinberg J et al.; Ceftriaxone, a third-generation cephalosporin, has been associated with the development of sludge or stones in the gallbladders of some patients treated with this medication . Such precipitates, which are usually reversible upon discontinuation of the drug, sometimes cause symptoms, have simulated acute cholecystitis, and have even led to cholecystectomy in some cases . We report the first known instance of biliary obstruction and secondary pancreatitis in association with reversible ceftriaxone-induced pseudolithiasis.

J Gen Microbiol, 1991 Jul, 137 ( Pt 7), 1625 - 34
Stringent response and initiation of secondary metabolism in Streptomyces clavuligerus; Bascaran V et al.; Cephalosporin biosynthetic activity and extracellular protease production increased during growth of Streptomyces clavuligerus in defined medium, while the level of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) remained very low and stable . Cephalosporin biosynthesis (measured in resting cell systems) was initiated during early exponential growth in complex media, without appreciable change in the small ppGpp pool . Nutritional shift-down induced by withdrawal of Casamino acids caused a transient increase in ppGpp and a reduction of RNA accumulation . The increase in ppGpp was small in very young cultures, but increased as the culture aged . Twenty-seven spontaneous thiostrepton-resistant mutants were isolated and partially characterized . Most of them had a reduced ppGpp-forming ability and gave normal titres of cephalosporin . However, in complex medium, some mutants did not produce cephalosporins or extracellular protease, whereas others overproduced cephalosporins . The results indicate that, in S . clavuligerus, there is no obligatory relationship between the initiation of secondary metabolism and the stringent response.

Toxicol Appl Pharmacol, 1991 Jun 15, 109(2), 314 - 26
Cephaloridine-induced biochemical changes and cytotoxicity in suspensions of rabbit isolated proximal tubules; Rush GF et al.; Cephalosporin antibiotics, such as cephaloridine (Cld), are known to be nephrotoxic in vivo and in vitro . In vivo, Cld causes proximal tubule necrosis in rabbits which is preceded by glutathione (GSH) depletion and, under certain conditions, inhibition of mitochondrial function . In vitro, Cld causes GSH depletion, lipid peroxidation, and inhibition of rat kidney slice organic ion uptake . The present investigations were designed to evaluate the temporal relationships of the biochemical "lesions" caused by Cld to the onset of lethal cell injury in suspensions of isolated rabbit proximal tubules . Cld was cytotoxic to suspensions of rabbit proximal tubules (EC50 = 1.10 +/- 0.33 mM) in the absence of amino acids (to support GSH synthesis) . In this model, Cld also caused GSH and ATP depletion, lipid peroxidation (malondialdehyde formation), and inhibition of tubule respiration . Probenecid prevented Cld accumulation, tubule injury, ATP depletion, and lipid peroxidation and markedly attenuated the GSH depletion . Addition of glycine, cystine, and glutamate to the incubation buffer to support GSH synthesis decreased the tubule accumulation of Cld (due solely to the presence of glutamate) and blocked Cld-induced tubule lethality, lipid peroxidation, ATP depletion, and GSH depletion . Glycine or glutamate alone had no effect on Cld-induced cytotoxicity, whereas cystine was cytoprotective . Buthionine sulfoximine partially reversed the amino acid protection against Cld-induced tubule injury . Thus amino acid-induced protection of tubules from Cld cytotoxicity was due to the combination of a high intracellular GSH content and cytoprotection by cystine . The antioxidant N-N'-diphenyl-p-phenylenediamine (DPPD) blocked tubule injury, ATP depletion, and lipid peroxidation but had no effect on Cld-induced GSH depletion when tubules were incubated for 3 hr . However, when incubations were allowed to run for up to 8 hr, DPPD had no effect on Cld cytotoxicity, despite continued inhibition of lipid peroxidation . These data demonstrate that Cld-induced tubule injury in short-term (3 hr) incubations in vitro occurs by a mechanism probably involving lipid peroxidation and occurs only in the absence of amino acids to support GSH synthesis . Inhibition of tubule respiration and ATP depletion could not clearly be causally linked to the onset of cell death in this model . The mechanism of the peroxidation-independent Cld toxicity in tubules incubated for 8 hr or longer is not known at this time.

Neurosurgery, 1991 Jun, 28(6), 789 - 91
Cranioplasty, vertebral body replacement, and spinal fusion with tobramycin-impregnated methylmethacrylate; Shapiro SA; A prospective analysis of cranioplasty, vertebral body replacement, and spinal fusion using tobramycin-impregnated methylmethacrylate in 65 patients is presented . Cranioplastic methacrylate (1 packet) was mixed with 1.2 g of powdered tobramycin and placed into the desired location . The polymer was irrigated with bacitracin until it became solid . All patients received prophylactic medication with intravenously administered nafcillin and cephalosporin perioperatively and for 48 hours postoperatively . The follow-up time ranged from 7 to 57 months (mean, 32.2 months) . Serum tobramycin levels remained below 0.5 microgram/ml in all patients tested, regardless of the time interval . Blood urea nitrogen and creatinine levels remained within normal limits in all patients, and there has been no nephrotoxicity or ototoxicity . There has been 1 infection among the 65 patients (1%) to date . It occurred in a patient who had a previously treated local infection . Cranioplasty, vertebral body replacement, or spinal fusion with tobramycin-impregnated methylmethacrylate is safe and may reduce the incidence of infection.

Acta Orthop Scand, 1991 Jun, 62(3), 232 - 7
Bone cement not weakened by cefuzonam powder; Morita M et al.; We report tensile, shearing, and bending tests on bone cement to which cefuzonam sodium (Cosmosin), a third generation cephalosporin, had been mixed . Mixing 3 g of cefuzonam sodium to 40 g of polymethyl methacrylate (PMMA) polymer did not diminish the strength of the bone cement in any of the tests . We speculated that this lack of influence was because the cefuzonam sodium powder used was in the form of relatively uniform-sized spheres and therefore did not become the origin of stress concentration within the cement.

Gastroenterology, 1991 Jun, 100(6), 1665 - 70
Ceftriaxone-associated gallbladder sludge . Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate; Park HZ et al.; Ceftriaxone, a third-generation cephalosporin, is partially excreted into bile . With its clinical use, the formation of gallbladder sludge detected by ultrasonography has been reported . Four surgical specimens were examined and no gallstones were found . Instead, fine precipitates of 20-250 microns were present . Microscopically, there was a small number of cholesterol monohydrate crystals and bilirubin granules among an abundant amount of granular-crystalline material that was not morphologically cholesterol monohydrate crystals . The chemical composition of the precipitates (n = 4) was determined . There was a small amount of cholesterol (1.7% +/- 0.8%) and bilirubin (13.9% +/- 0.74%) . The major component of the precipitate was a residue . On further analysis using thin-layer chromatography, high-performance liquid chromatography, and electron microprobe analysis, the residue was identified as a calcium salt of ceftriaxone . The residue also had identical crystal morphology and chromatographic elution profile as authentic calcium-ceftriaxone standards . It is concluded that ceftriaxone, after excretion and being concentrated in the gallbladder bile, can form a precipitate . The major constituent has been identified as a ceftriaxone-calcium salt.

Rev Infect Dis, 1991 May-Jun, 13 Suppl 7, S640 - 4
Infections in patients in intensive care units: can the combination of a monobactam and a penicillin replace the classic combination of a beta-lactam agent and an aminoglycoside?
Colardyn F, Gala JL, Verschraegen G, Wauters G, Vogelaers D, Dive A, Claeys G, Magis A, Vandercam B, Mahieu P.
An open, comparative, randomized study was performed in two medical intensive care units to compare the efficacy of the combination of aztreonam and either cloxacillin or oxacillin {(cl)oxacillin} with that of the combination of tobramycin and a cephalosporin . Of the 92 patients who were included in the study, 76 were evaluable . All patients suffered from severe, mostly pulmonary, infections and received ventilatory support . The aztreonam combination yielded an 80% rate of clinical cure; mortality was 15% . Use of the aminoglycoside combination resulted in a 51% rate of clinical cure; mortality was 23% . The difference in cure rate between the two combinations was statistically significant . Adverse effects were negligible in patients who received the aztreonam combination, and superinfection was seen in only 2% . Of the patients who received the aminoglycoside combination, 20% developed a superinfection and 11% developed a new renal insufficiency . Therefore, the combination of aztreonam and (cl)oxacillin is a valuable alternative to the combination of an aminoglycoside and a cephalosporin.

Biochem J, 1991 May 1, 275 ( Pt 3), 591 - 5
Inhibition of biliary cholesterol and phospholipid secretion by cefmetazole . The role of vesicular transport and of canalicular events; Cava F et al.; A number of organic anions selectively inhibit the biliary secretion of cholesterol and phospholipids without affecting bile acid secretion . We studied the effect of cefmetazole, a third-generation cephalosporin, on biliary lipid secretion in the rat . Injection of cefmetazole at a dose of 200 mumol/kg body wt . induced a choleretic effect and a significant decrease in the biliary output of cholesterol and phospholipid, without changes in bile acid secretion . The decrease was more marked for cholesterol than for phospholipid secretion, with a significant decrease in their molar ratio in bile . The effects were apparently unrelated to an inhibition of intracellular vesicular transport because, after injection of horseradish peroxidase, both the time course and total amount secreted of the protein did not significantly differ between control animals and those receiving cefmetazole . The secretory rate of the lysosomal marker acid phosphatase was not affected by cefmetazole administration . Biliary outputs of the plasma-membrane enzymes alkaline phosphatase and gamma-glutamyltransferase were significantly decreased by the antibiotic . These results point to an effect of cefmetazole at the level of the canalicular membrane.

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