Cephalosporin

Arch Surg, 1991 Apr, 126(4), 512 - 6
A comparison of the roles of cefamandole and ceftriaxone in abdominal surgery; Hall JC et al.; In a prospective, randomized study, we compared the ability of ceftriaxone sodium (serum half-life, 8.0 hours) and cefamandole naftate and sodium carbonate (serum half-life, 0.8 hours) to prevent wound infection in 1238 patients undergoing abdominal surgery . Prophylaxis consisted of single-dose therapy at the time of induction of anesthesia, and treatment regimens contained ceftriaxone sodium, 1 g/d intravenously, or cefamandole naftate and sodium carbonate, 1 g intravenously every 6 hours . Except for low-risk biliary procedures, cephalosporin therapy was accompanied by the administration of metronidazole . No significant difference was noted in the incidence of wound infection, ie, 5.6% for the ceftriaxone group (95% confidence interval, 3.8% to 7.4%) and 6.9% for the cefamandole group (95% confidence interval, 4.9% to 8.9%) . Single-dose prophylaxis with 1 g of cefamandole naftate and sodium carbonate was relatively inexpensive and provided a cost savings of 64% . When treatment was required, a 23% cost savings was associated with the use of a once-daily dose of 1 g of ceftriaxone sodium.

Arch Biochem Biophys, 1991 Apr, 286(1), 284 - 92
PMN elastases: a comparison of the specificity of human isozymes and the enzyme from other species toward substrates and inhibitors; Green BG et al.; The human elastases isolated from polymorphonuclear neutrophils (PMN) and purulent sputum displayed identical kinetic constants toward substrates and inhibitors . The elastases from the two sources yield identical N-terminal sequences and were recognized by antiserum prepared against human sputum elastase (HSE) isozyme-4 (I-4) . The data support the proposal put forth by Twumasi and Liener (1977, J . Biol . Chem . 252, 1917-1926) that the human elastase from sputum is of PMN origin . PMN elastases from other species displayed kinetic constants toward both substrates and inhibitors significantly different from the human enzyme . Therefore, extrapolation of inhibitor profiles from these elastases to the human source should be avoided . Four groups of isozymes were resolved from HSE by FPLC . Only the most basic isozyme (I-4) was obtained as a single species . The isozymes displayed identical macroscopic kinetic constants toward several substrates and two classes of inhibitors . The similar partition ratios observed with a cephalosporin-derived inhibitor suggest that the microscopic rate constants are also identical . The data support the proposal suggested by Baugh and Travis (1976, Biochemistry 15, 836-841) that HLE isozymes differ only in carbohydrate content . Whatever the source of human PMN elastase heterogeneity, it does not result in heterogeneous catalytic properties . In addition, a new protein was identified in elastase preparations derived from human sputum . This protein displayed homology to serine proteases and properties suggesting that it is identical to azurocidin.

Jpn J Antibiot, 1991 Apr, 44(4), 462 - 5
{Clinical evaluation of cefpirome in pediatric field}; Matsuoka S et al.; Cefpirome (CPR), a new synthetic cephalosporin antibiotic, was administered to 10 patients with infectious diseases . The patients included 5 boys and 5 girls from 1 month to 5 years of age . They were given the drug intravenously at dosages ranging 53-100 mg/kg/day for 4 to 10 days . Clinical efficacy was evaluated in 9 patients: excellent in 2 patients, good in 6 patients and fair in 1 patient . The overall efficacy rate was 88.9% . No adverse effects were observed except in one patient who showed a slight increase of serum GOT and GPT.

Curr Genet, 1991 Mar, 19(3), 235 - 7
Chromosome rearrangements in improved cephalosporin C-producing strains of Acremonium chrysogenum; Smith AW et al.; A number of A . chrysogenum strains from a lineage improved in cephalosporin C production were analysed by contoured-clamped homogeneous electric field gel electrophoresis (CHEF) . Although antibiotic titre was increased across the lineage, chromosome rearrangements were only observed at two points in it . In one member of the lineage the chromosomal changes included those which altered the size of the chromosome on which the isopenicillin N synthetase gene (pcbC) was located . It is proposed that chromosome changes are a chance event in an industrial strain improvement programme.

DICP, 1991 Feb, 25(2), 135 - 6
Thrombocytopenia possibly caused by structurally related third-generation cephalosporins; Hull RL et al.; Thrombocytopenia is defined as a decrease in the platelet count to less than 100 x 10(9)/L and it is the most commonly reported drug-induced blood dyscrasia . Heparin is the most commonly reported cause of drug-induced thrombocytopenia with a reported incidence between one and ten percent . Thrombocytopenia induced by cephalosporins has been reported but is relatively rare . This report does not completely document that two third-generation cephalosporins caused platelet counts to fall less than 100 x 10(9)/L in the patient described but there was no other explanation available . Platelet counts began to fall with the institution of third-generation cephalosporins and began to rise when these agents were stopped . In order to document that thrombocytopenia was induced by the third-generation cephalosporins a rechallenge would have been necessary; this was not considered to be safe in this patient . A review of the literature is presented describing similar cases of cephalosporin-induced thrombocytopenia.

Transfusion, 1991 Feb, 31(2), 176 - 9
A fatal case of ceftriaxone (Rocephin)-induced hemolytic anemia associated with intravascular immune hemolysis; Garratty G et al.; Fatal hemolytic anemia developed in a 52-year-old woman who was treated with a cephalosporin, ceftriaxone . The patient's red cells (RBCs) were coated with C3, but no RBC-bound IgG, IgA, or IgM was detected . Her serum contained an antibody that did not react with cephalosporin-coated RBCs but reacted strongly with RBCs in vitro when her serum was added to drug and RBCs . This is the first case of immune hemolytic anemia associated with ceftriaxone, the first case of fatal cephalosporin-induced hemolytic anemia, and the second case in which a cephalosporin antibody showed in vitro and in vivo characteristics usually thought to be associated with the so-called immune complex mechanism.

Curr Genet, 1991 Feb, 19(2), 73 - 6
Polymorphic karyotypes in related Acremonium strains; Walz M et al.; A restriction fragment length polymorphism (RFLP) analysis was performed on six related Acremonium strains . With respect to the restriction fragment pattern, all strains of A . chrysogenum were indistinguishable from each other but showed distinctive differences from those of A . strictum, A . flavum and Cephalosporium polyvaleurum . Using pulsed-field gel electrophoresis, we obtained different chromosome patterns from most of the Acremonium strains . Remarkably, the pattern varies in three related A . chrysogenum strains which also differ in their rate of cephalosporin C biosynthesis . The electrophoretic karyotyping was confirmed by the location of rDNA genes on separate chromosomes . Our data indicate that chromosome translocations in industrial strains may be responsible for increased beta-lactam synthesis.

J Urol (Paris), 1991, 97(1), 43 - 5
{Infections risk in transrectal prostate biopsy . An experience of antibioprophylaxis at a single dose}; Houdelette P et al.; Prostate biopsy remains the key-test in diagnosing clinically-detected prostatic carcinoma . Easy and efficient, the transrectal approach is credited with major infectious risk . The authors report a conclusive clinical experiment on 180 cases with antibioprophylaxy by injecting a single dose of third generation cephalosporin.

J Thorac Imaging, 1991 Jan, 6(1), 62 - 7
Radionuclide scanning in the detection of drug-induced lung disorders; Moinuddin M; Drug-induced pulmonary toxicity commonly results in interstitial lung disease characterized by the presence of inflammatory cells in pulmonary parenchyma . Gallium-67 citrate lung scintigraphy is currently the most sensitive test for the detection of inflammatory lesions in the lungs . Although chest radiographs often detect interstitial lung disease, they may be normal during the early alveolitis stage, when gallium scans are positive . Therefore, gallium scans can be utilized for the early diagnosis of drug-induced pulmonary reactions, leading to withdrawal of the drug and preventing the irreversible and potentially serious complication of pulmonary insufficiency . Gallium scintigraphy can also be used to follow these patients because it reflects the inflammatory changes in the lungs . This article presents a survey of the literature on gallium-67 scintigraphy in drug-related pulmonary inflammation . Gallium scans have been reported as abnormal in pulmonary toxicity caused by amiodarone, busulfan, bleomycin, procarbazine, nitrofurantoin, pentazocine, cephalosporin, cyclophosphamide, and cocaine, even in the absence of radiographic findings . The role of gallium scintigraphy in the early detection of pulmonary toxicity is emphasized.

Toxicol Appl Pharmacol, 1991 Jan, 107(1), 164 - 72
Comparative effects of disulfiram and N-methyltetrazolethiol on spermatogenic development in young CD rats; Hoover DM et al.; N-Methyltetrazolethiol (NMTT) and NMTT-containing cephalosporin antibiotics cause characteristic testicular lesions in young but not adult rats . In addition, NMTT-containing cephalosporins inhibit aldehyde dehydrogenase and have been associated with a disulfiram-like reaction in humans and animals . Therefore, the potential testicular toxicity of disulfiram (10, 30, or 100 mg/kg) was evaluated in 37-day-old rats given oral doses on Postpartum Days 6 through 36, and was compared to the toxicity induced by NMTT (100 mg/kg) . NMTT and each dose of disulfiram caused a decrease in testes weight . By DNA flow cytometry, testicular cell suspensions from rats given 100 mg/kg of NMTT had a 40% reduction in spermatids while those from rats given 10, 30, or 100 mg/kg of disulfiram had reductions of 52, 61, or 89%, respectively . Microscopically, the testes of rats given either NMTT or disulfiram had qualitatively similar changes, characterized by delayed maturity of the leading waves of germinal cells which had reached early maturation phase in control animals . Moderate to severe reduction occurred in the total number of spermatids with complete absence of acrosome phase and maturation phase spermatids . There was also a prominent reduction in the number of spermatocytes . Reduction in number of spermatogonia was minimal . While the mechanism of toxicity is not known for either compound, it is possible that the toxicity was related to the enzyme-inhibitory effects which both compounds possess . By defining the mechanism of testicular toxicity for compounds which cause a NMTT-like testicular toxicity in rats, biological differences in the spermatogenic process between the young and adult rat may be further understood . Direct extrapolation of the testicular effects in neonatal rats to man is not possible because of the substantial differences in initiation of spermatogenesis between rodents and humans.

Proteins, 1991, 11(1), 45 - 51
Gly-238-Ser substitution changes the substrate specificity of the SHV class A beta-lactamases; Lee KY et al.; The SHV-type beta-lactamase SHV-2A is related to SHV-1 by a Gly-238-Ser replacement . Strains carrying SHV-2A are resistant to the third generation cephems cefotaxime and ceftizoxime, whereas those that carry SHV-1 are sensitive to these drugs . We present a kinetic analysis of a SHV-1 and SHV-2A enzymes, with the goal of gaining insight into the role of residue 238 in hydrolyzing cefotaxime and ceftizoxime . SHV-2A shows altered kinetic properties for a number of other cephems that also have heterocyclic side chains at the amino position of the 7-aminocephalosporanic acid nucleus (R1 side chain), including a significantly higher kcat/Km than does SHV-1 for cephaloridine, cephalothin, and cefotiam . Two cephems with straight chain R1 substitutions, cephalosporin C and cephacetrile, are not hydrolyzed more efficiently by SHV-2A . These results indicate that the Ser-238-Gly substitution increases the affinity toward cephems with a heterocyclic ring in the R1 side chain . In addition, the data for ampicillin and benzylpenicillin show that addition of a nitrogen to the second carbon of the R1 side chain of a penem results in a lower kcat/Km for SHV-2A relative to SHV-1 . These data strongly suggest that the previously proposed hydrogen bond formation between Ser-238 and the second carbon nitrogen of cefotaxime is not an important factor in hydrolysis by SHV-2A . We propose that the Gly-238 to Ser-238 replacement in SHV-2A has altered the hydrophobic pocket so that it can better accommodate cephems with bulky R1 side chains.

Mol Gen Genet, 1991 Jan, 225(1), 56 - 64
Expression of the penDE gene of Penicillium chrysogenum encoding isopenicillin N acyltransferase in Cephalosporium acremonium: production of benzylpenicillin by the transformants; Gutierrez S et al.; No DNA sequence homologous to the penDE gene of Penicillium chrysogenum was found in the genome of three different strains of Cephalosporium acremonium . The pcbC-penDE gene cluster of P . chrysogenum complemented the isopenicillin N synthase deficiency of C . acremonium mutant N2 and resulted in the production of penicillin, in addition to cephalosporin, in cultures supplemented with phenylacetic acid . The penicillin formed was identified as benzylpenicillin by HPLC and NMR studies . The penDE gene of P . chrysogenum is expressed in C . acremonium forming a transcript of 1.15 kb . The transcript is processed and translated in C . acremonium resulting in the formation of acyl CoA: isopenicillin N acyl transferase . When the penDE gene was introduced into a cephalosporin producing strain, the total titre of beta-lactam antibiotics comprised distinct proportions of penicillin and cephalosporin in different transformants . Analysis of the hybridization patterns of the DNA of C . acremonium transformed with the pcbC or penDE genes indicated that integration occurs by non-homologous recombination.

Drugs Exp Clin Res, 1991, 17(2), 105 - 8
Effects of cefonicid on platelet aggregation; Cazzola M et al.; Beta-lactam antibiotics may interfere with platelet aggregation by inhibiting the binding of agonists of platelet aggregation, such as ADP and collagen, to specific receptor sites . The aim of this study was to evaluate in vitro the effects of cefonicid, a semi-synthetic cephalosporin, on platelet aggregation . Spontaneous platelet aggregation and platelet aggregation induced by ADP and collagen were assessed . Platelets from healthy subjects were incubated with cefonicid at final concentrations of 0.1 mg/ml, 1 mg/ml and 10 mg/ml (0.1 mg/ml is the concentration of cefonicid achieved in humans at therapeutic doses) . When compared with saline, cefonicid at a concentration of 0.1 mg/ml had no effect on platelet aggregation, but at 1 mg/ml it inhibited ADP-induced aggregation and at 10 mg/ml it also inhibited aggregation induced by collagen . These findings suggest that therapeutic doses of cefonicid do not affect platelet aggregation.

Int J Immunopharmacol, 1991, 13(8), 1099 - 107
Interference of cephalosporins with immune response: effects of cefonicid on human T-helper cells; Villa ML et al.; To determine the immunosuppressive effect(s) of cephalosporin cefonicid (CEFO) on human T-helper cells (Th), we exposed human peripheral blood mononuclear cells (PBMC) to various concentrations of CEFO during in vitro stimulation with a panel of T-lymphocyte stimulators that activate different Th/antigen presenting cell (APC) pathways . We evaluated the proliferation and IL-2 production induced by influenza virus (FLU), allogeneic lymphocytes (ALLO), xenogeneic mouse splenocytes (XENO) or phytohemagglutinin (PHA) . The proliferative responses to FLU and XENO were much more depressed by CEFO than those to ALLO or PHA . After 7 days of culture with the highest dose of CEFO tested (200 mg/l) the stimulation index (stimulated/unstimulated culture) was near to 0 in FLU and XENO treated cultures, indicating that the response against these antigens was completely abrogated . The responses to ALLO and PHA were also impaired, but not abrogated (stimulation index greater than 1) . Since FLU and XENO utilize the CD4+ Th/self-APC pathway our data suggested that this pathway was extremely sensitive to CEFO-induced inhibition both when the response requires memory Th cells (FLU) and virgin Th cells (XENO) . The incubation with CEFO (200 mg/l) reduced the IL-2 production by XENO, FLU and ALLO to less than 20% of control cultures, while paradoxically increases to 120% the production by PHA.

Drugs Exp Clin Res, 1991, 17(9), 445 - 50
Immunophenotypization of cells involved in local immune response and serum antibodies in cephalosporin-treated mice; Mazuran R et al.; The in vivo potency of cefodizime (HR 221), tiprotimod (a new synthetic thiazole derivative of HR 221, HBW 538) and cefotaxime to modulate the initiation of immune response in the draining lymph node (LN) after subcutaneous injection of SRBC was evaluated . The timing and sequence of events in the regional LN was investigated by immunophenotypization of node cells with monoclonal antibodies, and the systemic reaction was estimated as primary antibody response to SRBC . From the results it is possible to conclude that: (1) subcutaneous administration of a small dose (2.5-3.0 mg/kg) of cephalosporins, together with antigen, enhanced primary antibody production and persistence; (2) the increase in serum antibodies was preceded by a change in percentage of L3T4+ cells within the regional (popliteal) lymph node . In comparison to antigen alone, cephalosporins (during early immune response) increased the percentage of L3T4+ cells; (3) LN cellularity was strongly enhanced by cephalosporins; (4) cefotaxime influenced the kinetics of the cellularity and the L3T4/Lyt-2 index differently than cefodizime and HBW 538 . HBW 538 had either a similar or stronger effect than cefodizime, as judged by the adjuvant effect on antibody production and the appearance of L3T4+ cells during the immunizing period.

Infection, 1991, 19 Suppl 5, S284 - 95
Effect of flomoxef on blood coagulation and alcohol metabolism; Uchida K et al.; The effect of flomoxef, a newly developed oxacephem antibiotic with an N-hydroxyethyltetrazolethiol (HTT) side chain, on blood coagulation and alcohol metabolism was compared with that of a series of cephalosporin antibiotics with N-methyltetrazolethiol (NMTT), thiadiazolethiol (TDT) or methylthiadiazolethiol (MTDT) side chains in position 3' of the cephalosporin nucleus known to cause hypoprothrombinemia and bleeding in patients who are malnourished, debilitated and/or of high age . A disulfiram-like effect caused by inhibition of aldehyde dehydrogenase was observed for NMTT-containing antibiotics . Studies were carried out on healthy volunteers and on rats . Eight-day treatment with 2 g flomoxef i.v . once or twice daily in five and six healthy male volunteers, respectively, did not cause any significant changes in prothrombin time (PT), coagulation factors II, VII, IX or X, in hepaplastin values or fibrinogen levels, activated partial thromboplastin time (APTT), platelet counts, bleeding time, or collagen- and ADP-induced platelet aggregation . Inhibition of vitamin K epoxide reductase was observed in rats treated with flomoxef, yet to a much lesser extent than observed for cephalosporins with NMTT, TDT or MTDT side chains . This defect was quickly normalized by vitamin K injection . There were no differences between oxacephem (1-O) and cephem (1-S) compounds with respect to effects on blood clotting and platelet aggregation . Flomoxef and its side chain HTT showed no influence on alcohol metbolism.

Eur J Clin Pharmacol, 1991, 41(5), 489 - 91
Drug prescription in young children: results of a survey in France . Epicrèche Research Group; Collet JP et al.; A 8.5-month prospective study was performed in the Rhone area of France to study the incidence of infectious diseases in children in day care, and the qualitative and quantitative aspects of drug prescriptions for young children . The families of 1.359 children agreed to participate (98.5% of those selected) . During the follow-up period 3.605 infections episodes were reported and 10.706 medications were used, an average of 3.0 medications per episode . Antibiotics were used in the treatment of 2.333 infectious episodes (65%) amoxycillin (36%), cephalosporin (23%), macrolide (17%) and trimethoprim-sulphamethoxazole (9%) . Acetylsalicylic acid and paracetamol were used 865- and 1.568-times, respectively . Drugs with multi-active components represented 11.3% of the total number of systemic medicines reported . Paracetamol was prescribed in 59% of cases in a multi-active component drug, whereas this type of product accounted for 83.5% of the antihistamines (used 932-times) . The rationale behind the paediatric prescribing habits of French medical doctors is discussed in relation to results previously obtained in other European countries.

J Antimicrob Chemother, 1990 Dec, 26 Suppl E, 29 - 34
Multiple dose pharmacokinetics of cefpodoxime in young adult and elderly patients; Backhouse C et al.; Multiple dose pharmacokinetics of a new third-generation cephalosporin, cefpodoxime, were evaluated in adults (15, 18-60 years) and elderly adults (10, greater than or equal to 70 years), all out-patients suffering from acute lower respiratory tract infection . A dose of 200 mg cefpodoxime proxetil (expressed in mg cefpodoxime) was administered 12-hourly for seven to ten days and timed blood samples were evaluated on days 0, 3, 5, 6/7 and on the last day of treatment . Results showed that the pharmacokinetics in adult and elderly patients were comparable with those of healthy volunteers and with each other, with the exception of one elderly patient with severe renal impairment . Dosage adjustment of cefpodoxime proxetil does not therefore appear to be necessary in the elderly unless there is evidence of severe renal insufficiency.

J Antibiot (Tokyo), 1990 Dec, 43(12), 1564 - 72
Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-{(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido}-3-{(Z)-1- propenyl}-3-cephem-4-carboxylate (BMY-28271); Kamachi H et al.; 1-Acetoxyethyl 7-{(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido}-3- {(Z)-1-propenyl}-3-cephem-4-carboxylate (BMY-28271) is an ester-type prodrug of cephalosporin for oral use . Methods suitable for large scale preparation were investigated . The yield was improved by esterification of 7-{(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido}cep hem-4-carboxylic acid (11) followed by removal of the trityl group and, in addition, column chromatographic purification at each step was eliminated by optimization of the reaction conditions.

Gastroenterology, 1990 Dec, 99(6), 1772 - 8
Pathogenesis of ceftriaxone-associated biliary sludge . In vitro studies of calcium-ceftriaxone binding and solubility; Shiffman ML et al.; Ceftriaxone, a semisynthetic third-generation cephalosporin, has recently been associated with biliary sludge formation . Analysis of the biliary concretions induced by this agent shows a calcium salt of ceftriaxone . The present in vitro studies were undertaken to provide insight into the pathogenesis of ceftriaxone-associated biliary sludge formation by evaluating possible interactions that may exist between calcium, bile salts, and ceftriaxone . Ceftriaxone possessed high calcium-binding affinity . The formation constant for the calcium ceftriaxone salt at 37 degrees C was about 157.3 L/mol; stoichiometry of the salt was 1:1, i.e., calcium ceftriaxone . The calcium-binding property of ceftriaxone was observed to be additive to that of taurocholate in mixed taurocholate-ceftriaxone solutions . Although the solubility product constant for calcium ceftriaxone was only 1.62 x 10(-6) mol/L2, marked metastability was observed; neither visible nor microscopic precipitates developed until the {Ca2+} x {ceftriaxone} ion product exceeded the solubility product constant by a factor of 10.4 . Metastability of the calcium ceftriaxone salt was also observed in human gallbladder bile in vitro . Estimates of human biliary calcium ceftriaxone solubility in vivo were than calculated from previously-reported values for biliary {Ca2+}, {ceftriaxone}, and from the solubility product constant as defined in this study . Calculated saturation indices for calcium-ceftriaxone in human bile generally increased (corresponding to a decrease in solubility) with increasing ceftriaxone dose . At doses less than or equal to 1 g, saturation index was well within the metastable range of this calcium-salt . However, at doses greater than or equal to 2 g, the saturation index surpassed the metastable limit . Under these conditions, precipitation of ceftriaxone could occur . It was concluded that the development of ceftriaxone-induced biliary sludge is a solubility problem that occurs in patients receiving high-dose treatment (greater than or equal to 2 g) . This study proposes that the risk of developing ceftriaxone-associated biliary "pseudolithiasis" increases with increasing ceftriaxone dose and in patients with impaired gallbladder emptying.

Br J Clin Pract, 1990 Dec, 44(12), 649 - 51
Remember primary peritonitis; Davies MJ; Two cases of primary peritonitis are reported . One, which we believe to be the first case reported in an elderly female, raised our index of suspicion and thus enabled the second case to be diagnosed by fine-needle paracentesis and treated without operation . Both cases outline the inadequacy of prophylactic antibiotic cover with a cephalosporin and metronidazole . The case reports are followed by a general discussion outlining the incidence, aetiology and treatment of primary peritonitis.

J Biochem (Tokyo), 1990 Dec, 108(6), 1063 - 9
Structure and expression of cDNA for D-amino acid oxidase active against cephalosporin C from Fusarium solani; Isogai T et al.; D-Amino acid oxidase (DAO) was extracted and purified from cultured mycelia of Fusarium solani M-0718 (FERM P-2688) . The enzyme was able to oxidatively deaminate cephalosporin C to 7-beta-(5-carboxy-5-oxopentanamido)cephalosporanic acid . Ninety-eight amino acid residues of the F . solani DAO were determined by sequence analysis of 9 peptides derived from Acromobacter protease I digests of the protein . Complementary DNAs encoding F . solani DAO were isolated from the F . solani cDNA library by hybridization with synthetic oligonucleotide probes corresponding to the partial amino acid sequences . Analysis of the nucleotide sequences of the clones revealed a 1,186-nucleotide sequence with a 5'-terminal untranslated region of 41 nucleotides, an open reading frame of 1,083 nucleotides that encoded 361 amino acids, and a 3'-terminal untranslated region of 62 nucleotides . The amino acid sequence of F . solani DAO had 25% homology to that of porcine kidney DAO {EC 1.4.3.3} and 37% homology to that of Trigonopsis variabilis DAO . The constructed plasmid overproduced F . solani DAO in Escherichia coli . The recombinant DAO had almost the same molecular activity as the native DAO against cephalosporin C.

Med Clin North Am, 1990 Nov, 74(6), 1603 - 15
Pelvic inflammatory disease; Peterson HB et al.; The costs of PID to both individuals and society are enormous . Although primary prevention of PID through control of lower genital tract infections is the most effective prevention strategy, early diagnosis and treatment of acute PID may minimize some of its serious sequelae . Although laparoscopy is helpful for establishing the diagnosis of salpingitis, other less invasive tests along with selected clinical criteria may also be useful . Treatment of PID, which is empiric and broad spectrum, is oriented toward polymicrobial PID . Whenever possible, women with PID should be hospitalized for parenteral therapy . The 1989 CDC STD treatment guidelines recommend two regimens for inpatient parenteral therapy: clindamycin/gentamicin and cefoxitin, or equivalent cephalosporin/doxycycline . Outpatient management of PID should be monitored closely; the CDC-recommended regimen includes use of intramuscular cephalosporins and oral doxycycline . Oral penicillins are no longer recommended.

J Pharmacol Exp Ther, 1990 Nov, 255(2), 436 - 41
Effect of DQ-2556, a new cephalosporin, on organic ion transport in renal plasma membrane vesicles from the dog, rabbit and rat; Sokol PP; The effect of the new cephalosporin antibiotic DQ-2556 {(6R, 7R)-7-{(Z)-2-(2-aminothiazol-4-yl-2-(methoxyimino)acetamido}-3-{4- (oxazol-5-yl)-1-pyridinio}methyl-8-oxo-5-thia-1-azabicyclo{4 .2.0}oct-2- ene--2-carboxylate} on the transport of organic cations (N1-{3H}methylnicotinamide, NMN and {3H}tetraethylammonium), organic anions ({3H}p-aminohippurate) and dipeptides ({14C}glycylsarcosine) was examined in brush border membrane vesicles (BBMV) and basolateral membrane vesicles from the dog, rabbit and rat . In BBMV, DQ-2556 was more effective in cis-inhibiting the uptake of NMN in the rat than in the dog . No effect was seen in the rabbit . DQ-2556 had no effect on brush border transport systems for organic anions or dipeptides and basolateral transport systems for organic cations or anions in dogs, rabbits and rats . In contrast, cephaloridine, a nephrotoxic cephalosporin, inhibited NMN and p-aminohippurate uptake in dog BBMV and basolateral membrane vesicles, respectively . Cephaloridine had no effect on the other organic ion transport systems in the species being tested . A dose-response curve was constructed for DQ-2556 inhibition of NMN transport in rat BBMV . An IC50 value of 2.5 mM was obtained . In counterflow studies DQ-2556 did not demonstrate trans- stimulation of tetraethylammonium uptake . Kinetic studies revealed that DQ-2556 increased the Km value of NMN from 130 to 190 microM, while having no effect on the Vmax value (1.72 nmol/min x mg of protein vs . 1.75 nmol/min x mg of protein in the presence of DQ-2556) . These data are most consistent with DQ-2556 being a low affinity competitive inhibitor of NMN transport in rat BBMV.

Fundam Appl Toxicol, 1990 Nov, 15(4), 697 - 709
Rat paw-lick/muscle irritation model for evaluating parenteral formulations for pain-on-injection and muscle damage; Chellman GJ et al.; A two-phase assay was developed in the rat to evaluate parenteral formulations intended for intramuscular administration for the induction of both acute pain-on-injection and delayed pain/discomfort at the injection site (secondary to muscle damage) . Phase 1 of the assay assessed pain-on-injection using a modified version of the previously published rat paw-lick assay . Adult male CD rats (10/group) were given subplantar (footpad) injections of 0.1 ml and then observed for 15 min for paw-lick responses . To increase assay sensitivity, responses more subtle than paw licks (ie., paw lifts) were scored, and injection-site clinical signs were recorded 6, 24, and 48 hr after injection . Phase 2 of the assay assessed myotoxic potential, using the same rats after a 1-week recovery period . The rats were injected intramuscularly in the anterior thigh with 0.2 ml, bled from the orbital sinus at 2, 6, and 24 hr for analysis of serum creatine kinase (CK), and then necropsied at 24 hr to prepare tissue sections of the injection site for microscopic examination . A series of cephalosporin-type antibiotics produced pain-on-injection and muscle damage consistent with reported clinical experience (cefazolin less than cephalothin less than cefoxitin) . Several nonantibiotic parenteral formulations (diazepam, digoxin, phenytoin, and lidocaine) tested in the paw-lick/muscle irritation model also produced responses that correlated with the clinic, i.e., virtually no acute pain but moderate to marked muscle damage . The results indicate that the two-phase rat paw-lick/muscle irritation model is effective in evaluating parenteral formulations for clinical acceptability, and that both phases of the assay are necessary to optimize predictability of the assay for human clinical experience.

Biochem J, 1990 Oct 15, 271(2), 399 - 406
Role of the conserved amino acids of the 'SDN' loop (Ser130, Asp131 and Asn132) in a class A beta-lactamase studied by site-directed mutagenesis; Jacob F et al.; Ser130, Asp131 and Asn132 ('SDN') are highly conserved residues in class A beta-lactamases forming one wall of the active-site cavity . All three residues of the SDN loop in Streptomyces albus G beta-lactamase were modified by site-directed mutagenesis . The mutant proteins were expressed in Streptomyces lividans, purified from culture supernatants and their kinetic parameters were determined for several substrates . Ser130 was substituted by Asn, Ala and Gly . The first modification yielded an almost totally inactive protein, whereas the smaller-side-chain mutants (A and G) retained some activity, but were less stable than the wild-type enzyme . Ser130 might thus be involved in maintaining the structure of the active-site cavity . Mutations of Asp131 into Glu and Gly proved to be highly detrimental to enzyme stability, reflecting significant structural perturbations . Mutation of Asn132 into Ala resulted in a dramatically decreased enzymic activity (more than 100-fold) especially toward cephalosporin substrates, kcat . being the most affected parameter, which would indicate a role of Asn132 in transition-state stabilization rather than in ground-state binding . Comparison of the N132A and the previously described N132S mutant enzymes underline the importance of an H-bond-forming residue at position 132 for the catalytic process.

Arzneimittelforschung, 1990 Oct, 40(10), 1140 - 4
Biochemical aspects of the renal tolerance for cefpirome and other cephalosporins; Cojocel C; Effects of cefpirome (CFP, HR 810; CAS 84957-29-9) and other cephalosporins such as cefotaxime (CFX), cephaloridine (CPH) and ceftazidime (CFZ) on the renal biochemical processes such as peroxidation of lipids, organic cation transport or gluconeogenesis were investigated in vitro or after i.v.-administration of cephalosporins to 200 g male Wistar rats . In a series of in vitro experiments renal cortical slices were incubated for 60 min in a cephalosporin free medium or in a cephalosporin containing medium (1.25, 2.5, 5.0 and 10 mg/ml) at 37 degrees C under a 100% O2 atmosphere . Subsequently, peroxidation of lipids (LPO), measured as malondialdehyde (MDA) production, tissue accumulation of the organic cation tetraethylammonium (TEA) and gluconeogenesis were determined . In one series of in vivo experiments, 2 h after i.p.-administration of saline, CFP, CFX, CPH and CFZ (0, 500, 1000 and 2000 mg/kg), rats were killed and the amount of the reduced glutathione (GSH) in the renal cortex was measured . In another series of experiments, CFP, CFX, CPH and CFZ were administered (1200 mg/kg/d, i.v.) for 5 days . Subsequently, the effects of these cephalosporins on MDA production, cytosolic lactate dehydrogenase (LDH) activity, TEA accumulation and gluconeogenesis in the renal cortex were investigated . Results of the in vitro experiments show a significant concentration-dependent increase in MDA production only after incubation of renal cortical slices with CPH . CFZ and CPH caused a dose-dependent decrease in gluconeogenesis and except CFX, all other investigated cephalosporins induced a dose-dependent decrease in TEA accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochim Biophys Acta, 1990 Sep 7, 1027(3), 211 - 7
Uptake of the cephalosporin, cephalexin, by a dipeptide transport carrier in the human intestinal cell line, Caco-2; Dantzig AH et al.; The transport of the orally absorbed cephalosporin, cephalexin, was examined in the human epithelial cell line, Caco-2 that possesses intestinal enterocyte-like properties when cultured . In sodium-free buffer, the cells accumulated 1 mM D-{9-14C}cephalexin against a concentration gradient and obtained a distribution ratio of 3.5 within 180 min . Drug uptake was maximal when the extracellular pH was 6.0 . Uptake was reduced by metabolic inhibitors and by protonophores indicating that uptake was energy- and proton-dependent . Kinetic analysis of the concentration dependence of the rate of cephalexin uptake showed that a non-saturable component (Kd of 0.18 +/- 0.01 nmol/min per mg protein per mM) and a transport system with a Km of 7.5 +/- 2.8 mM and a Vmax of 6.5 +/- 0.9 nmol/min per mg protein were responsible for drug uptake . Uptake was competitively inhibited by dipeptides . The transport carrier exhibited stereospecificity for the L-isomer of cephalexin . Drug uptake was not affected by the presence of amino acids, organic anions, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid or 4,4'-diisothiocyano-2,2'-disulfonic stilbene . Therefore, Caco-2 cells take up cephalexin by a proton-dependent dipeptide transport carrier that closely resembles the transporter present in the intestine . Caco-2 cells represent a cellular model for future studies of the dipeptide transporter.

J Med Chem, 1990 Sep, 33(9), 2529 - 35
Inhibition of human leukocyte elastase . 3 . Synthesis and activity of 3'-substituted cephalosporins; Shah SK et al.; Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate . A method was also developed to prepare a 3-vinylcephalosporin . Some of these compound were found to be potent time-dependent inhibitors of human leukocyte elastase (HLE) . The HLE inhibitory activity was correlated with sigma 1 and it was concluded that the potency was determined by the electron-withdrawing ability as well as the size of the substituent . A mechanism for inhibition of HLE by cephalosporin sulfones is proposed.

J Med Chem, 1990 Sep, 33(9), 2522 - 8
Inhibition of human leukocyte elastase . 2 . Inhibition by substituted cephalosporin esters and amides; Finke PE et al.; A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases . The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides . However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c . These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.

J Med Chem, 1990 Sep, 33(9), 2513 - 21
Inhibition of human leukocyte elastase . 1 . Inhibition by C-7-substituted cephalosporin tert-butyl esters; Doherty JB et al.; Time-dependent inhibitors of the enzyme human leukocyte elastase have been developed based on the cephem nucleus . A series of cephalosporin tert-butyl esters has been examined, and the activity of these compounds has been found to be very sensitive to C-7 substituents, with small, alpha-oriented, electron-withdrawing groups showing greatest activity . Additionally, the oxidation state of the sulfur atom has been found to play a role in potency, with sulfones showing considerably greater activity than the corresponding sulfides or beta-sulfoxides . The alpha-sulfoxides were inactive.

J Pharm Sci, 1990 Sep, 79(9), 802 - 5
Synthesis and mechanisms of decomposition of some cephalosporin prodrugs; Saab AN et al.; The delta-3 and delta-2 methyl esters of cefazolin were synthesized . The kinetics and mechanisms of degradation of the methyl esters and the delta-3 and delta-2 isomers of pivaloyloxymethyl prodrug esters of the new cephalosporin ceftetrame (Ro 19-5247) were investigated in buffer systems and in human plasma in vitro . The major hydrolytic products of all the delta-3 and delta-2 esters were the inactive delta-2 cephalosporin free acids . The following reaction scheme describes the in vitro hydrolysis of these compounds: {formula: see text} . In addition, there was evidence of opening of the beta-lactam ring to form cephalosporoic acid when the methyl ester of cefazolin was studied in human plasma and in the presence of penicillinase . For the methyl esters, the processes represented by k12, k21, and k20 were operative in buffers; in human plasma, the processes represented by k12, k21, and k20 were operative in addition to cephalosporoic acid formation . For the isomers of the cephalosporin prodrug ester Ro 19-5248 only k12 and k20 were operative in buffers; in human plasma all pathways were operative and there was no evidence of cephalosporoic acid formation . In all cases, the processes represented by k12, k21, and k20 were subject to general and/or specific base catalysis.

J Clin Pharmacol, 1990 Aug, 30(8), 737 - 42
Lack of effect of cefixime on the metabolism of vitamin K1; Trenk D et al.; It seems that cephalosporins bearing a N-methyl-thio-tetrazole or a methyl-thiadiazole moiety in their molecule can cause hypoprothombinemia in patients via inhibition of the metabolism of vitamin K1 if they are in addition in a vitamin K1-deficient state . The authors therefore studied the effects of two different oral doses (200 and 400 mg) of the cephalosporin cefixime on the metabolism of vitamin K1 in healthy volunteers, because the accumulation of vitamin K1-2,3-epoxide in plasma is a sensitive marker of coumarin-like activity of drugs . The results indicate that the development of hypoprothrombinemia due to an impairment of the metabolism of vitamin K1 by cefixime seems unlikely because only trace amounts of vitamin K1-2,3-epoxide could be determined in the plasma of the subjects investigated.

Gastroenterology, 1990 Aug, 99(2), 454 - 65
Concentrative biliary secretion of ceftriaxone . Inhibition of lipid secretion and precipitation of calcium ceftriaxone in bile; Xia Y et al.; The hepatic transport of ceftriaxone, a third-generation cephalosporin, was characterized in the rat and hamster; its effect on bile flow and bile acid-induced biliary lipid secretion was also measured . In anesthetized rats with biliary fistulae, the Tmax was about 5 mumol.min-1.kg-1, and in the hamster the Tmax was about 1 mumol.min-1.kg-1 . The compound was not biotransformed . At high secretion rates, the concentration of cephalosporin in bile increased to 27 mmol/L, a concentration far exceeding the solubility product of its calcium salt {2 x 10(-6) (mol/L)2}, which precipitated from bile . In the rat, ceftriaxone induced choleresis (22 microL/mumol ceftriaxone, the expected value for a dianionic compound) . In the isolated perfused rat liver, ceftriaxone had a fractional hepatic extraction rate averaging 3%; the compound was concentratively secreted into bile, the bile-perfusate ratio ranging from 35-250 . Ceftriaxone inhibited phospholipid and cholesterol secretion induced by endogenous or exogenous bile acids; the rate of inhibition was linearly proportional to the canalicular secretion rate of ceftriaxone . Hepatic transport of ceftriaxone had no influence on hepatic secretion of ursodeoxycholyltaurine . In contrast, the net hepatic transport of ursodeoxycholic acid, ursodeoxycholyltaurine, or cholyltaurine inhibited ceftriaxone transport in a dose-dependent manner . It is concluded that ceftriaxone and bile acids share a common mechanism for hepatic transport in the rat and also interact in the processes involved in biliary lipid secretion . Biliary secretion of unbiotransformed ceftriaxone occurs at high concentrations; secondary Ca2+ entry results in the formation of supersaturated canalicular bile and subsequent precipitation as a calcium salt in the biliary tract . These data explain the formation of biliary sludge that occurs in patients undergoing high-dose ceftriaxone therapy.

Antibiot Khimioter, 1990 Aug, 35(8), 7 - 9
{Cloning in Escherichia coli of a mitochondrial DNA fragment from Acremonium chrysogenum containing a region responsible for DNA replication}; Petiushenko RM et al.; A bireplicone plasmid pSU901,4.6 kb in length, was constructed on the basis of plasmid pUC19 and the pstIB fragment, 1.9 kb in length, from mitochondrial DNA of A . chrysogenum . Based on the hybrid plasmid pSU901 and kanamycin resistance determinant, an autonomically replicating vector for A . chrysogenum, a culture producing cephalosporin C, is being constructed.

Chem Pharm Bull (Tokyo), 1990 Jul, 38(7), 1998 - 2002
Stability and degradation pattern of cefpirome (HR 810) in aqueous solution; Sugioka T et al.; The stability and degradation pathways of a new semi-synthetic cephalosporin, 1-{{(6R,7R)-7-{2-(2-amino-4-thiazolyl)glyoxylamido}-2-carboxy-8-ox o-5-thia-1-azabicyclo{4.2.0}oct-2-en-3-yl}methyl}-6,7-dihydro-5H-1- pyridinium hydroxide, inner salt, 7(2)-(Z)-(O-methyloxime) sulfate (cefpirome sulfate, HR 810), were studied . Cefpirome in various buffer solutions was allowed to stand at 40 degrees C and its degradation patterns were investigated by high performance liquid chromatography . Cefpirome was stable in the region of pH 4-7 and slightly unstable beyond this range . In aqueous solution from the neutral to alkaline regions, the produced degradation products were: 1- {{(6R,7S)-7-{2-(2-amino-4-thiazolyl)glyoxylamido}-2-carboxy-8-oxo -5-thia-1-azabicyclo{4.2.0}oct-2-en-3-yl}methyl}-6,7-dihydro-5 H-1- pyridinium hydroxide, inner salt, 7(2)-(Z)-(O-methyloxime) (epi-cefpirome); 1-{{(6R,7R)-7-{2-(2-amino-4-thiazolyl)glyoxylamido}-2-carboxy-8-ox o-5-thia-1-azabicyclo{4.2.0}oct-3-en-3-yl}methyl}-6,7-dihydro-5H-1- pyridinum hydroxide, inner salt, 7(2)-(Z)-(O-methyloxime) (delta 2-cefpirome); 2-{{(2-amino-4-thiazolyl)((Z)-methoxy-imino)acetyl}amino}acetaldehyde; and 6,7-dihydro-5H-1-pyrindine . On the other hand, 1-{{(6R,7R)-7-{2-(2- amino-4-thiazolyl)glyoxylamido}-2-carboxy-8-oxo-5-thia-1- azabicyclo{4.2.0}oct-2-en-3-yl}methyl}-6,7-dihydro-5H-1-pyridinium++ + hydroxide, inner salt, 7(2)-(E)-(O-methyloxime) (anti-cefpirome), 2-{{(2- amino-4-thiazolyl)-((Z)-methoxyimino)-acetyl}aminomethyl}-1,2,5,7- tetrahydro-7-oxo-4H-furo{3,4-D}-{1,3}thiazine, and 6,7-dihydro-5H-1- pyrindine were produced in strongly acidic solution or under irradiation by artificial sunlight.

Chem Pharm Bull (Tokyo), 1990 Jul, 38(7), 1906 - 10
Studies on orally active cephalosporin esters . V . A prodrug approach for oral delivery of 3-thiazoliomethyl cephalosporin; Miyauchi M et al.; Oral delivery of 3-thiazoliomethyl cephalosporin 1 was attempted through a prodrug approach by applying thiamine chemistry . The 3-thiazoliomethyl group was modified to a ring-opened structure with no ionic charge, and the 4-carboxyl group was converted to pivaloyloxymethyl ester . Lipophilicity of the resulting derivatives (8-10) was suitable for passive absorption from the intestinal tract, and chemical stability in phosphate buffer solution (pH 6.86) was moderate . When administered orally to mice, these derivatives were mainly transformed to a novel 3-spiro cephalosporin 11, and desired reconversion to the 3-thiazoliomethyl cephalosporin was minor . Isomerization to delta 2-cephalosporin 14 was also observed . These results showed that the derivatives (8-10) tested in this study did not serve as orally active prodrugs of 3-thiazoliomethyl cephalosporin 1.

Acta Otolaryngol, 1990 Jul-Aug, 110(1-2), 128 - 35
Treatment of sinus empyema in adults . A coordinated Nordic multicenter trial of cefixime vs . cefaclor; Carenfelt C et al.; In sinus empyema, H . influenzae is the most prevalent pathogen in some subpopulations and in case of therapeutic failure . Cefixime, the first oral cephalosporin of the 3rd generation, is highly potent in vitro against H . influenzae . To study the efficacy and safety of cefixime in adults with acute sinusitis, a coordinated, double-blind multicenter trial was designed for purulent cases, as confirmed by antral aspiration . A total of 364 patients were enrolled in the study with 125 cases randomized to the reference group, assigned to treatment with cefaclor . Evaluation was based on clinical outcome and on antral reaspiration (86% of the cases) . No significant differences between the treatment groups were found, as regards short-term or long-term clinical outcome . However, the clinical examination overestimated the therapeutic results . Only 4% of the patients were considered as failures, but the re-aspiration demonstrated remaining suppuration in 14% of all cases (p less than 0.001) . Based on re-aspiration, the failure rate among patients with initial growth of pathogens was lower for cefixime (8%) than for cefaclor (20%) (p less than 0.05) . Such a difference was not found among patients with growth of H . influenzae . No serious adverse reactions were recorded, but loose stools and diarrhoea were significantly more frequent in the cefixime treatment group . Five patients (2%) in the cefixime treatment group discontinued their treatment due to adverse events.

Br J Dermatol, 1990 Jul, 123(1), 119 - 24
Toxic pustuloderma: a self-limiting eruption; Rustin MH et al.; Three patients are described who developed numerous pinhead sized pustules within areas of a widespread toxic erythema . The eruption was precipitated by food poisoning in one patient, a suspected, but blood-culture-negative septicaemia in another and in the third patient, by a cephalosporin . This self-limiting syndrome consists of fever, a pustular and erythematous eruption, a neutrophil leucocytosis, subcorneal and spongiform pustules but without a history of psoriasis . We believe that this entity of toxic pustuloderma represents a severe form of toxic erythema.

Diagn Microbiol Infect Dis, 1990 Jul-Aug, 13(4), 317 - 27
Review of cefotaxime sodium for surgical prophylaxis . A model for the evolution toward single-dose or short-course cost-effective regimens; Jones RN; Cefotaxime is a parenteral broad-spectrum cephalosporin, used extensively worldwide for chemotherapy of serious infections . Since its release in 1979, cefotaxime has also been studied to minimize surgery-related infections and, more than any other new compound, has been used in a volume of evaluable cases . Because of the current cost-containment medical practice environment, most cefotaxime prophylaxis studies have established single-dose or short-course regimens . Over 9000 published cefotaxime prophylaxis cases were reviewed, and 81 references were cited . Single-dose cefotaxime was clearly indicated for a wide variety of operations, including hysterectomy, cesarean sections, bone and joint procedures, upper gastrointestinal cases, biliary tract procedures, transurethral resections, open urologic procedures, and some vascular cases . Approximately 24 hr of prophylaxis (cefotaxime X 4 doses) may be required for colorectal resections, cardiac surgery, head and neck surgery, transplants, and some pediatric surgical cases . Although contaminated abdominal cases and trauma surgery were not a true prophylaxis use, cefotaxime regimens have reduced wound morbidity to less than or equal to 10% . Changing to one- to four-dose schedules will have very favorable clinical impact by reducing prophylaxis cost, pharmacy preparation time, adverse reactions, and antimicrobic-resistance pressures . Surgeons should not hesitate to employ new cephalosporins (cefotaxime and others) with proved limited dose indications that would greatly benefit their patients and the hospital environment.

Antimicrob Agents Chemother, 1990 Jun, 34(6), 1128 - 31
Assessment of cefazolin and cefuroxime tissue penetration by using a continuous intravenous infusion; Connors JE et al.; A continuous intravenous infusion was used to assess the tissue penetration of cefazolin (14 subjects) and cefuroxime (15 subjects) in orthopedic surgery patients . Subjects were randomly assigned to receive a continuous intravenous infusion of cefazolin (mean, 178.6 mg/h) or cefuroxime (mean, 330.0 mg/h) at a rate estimated to achieve a target steady-state total concentration of 50 micrograms/ml in serum . The infusion was initiated 12 to 14 h before surgery, and blood and muscle tissue samples were collected intraoperatively at the times of incision and wound closure . Although there was a significant difference between the free concentrations of cefazolin (at incision, 9.3 micrograms/ml; at closure, 9.2 micrograms/ml) and cefuroxime in serum (at incision, 26.9 micrograms/ml; at closure, 31.8 micrograms/ml), there was no difference in the total concentrations in muscle at either surgical incision (cefazolin, 6.1 micrograms/g; cefuroxime, 5.6 micrograms/g) or wound closure (cefazolin, 7.7 micrograms/g; cefuroxime, 7.4 micrograms/g) . There was a significant correlation between the pooled free serum and total muscle concentrations for cefazolin (P = 0.001); however, there was no correlation between these variables with the pooled cefuroxime data (P = 0.403) . These findings indicate that the free drug concentration in serum alone is not consistently predictive of the total concentration of cephalosporin in muscle.

Analyst, 1990 May, 115(5), 613 - 6
Continuous flow molecular emission cavity analysis of cephalosporins by alkaline degradation to sulphide; Grekas N et al.; A continuous flow method for the determination of some cephalosporins (cephradine, cephalexin, cephalosporin C, cefadroxil, cephapirin and cephalothin) in the general range 10.0-250.0 micrograms ml-1 is described . The sample is mixed with sodium hydroxide and remains for 20 min at 90 degrees C in the delay coil of an air-segmented system . The solution is then mixed with an excess of orthophosphoric acid, and the hydrogen sulphide evolved is continuously transferred into the cavity for generation of the S2 molecular emission . The analysis is automated, requires no sample pre-treatment and samples can be analysed at a rate of 30 per hour with a relative error of 1-2% . The method was evaluated by carrying out recovery experiments and by the analysis of commercial formulations . Results agreed well with those obtained by the standard methods.

Ann Ital Chir, 1990 May-Jun, 61(3), 299 - 302; discussion 302-3
{Surgical chemoprophylaxis with ceftriaxone}; Cavallaro V et al.; Ceftriaxone is a cephalosporin of third generation . It is characterized by a broad spectrum, a long half-life and a good capacity of diffusion in tissue . We have studied 67 patients . Age ratio was 44 years . 25 patients did not receive short term prophylaxis; 42 patients did (2 gr iv of ceftriaxone one hour before the operation) . In clean surgery, only patients immunodepressed or malnourished received chemoprophylaxis . Patients who received 2 gr iv of ceftriaxone one hour before incision, received antibiotic therapy only on the appearance of septic complications . Results: two patients submitted to chemoprophylaxis (4.8%) showed complications (cystitis and bronchial pneumonia) . In the control group antibiotic therapy was undertaken only if septic complication appeared . 19 patients (76%) did not showed any complications . 6 patients (24%) showed surgical wound infection, acute pharyngo-tracheitis, cystitis . Finally, wound infections were limited exclusively to the control group . The ratio of respiratory infections was not statistically significant in the two groups; cystitis resulted more frequent in the control group than in the prophylaxis group . Prophylaxis with 2 gr single dose of ceftriaxone intravenously is effective in reducing the influence of infective complications in clean/contaminated surgery and clean risk surgery.

J Pharmacobiodyn, 1990 May, 13(5), 310 - 5
Cross-antigenicity between penams and cephems by intradermal skin test and leucocyte migration test in guinea pigs; Nagakura N et al.; The delayed-type hypersensitivity (DTH) reactions for penams or cephems of beta-lactam antibiotics were investigated by intradermal skin test and leucocyte migration test (LMT) in guinea pigs . The animals were immunized with ampicillin (ABPC) or cephalexin (CEX) using Freund's complete adjuvant . The cross-reactivities among ABPC, penicillin G (PCG) and cloxacillin as penam and CEX, cephalothin (CET) and cephalosporin C (CEPC) as cephem and phenylglycine (PhGly), which is the amino acyl side chain of ABPC and CEX, were examined . By intradermal reaction, ABPC-sensitized animals showed a cross-reaction with CEX, PCG and CET, but CEX-sensitized animals did not cause cross-reaction with ABPC . The CEX-sensitized group exhibited slight cross-reactions to CET and PhGly . PhGly exhibited low immunogenicity only in maximization test of guinea pig . The above results indicate that there is the difference in cross-reactivity between penams and cephems in skin test . In LMT, all the ABPC-sensitized animals reacted with ABPC and showed cross-reactions with all drugs tested . The CEX-sensitized group reacted with 4 out of 7 animals with CEX and exhibited cross-reactivities to ABPC, PCG, CET, CEPC and PhGly . The cross-reactivity between intradermal skin reaction and LMT elicited some different results.

Antibiot Khimioter, 1990 Apr, 35(4), 3 - 6
{Isolation and characteristics of mitochondrial DNA from Acremonium chrysogenum}; Petiushenko RM et al.; Circular mDNAs 26.85 and 26.94 kb in length were isolated from two isogenic strains of A . chrysogenum producing cephalosporin C . The strains differed in antibiotic production capacity . Restriction analysis of the mDNAs was performed with using 6 endonucleases . Comparison of the restriction data revealed identity of mDNAs . A restriction map of the mDNAs was constructed . It is useful as a basis for further studies with molecular cloning.

J Pharm Sci, 1990 Apr, 79(4), 351 - 3
Differential pulse adsorptive stripping voltammetric determination of ceftriaxone at a static mercury dropping electrode; Altinoz S et al.; Ceftriaxone is a member of the "third generation" of cephalosporin antibiotics which adsorbs strongly onto a mercury electrode . By using this phenomenon and by accumulating this compound at a static mercury dropping electrode prior to differential pulse voltammetric measurements, very high sensitivities can be readily achieved . The influence of several variables (including accumulation time, modulation amplitude, rest period, scan rate, and drop size) on the adsorptive stripping response has been evaluated . Peak currents were measured with a hanging mercury dropping electrode at -0.78 V versus an Ag/AgCl reference electrode in pH 3.0 Britton-Robinson buffer . The linear calibration range was 3.31 x 10(-11) to 2.17 x 10(-6) M.

Pathol Biol (Paris), 1990 Apr, 38(4), 307 - 9
{Alteration of IgE production by cefadroxil}; Clot J et al.; The effect of two cephalosporins, cefadroxil and cefalexine, was in vitro studied by using two models of regulation of the IgE production in healthy humans, e.g . the induction of CD23-antigens on B-cells and the IgE synthesis in cell culture supernatants after stimulation by recombinant interleukin-4 . Cefadroxil clearly inhibited CD23 membrane expression on normal human B-lymphocytes . In the same way, this cephalosporin blocked up to 90% of the in vitro interleukin-4-dependent IgE production by normal peripheral blood mononuclear cells . Cefalexine was unable to do the same . There results suggest that cefadroxil interplays with the regulation processes of the IgE production in humans.

Transfusion, 1990 Mar-Apr, 30(3), 263 - 6
Cefotaxime-induced immune hemolytic anemia due to antibodies reacting in vitro by more than one mechanism; Shulman IA et al.; Until recently, all cephalosporin-induced immune hemolytic anemias appeared to react by a "penicillin-type" drug adsorption mechanism, and hemolysis was extravascular . In 1987 and 1988, the first two cases of cephalosporin-induced immune hemolytic anemia with intravascular hemolysis associated with a so-called immune complex mechanism were reported . This report describes a case of extravascular hemolysis due to a third-generation cephalosporin, cefotaxime, which, to the authors' knowledge, is the first to show in vitro characteristics of both the drug adsorption and the so-called immune complex mechanisms.

DICP, 1990 Mar, 24(3), 262 - 5
Cephalosporin-induced nephrotoxicity: does it exist?
Zhanel GG.
The literature has been reviewed to determine whether cephalosporins have been implicated in causing nephrotoxicity and to assess the influence of concomitant aminoglycoside therapy . Animal and human data have implicated cephaloridine and cephalothin in causing nephrotoxicity, both alone and in combination with aminoglycosides . There are few data implicating other cephalosporins in causing nephrotoxicity . Cefazolin, which is nephrotoxic in animals, has not been reported to produce nephrotoxicity in humans . Two studies have documented nephrotoxicity due to ceftazidime, especially in patients with preexisting renal impairment . Such patients should have their dosage adjusted to minimize ceftazidime-induced renal impairment . Finally, cephalosporins other than cephaloridine and cephalothin have not been documented to increase the risk of nephrotoxicity when used in combination with aminoglycosides compared with aminoglycosides alone.

J Biotechnol, 1990 Mar, 13(4), 251 - 6
Comparison of the performances of stirred tank and airlift tower loop reactors; Schugerl K; Following a consideration of the prerequisites for reactor comparison and the fundamental differences between stirred tank and airlift tower loop reactors, their performances are compared for the production of secondary metabolites: penicillin V by Penicillium chrysogenum, cephalosporin C by Cephalosporium acremonium, and tetracycline by Streptomyces aureofaciens . In stirred tank reactors, cell mass concentrations, volumetric productivities, and specific power inputs are higher than in airlift tower loop reactors . In the latter, efficiencies of oxygen transfer are higher, and specific productivities with regard to power input, substrate and oxygen consumptions, and yield coefficients of product formation with regard to substrate and oxygen consumptions are considerably higher than in stirred tank reactors . The prerequisites for improved performance are discussed.

Appl Microbiol Biotechnol, 1990 Mar, 32(6), 680 - 5
Investigations on cephalosporin C adsorption kinetics and equilibria; Hicketier M et al.; The kinetics and equilibria of cephalosporin C adsorption on different commercial adsorbents were investigated . Adsorption isotherms could be analysed according to the Brunauer, Emmett and Teller theory . For the interpretation of adsorption kinetics it was necessary to develop a more complex model comprising both a rapid and a slower step . An integrated approach combining kinetics and equilibria allowed for simulation of the experimental data and can be used as a basis for predicting technical approaches such as fluidized-bed technology.

J Pharm Pharmacol, 1990 Feb, 42(2), 128 - 31
Cephalosporin C acylase in the autolysis of filamentous fungi; Reyes F et al.; Cephalosporin C acylase activity was studied using fluorescamine determination of free--NH2 groups produced in the deacylation of cephalosporin C by the enzyme . Fourteen fungi from different genera were studied and low extracellular cephalosporin C acylase activity was found in the genera Aspergillus, Fusarium and Penicillium . Forty one fungi of these genera were checked but not all presented acylase activity . The enzyme was generally found to be an extracellular enzyme and during the process of autolysis its activity increased with incubation time and with increasing pH of the medium . In no case was beta-lactamase activity detected . Penicillium rugulosum and Penicillium griseofulvum were identified as good cephalosporin C acylase producers . Deacetyl esterase activity was also detected in these fungi.

Appl Microbiol Biotechnol, 1990 Feb, 32(5), 560 - 7
Characterization and complementation of a cephalosporin-deficient mutant of Streptomyces clavuligerus NRRL 3585; Piret J et al.; We have characterized a mutant of Streptomyces clavuligerus NRRL 3585 which is almost completely blocked in cephalosporin biosynthesis and exhibits depressed activities of both the delta(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase and cyclase enzymes of the cephalosporin pathway . A wild-type DNA region was cloned which partially restores antibiotic production, ACV synthetase and cyclase activities to this mutant . The recombinant plasmid exhibits a variable copy number in different transformants . Hybridization experiments indicate that sequences homologous to the cloned region are present in various beta-lactam-producing Streptomyces spp . but absent in species which are not known to produce this class of antibiotics . Furthermore, the chromosomal copy of the cloned region lies in close proximity to a gene coding for the isopenicillin N synthase gene of the cephalosphorin pathway.

Antibiot Khimioter, 1990 Jan, 35(1), 11 - 4
{Study of the optimal conditions of preservation of cephalosporin C-producing fungus Acremonium chrysogenum}; Sidiakina TM et al.; The influence of various preservation conditions of viability and antibiotic activity of Acremonium chrysogenum 281A and 305A strains producing cephalosporin C was studied . Cryogenization of the culture in the form of suspension of the vegetative mycelium in 20 per cent glycerol solution at a rate of 1 degree/min showed to be advantageous over lyophilization and L-drying . Cryogenization under such conditions provided rather high viability of the culture and preservation of its initial antibiotic activity for the period of its storage for at least 1.5 years in liquid nitrogen at a temperature of -196 degrees C.

J Orthop Trauma, 1990, 4(1), 39 - 41
Management of low velocity gunshot-induced fractures; Geissler WB et al.; Bullets fired from civilian weapons are usually of low velocity, resulting in minimal tissue cavitation as compared to high-velocity weapons . A prospective protocol was initiated for patients sustaining a low-velocity gunshot to the extremity resulting in a stable, nonoperative fracture configuration . Treatment consisted of local irrigation and debridement, tetanus prophylaxis as required, a long acting cephalosporin intramuscularly, and splinting or casting of the fractured extremity . Twenty-five patients were managed by this protocol . This patient population was compared to a random retrospective sample of 25 patients with similar ballistic induced fractures and wounds managed by local debridement and 48 h of intravenous antibiotics . One infection occurred in each group, requiring further therapy . We conclude that the patient with a low-velocity gunshot induced fracture can be managed without the use of short-term intravenous antibiotics with no increased risk of infection.

Biochem J, 1990 Jan 1, 265(1), 131 - 46
The diversity of the catalytic properties of class A beta-lactamases; Matagne A et al.; The catalytic properties of four class A beta-lactamases were studied with 24 different substrates . They exhibit a wide range of variation . Similarly, the amino acid sequences are also quite different . However, no relationships were found between the sequence similarities and the substrate profiles . Lags and bursts were observed with various compounds containing a large sterically hindered side chain . As a group, the enzymes could be distinguished from the class C beta-lactamases on the basis of the kappa cat . values for several substrates, particularly oxacillin, cloxacillin and carbenicillin . Surprisingly, that distinction was impossible with the kappa cat./Km values, which represent the rates of acylation of the active-site serine residue by the beta-lactam . For several cephalosporin substrates (e.g . cefuroxime and cefotaxime) class A enzymes consistently exhibited higher kappa cat . values than class C enzymes, thus belying the usual distinction between 'penicillinases' and 'cephalosporinases' . The problem of the repartition of class A beta-lactamases into sub-classes is discussed.

J Pharmacol Exp Ther, 1990 Jan, 252(1), 65 - 9
The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake; Tune BM et al.; Previous work in this laboratory has demonstrated a reduction by the nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin and imipenem of renal mitochondrial uptake of and respiration with the anionic substrate succinate . The present studies were done to test further the hypothesis that reduced substrate uptake and decreased respiration are causally related . Using cephaloridine in the rabbit, we examined the specificity of this association in regard to the toxic cephalosporin insult, the involvement of renal mitochondria and the reduction of carrier-mediated anionic substrate transport . 1) Specificity of insult in renal cortical mitochondria: cephaloridine (300 mg/kg bwt . i.v., 1 hr before sacrifice) reduces both the uptake of and respiration with succinate, whereas the same dose of cephalexin, which is not nephrotoxic, has neither effect; 25 min of acute unilateral renal artery occlusion reduces both the uptake of and respiration with succinate, but, unlike cephaloridine, ischemia causes a large increase of substrate efflux; and the respiratory toxins cyanide (1 mM) and oligomycin (2 micrograms/g of protein) reduce respiration by a direct effect on the mitochondrial respiratory chain and therefore have no effect on substrate uptake . 2) Specificity of target organ: cephaloridine has no significant effect on either the uptake of or respiration with succinate in hepatic mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology, 1990, 41(3), 113 - 8
Advances in understanding the pharmacology of agents used to treat bacterial meningitis; Spector R; Recently, substantial progress has been made in the therapy of bacterial meningitis related in part to better understanding of and predictions about the pharmacokinetics of antibiotics in the central nervous system . This review summarizes new data on pertinent anatomy and physiology of penicillin and cephalosporin transport in the central nervous system, focusing on the choroid plexus, which transports many antibiotics out of the central nervous system . These new pharmacological data provide the scientific basis for understanding recent advances in therapy of meningitis.

Yao Xue Xue Bao, 1990, 25(2), 142 - 6
{Study on prolonged action cefotoxime}; Xu GQ et al.; A prolonged action cephalosporin was prepared by the reaction of cefotaxime sodium (CTX) with N,N-dibenzylethylene diamine acetate . It is reasonable to consider the resultant as benzathine cefotaxime (BCTX) by means of elemental analysis, DSC, UV spectra, IR spectra, NMR spectra and mass spectra . In contrast to CTX, BCTX appeared to be almost insoluble in water and its intrinsic dissolution rate was 0.183 micrograms/ml.min . The stability revealed that the degradation of BCTX suspension in water followed zero-order kinetics and the rate of degradation at room temperature was found to be 1.67 X 10(-7) mg/ml.s . An in vivo test by using 12 rabbits given BCTX suspension and CTX solution intramuscularly was conducted . The results showed that the former was longer in maintaining serum drug level than the latter.

Recenti Prog Med, 1990 Jan, 81(1), 47 - 8
{Disulfiram-like effect of cefonicid: first observation}; Marcon G et al.; The disulfiram-like reaction is linked to the assumption of ethyl alcohol during therapy with the cephalosporin latamoxef, cefamandole and cefoperazone . The reaction is commonly ascribed to the methyl-thiotetrazole group, resembling part of the disulfiram molecule . We describe the case of a patient who experienced on two different occasions a disulfiram-like effect during therapy with cefonicid . This cephalosporin contains the methylsulphothiotetrazole group in place of the methylthiotetrazole group . Our observation is the first related to cefonicid.

J Basic Microbiol, 1990, 30(5), 313 - 20
Acremonium chrysogenum differentiation and biosynthesis of cephalosporin; Bartoshevich YuE et al.; On the basis of structure-functional analysis of the development of Acremonium chrysogenum, e.g . under conditions either stimulating antibiotic synthesis or not conductive to production, a scheme was proposed representing the various ways in which morphological differentiation occurs in the culture in dependence on the directions of its metabolism . Three types of culture differentiation were determined . Type 1 differentiation is characterized by the transition of the vegetative stage into the reproductive one with the formation of conidia . Type 2 differentiation is characterized by the formation of typical arthrospores also being the reproductive form . Type 3 differentiation is characterized by the multistage transformation of the mycelium organization into the yeast-like one which is metabolically more active and is a producer of antibiotics and enzymes . In addition to the defined regularities in the development and differentiation of Acremonium chrysogenum structural peculiarities were observed which could be helpful to the search for regulators or specific enzymes taking part in the culture development.

Clin Ther, 1990, 12 Suppl C, 53 - 73
A comparison of the efficacy and safety of ceftizoxime with doxycycline versus conventional CDC therapies in the treatment of upper genital tract infection with or without a mass; Roy S et al.; It is well known that sexually transmitted infections of the upper genital tract are widespread . A variety of regimens are used to treat these conditions, many of which have not been subjected to randomized, prospective clinical trials (including the 1985 Centers for Disease Control {CDC} Guidelines for the treatment of upper genital tract infections {UGTI}) . This investigation was undertaken to compare the 1985 CDC treatment guidelines with different doses of ceftizoxime, a third-generation cephalosporin with an intermediate half-life, plus doxycycline in patients with UGTI . The patients were divided into subgroups, depending on the presence or absence of a pelvic mass . Sixty-seven women participated in the study . They were older than 14 years of age and required hospitalization for the treatment of UGTI . These women had lower abdominal pain and tenderness, cervical motion or adnexal tenderness, and one of the following: temperature greater than 100.4 degrees F orally, leukocytosis greater than 10,500/mm3, or presence of a suspected inflammatory pelvic mass on pelvic examination or by ultrasound . Informed consent was obtained from all patients in a manner approved by the Institutional Review Board . Pelvic examinations and ultrasound evaluations of the pelvic soft tissues were performed on all patients at the time of admission . Those who were found not to have a pelvic mass or who had a pelvic mass less than 4 cm in transverse diameter were randomly allocated to receive either ceftizoxime 2 gm intravenously every 12 hours with doxycycline 100 mg intravenously twice daily (Rx 1, n = 13) or cefoxitin 2 gm intravenously every six hours with doxycycline 100 mg intravenously twice daily (Rx 2, n = 14) . Those patients found to have a pelvic mass (greater than 4 cm in transverse diameter) were randomly allocated to receive either ceftizoxime 2 gm intravenously every eight hours with doxycycline 100 mg intravenously twice daily (Rx 3, n = 19) or clindamycin 900 mg intravenously every eight hours with a 2-mg/kg loading dose of gentamicin followed by 1.5 mg/kg intravenously every eight hours, with adjustments as necessary (Rx 4, n = 21) . All UGTI patients without a mass treated with either Rx 1 or Rx 2 responded adequately . However, UGTI patients with a mass treated with Rx 4 were more likely than those treated with Rx 3 to require a change in antibiotics or need extirpative surgery in order to obtain a satisfactory clinical response (Fisher's exact test = 0.046, two-sided).(ABSTRACT TRUNCATED AT 400 WORDS)

Chin J Biotechnol, 1990, 6(1), 1 - 9
Regulation of ACV synthetase: biosynthesis and action; Zhang JY et al.; The biosynthesis of cephalosporins has been studied for almost 30 years . Development of cell-free systems began with the later enzymes of the pathway and, in recent years, moved to the early part of the pathway . The first enzyme, delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase was one of most difficult to demonstrate in cell-free extracts . We recently developed a reproducible system from Cephalosporium acremonium (Banko et al., 1987) and similar activity has been found in Streptomyces clavuligerus (Jensen et al., 1988) . With this assay, we have been able to study the regulation of ACV synthetase formation and action . Our results are summarized in this communication . Our comparison of the intracellular specific activities of the beta-lactam synthetases in both C . acremonium c-10 and S . clavuligerus NRRL 3585 indicates that ACV synthetase possesses the lowest activity and appears to be the rate-limiting step in the cephalosporin biosynthetic process . Since it is the initial enzyme in the biosynthetic pathway common to both penicillins and cephalosporins, this makes sense from a cellular economy viewpoint . It is therefore understandable that ACV synthetase would be subject to greater regulatory control than other steps.

Int Arch Allergy Appl Immunol, 1990, 92(4), 439 - 44
Drugs as allergens: an immunoassay for detecting IgE antibodies to cephalosporins; Harle DG et al.; A radioimmunoassay employing cephalothin linked to a solid phase has been developed for the detection of cephalosporin-reactive IgE antibodies . Direct binding and inhibition studies demonstrated allergenic cross-reactivity between cephalosporins and penicillins, and quantitative hapten inhibition experiments identified the 2-thiophene group, and particularly the attached methylene group, of cephalothin as an allergenic determinant.

Fortschr Ophthalmol, 1990, 87 Suppl, S33 - 40
{Acute and chronic inflammatory reactions following implantation of artificial lenses}; Treumer H; Inflammatory reactions following IOL-implantation are being caused by different factors . A recent finding refers to the fact that bacteria of usually low pathogenity (i.e . Probionibacterium acnes, Staph . epidermidis, Staph . aureus haemolyticus) can enter the eye during implantation into the capsular bag and can cause an initially localized endophthalmitis . Previously this clinical appearance had frequently been mistaken as a "Toxic Lens Syndrome" . Clinically, a persisting or increasing fibrin reaction with or without hypopyon, a typical whitish appearance of the capsule and a more or less marked vitreous infiltration up to a generalized endophthalmitis may be observed . For diagnostic purposes an isolation of germs from the fibrin network in the pupillary area or from the excised fragments of the capsular bag can be successful . Therapy of choice are locally applied antibiotics (i.e . the combination of Cephalosporin with Tobramycin) or eventually an operative intervention . If this is performed in the early course, the IOL can be saved in the majority of cases, although the visual acuity is usually reduced . Postoperative inflammatory reactions can also be caused by individual disposition (pseudoexfoliation, glaucoma, uveitis) . No importance is being attributed furthermore to diagnoses like "Toxic Lens Syndrome" or "Pseudo-phako-anaphylactic Endophthalmitis' . Postoperative inflammatory reactions can be divided into five different clinical courses . In cases of bacterial contamination the prognosis is worsened by mono-steroid therapy.

Infection, 1990, 18 Suppl 3, S119 - 21
{Clinical experiences with cefixime in the treatment of bacterial infections of the lower respiratory tract}; Kersten W et al.; In a prospective, open clinical trial 21 patients suffering from lower respiratory tract infections were treated with the new oral cephalosporin cefixime . The antibiotic was given at a dosage of 200 mg b . i . d . for seven to eleven days . Seventeen of 18 evaluable patients were cured or distinctly improved at the end of therapy as well as two days after the end of treatment . Clinical results correlated well with the results of the lung function tests, especially with the significant decrease of resistance . At the end of therapy all initially isolated pathogens were eradicated . The tolerability of cefixime was good, only in two patients treated mild and transient side effects were noticed (1 x diarrhea, 1 x epigastric pain).

Biochem Int, 1990, 20(6), 1169 - 78
Characterization of a D-amino acid oxidase with high activity against cephalosporin C from the yeast Trigonopsis variabilis; Szwajcer-Dey E et al.; We describe an improved method to purify D-amino acid oxidase with activity towards cephalosporin C . The protein has a carbohydrate content of 1.3% and two molecules of non-covalently bound flavin cofactor per protein molecule . HPLC profiles and enzymatic analysis have indicated that the cofactor is FAD, even though fluorescence spectroscopy shows a slightly altered spectral profile in the 400-500 nm range compared to authentic FAD . N-terminal sequencing of the protein revealed a high level of similarity (56% identity in 25 amino acids) between the fungal and mammalian oxidase, and probably represents a "Rossman fold" with a beta-alpha-beta structure for the binding of the adenosyl moiety of the cofactor.

Gene, 1989 Dec 21, 85(1), 267 - 73
Characterization of a loss-of-function mutation in the isopenicillin N synthetase gene of Acremonium chrysogenum; Ramsden M et al.; The N-2 strain of Acremonium chrysogenum accumulates the beta-lactam precursor tripeptide delta-(L-alpha-amino-adipoyl)-L-cysteinyl-D-valine and has no discernible activity for three of the cephalosporin C (Ce) biosynthetic enzymes . This phenotype is consistent with a mutation either within pcbC {the isopenicillin N synthetase (IPNS)-encoding gene} or in a pathway-regulator gene . To distinguish these possibilities we have cloned and sequenced pcbC from strain N-2 . There is a single C----T mutation at nt 854 within the coding sequence, changing aa 285 from proline to leucine . An IPNS-specific monoclonal antibody recognises a catalytically inactive IPNS protein in extracts of N-2 cells . These findings suggest that strain N-2 carries a simple IPNS mutation and that IPNS or its biosynthetic product isopenicillin N is involved in regulation of the later stages of the Ce biosynthetic pathway.

Chest, 1989 Dec, 96(6), 1292 - 7
Comparison of ceftriaxone with cefotaxime in serious chest infections; Reeves JH et al.; Ceftriaxone is a new, third-generation cephalosporin that, because of its long half-life, offers potential advantages of cost and convenience over similar agents such as cefotaxime . We compared the two drugs in a prospective, randomized study of the treatment of chest infections in seriously ill patients . Fifty-one patients (90 percent of whom were mechanically ventilated) received either ceftriaxone, 2g IV once daily, or cefotaxime, 2 g IV thrice daily, for five days . The two groups of patients appeared demographically comparable . Ceftriaxone in a single daily dose of 2 g once daily may not be satisfactory for the treatment of serious chest infections.

J Antimicrob Chemother, 1989 Dec, 24(6), 1001 - 10
Cephalosporin and aminoglycoside utilization in different parts of the world; Kumana CR et al.; Cephalosporin and aminoglycoside utilization in Hong Kong during 1984, 1985 and 1986, were evaluated from wholesale data and compared with corresponding Swedish statistics and with UK data from a survey of non-hospital prescriptions . Details regarding each drug and category were collated, adjusted for population and if appropriate expressed as defined daily doses (DDDs)/1000 inhabitants/day . With respect to cephalosporins: (a) overall sales (especially those of the newer and more expensive parenteral drugs) were increasing; (b) parenteral sales were much larger in Hong Kong hospitals than in the community (up to about 106 versus 16 kg/million inhabitants/year respectively), but in Sweden they were comparable (up to about 38 and 41 kg/million inhabitants/year respectively); (c) non-hospital oral utilization appeared greater in the UK than in Sweden and Hong Kong (up to about 0.7, 0.4 and 0.4 DDDs/1000 inhabitants/day respectively); (d) oral sales to hospitals were greater in Hong Kong than Sweden (up to 0.3 compared to 0.1 DDDs/1000 inhabitants/day respectively) and (e) oral paediatric formulations (liquids) were most popular in Hong Kong, a higher proportion of children in Hong Kong being one possible reason . Non-hospital sales of gentamicin and kanamycin in Hong Kong were much greater than in Sweden (up to about 0.20 and 0.06 vs . 0.01 and 0.00 DDDs/1000 inhabitants/day respectively), whereas UK utilization appeared almost non-existent . Topical neomycin sales in Hong Kong were much more popular than in Sweden (up to about 60 vs . 9 g/million inhabitants/day) . These regional differences in antibiotic utilization may be related to respective health care systems (and thus the affordability and availability of drugs) and prescribing preferences (cultural and/or promoted by drug companies), quite apart from possible differences in drug efficacy, drug tolerance and the prevalence and severity of various infections.

Clin Pharmacol Ther, 1989 Dec, 46(6), 674 - 85
The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil; Hughes GS et al.; The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects . In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc) . Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given . Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001) . Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both) . In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets . There were six meals in each diet . Dosing with the antibiotic was done at the midpoint of the fourth meal . Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged . These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.

Orv Hetil, 1989 Nov 5, 130(45), 2419 - 24
{Experience with Cefobid in severe infections complicating immunodeficiency diseases}; Istvan L et al.; As a 3rd generation cephalosporin Cefobid monotherapy was applied during 1985-1986 with 16 hematological patients in immunodeficient, immunosuppressive states where the available aimed and combined antibiotic therapy failed to be effective for the treatment of bacterial infections of grave course and septic character . 4 g/day was the average I.V . dose of Cefobid, higher doses were applied only in especially grave septic states . The hematological patients tolerated well the Cefobid in monotherapy . Recovery form the septic state and excellent clinical effect was found with 9 patients, good effect with 4 and satisfactory effect with 1 patient . In 1 case the therapy had to be stopped owing to drug hypersensitivity . Cefobid is regarded as an antibiotic drug that is effective if used in monotherapy for treating grave, septic infections of hematological patients in immunodeficient--immunosuppressive--myelodepressive states having received earlier antineoplasmic polychemotherapy.

Antimicrob Agents Chemother, 1989 Nov, 33(11), 1970 - 4
Biliary excretion and choleretic effect of cefmetazole in rats; Gonzalez J et al.; The effect of cefmetazole, a broad-spectrum cephalosporin, on bile flow and composition in rats was studied . Intravenous injection of cefmetazole at doses ranging from 40 to 400 mumol/kg of body weight led to an increase in its biliary concentration and excretion rate, with a maximum at 30 min after injection . Excretion of cefmetazole into bile was associated with a marked choleresis . The magnitude of the increase in bile flow was dose dependent, with a maximal increase at a dose of 200 mumol/kg . Cefmetazole administration did not affect the secretion of bile acids or their osmotic activities, whereas the bile acid-independent bile flow increased by 49% at a dose of 200 mumol/kg . Cefmetazole administration at a dose of 200 mumol/kg significantly increased the biliary outputs of sodium, potassium, chloride, and bicarbonate (+36, +56, +28, and +31%, respectively) compared with outputs of controls . A linear relationship was observed between bile flow and cefmetazole excretion, 44 microliters of bile being produced per mumol of cefmetazole excreted into bile . Our results demonstrate that cefmetazole induces choleresis by stimulating bile acid-independent bile flow . This effect appears to be partly due to the osmotic properties of cefmetazole transported into bile.

Anaesth Intensive Care, 1989 Nov, 17(4), 433 - 9
Failure of intravenous infusions from extravasation and phlebitis; Hecker JF; A survey was done to compare the rates at which phlebitis and extravasation cause failure of intravenous infusions lasting more than 24 hours . Slightly more infusions failed due to phlebitis than to extravasation but extravasation did not occur earlier or later than phlebitis or differ significantly from it in frequency when different types of infusions were compared . Univariate life table analysis indicated that the co-infusion of blood, potassium or cephalosporin antibiotics slightly increased and that higher flow rates markedly increased failure, that infusions including continuous heparin and steroids had markedly decreased failure, and that failure was not significantly affected by other antibiotics or by differences in sex, age, location of infusion site or time of year . Multivariate analysis showed that the above differences were statistically significant only for infusion rate, heparin and steroids.

Presse Med, 1989 Oct 11, 18(32), 1605 - 7
{Efficacy and tolerability of cefixime in lower respiratory tract infections in adults . French multicentric study}; Modai J; Cefixime is a new oral cephalosporin with the same activity as that of third generation cephalosporins, particularly against organisms responsible for lower respiratory tract infections . The effectiveness and safety of cefixime were evaluated in the multicentre study reported here . Cure was obtained in 54 of 61 assessable patients suffering from bronchopneumonia (40/44), acute bronchitis (3/5) or acute exacerbations of chronic bronchitis (11/12) . The causative agents were eradicated in 35 of 41 assessable cases . No clinical side-effect was observed . Thrombocytosis without clinical manifestations was reported in 14 cases . Administered in doses of 200 mg twice daily, cefixime proved effective and safe in the treatment of lower respiratory tract infections.

Clin Pharmacokinet, 1989 Oct, 17(4), 223 - 35
Clinical pharmacokinetics of ceftriaxone; Yuk JH et al.; Ceftriaxone is a third-generation cephalosporin that exhibits saturable plasma protein binding, which influences its pharmacokinetic parameters depending on the dose . Systemic clearance and volume of distribution of total drug show dependence on both concentration and time, whereas for unbound drug these parameters remain constant . The decrease in renal or non-renal clearance with age or in the presence of disease states is often compensated by the concurrent increase in free fraction, resulting in no apparent changes in half-life and no need for dose adjustment . Because of its unusually long plasma half-life, the availability of intramuscular administration and its high intrinsic activity against many organisms, ceftriaxone has become a popular agent in once-daily therapy of infections in paediatric patients, gonococcal infections and outpatient management of pneumonia and osteomyelitis.

J Mol Biol, 1989 Sep 20, 209(2), 281 - 95
Crystallographic mapping of beta-lactams bound to a D-alanyl-D-alanine peptidase target enzyme; Kelly JA et al.; X-ray crystallography has been used to examine the binding of three members of the beta-lactam family of antibiotics to the D-alanyl-D-alanine peptidase from Streptomyces R61, a target of penicillins . Cephalosporin C, the monobactam analog of penicillin G and (2,3)-alpha-methylene benzylpenicillin have been mapped at 2.3 A resolution in the form of acyl-enzyme complexes bound to serine 62 . On the basis of the positions of these inhibitors, the binding of a tripeptide substrate for the enzyme, L-lysyl-D-alanyl-D-alanine, has been modeled in the active site . The binding of both inhibitors and substrate is facilitated by hydrogen-bonding interactions with a conserved beta-strand (297-303), which is antiparallel to the beta-lactam's acylamide linkage or the substrate's peptide bond . The active site is similar to that in beta-lactamases.

Jpn J Antibiot, 1989 Sep, 42(9), 2016 - 22
{A clinical study on cefteram pivoxil granule in the field of pediatrics}; Haruta T et al.; The clinical effectiveness of cefteram pivoxil (CFTM-PI) granule, a new oral cephalosporin, was studied in pediatric patients . The results are summarized as follows . 1 . CFTM-PI was given orally to 17 children in daily doses of 9.5 to 31.8 mg/kg in 3 to 4 divided portions for 2 to 10 days . Clinical evaluations were made on 14 patients . Clinical effects of CFTM-PI were excellent in 4, good in 5 of 9 patients with tonsillitis or pharyngitis, excellent in all cases of 2 patients with pneumonia, 1 patient with scarlet fever and 1 patient with pyelonephritis, and fair in 1 patient with purulent cervical lymphadenitis . Overall clinical effects were excellent in 8, good in 5, and fair in 1 with an efficacy rate of 92.9% . 2 . No side effects were observed in any of the 17 patients . Hematological tests showed a slight elevation of blood platelet counts in 1 patient . 3 . The taste and odor of CFTM-PI granule were well accepted by the children . 4 . CFTM-PI is a useful oral antibiotic for the treatment of bacterial infections in pediatrics.

Mol Pharmacol, 1989 Sep, 36(3), 478 - 83
Ceftriaxone binding to human serum albumin: competition with bilirubin; Brodersen R et al.; Ceftriaxone, a cephalosporin, is bound reversibly to defatted human serum albumin from adults, with a first stoichiometric binding constant of 60,000 M-1, as found by equilibrium dialysis at pH 7.4, 37 degrees . A second molecule is weakly bound, with a binding constant of 500 M-1 . Possible cobinding with bilirubin was studied by the peroxidase method and by equilibrium dialysis with and without added bilirubin . Results indicated competitive binding; formation of an albumin complex containing both bilirubin and ceftriaxone could not be demonstrated . Light absorption spectra of bilirubin-albumin showed little change on addition of ceftriaxone, in agreement with the competitive biding mechanism . Binding to serum albumin from newborn infants is weaker than to the protein from adults, with the first binding constant being about 36,000 M-1 . Cobinding of ceftriaxone and bilirubin to albumin from newborn infants is likewise competitive . It is concluded that ceftriaxone is a strong bilirubin displacer with a potential of inducing bilirubin encephalopathy in predisposed newborns.

Antibiot Khimioter, 1989 Sep, 34(9), 705 - 7
{Use of cephalosporins for the prevention of mixed infection during surgical treatment of rectal cancer}; Spitsyna TA et al.; Cephalosporin antibiotics such as cephaloridine, cephazolin and cephalothin++ were used during operations for rectum cancer . The antibiotics were administered intravenously and immediately into the superior rectal artery . It provided high levels of the antibiotics in blood and discharge of the small pelvis cavity and prevented development of infectious complications during the postoperative period.

Antibiot Khimioter, 1989 Sep, 34(9), 699 - 701
{Use of cephalosporins in pediatric practice with the study of the immunoleukolysis (leukocytolysis) reaction}; Poshekhonov SA et al.; The aim of the study was to determine the value of preliminary assay of hypersensitivity to cephalosporin antibiotics such as cephazolin, cefuroxime and cefotaxime with the immunoleukolysis test (ILT) . 130 children at the age of 2 months to 7 years treated with one of the antibiotics for various inflammatory diseases of the bronchopulmonary system were examined . Hypersensitivity (the ILT indices over 30 per cent) was observed in 9.2 per cent of the children with respect to cephazolin (kefzol), in 3.9 per cent of the children with respect to cefuroxime (ketocef) and in 0.8 per cent of the children with respect to cefotaxime (klaforan) . The results of the ILT combined with those of the conjunctival test allowed to increase the number of indications to differential use of the cephalosporins in children with various pathological processes in the bronchopulmonary system.

Chem Pharm Bull (Tokyo), 1989 Sep, 37(9), 2375 - 8
Studies on orally active cephalosporin esters . III . Effect of the 3-substituent on the chemical stability of pivaloyloxymethyl esters in phosphate buffer solution; Miyauchi M et al.; The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of delta 3 cephalosporin in phosphate buffer solution (pH 6-8) was investigated . In the degradation, the isomerization process to the delta 2 ester was the rate-determining step . In this study, the logarithm of the isomerization rate to the delta 2 ester (log k12) correlated with the carbon-13 nuclear magnetic resonance chemical shift difference value at C-3 and C-4 of the delta 3 ester (delta delta (4-3)) . The energy level of the lowest unoccupied molecular orbital (LUMO) of the delta 3 esters also correlated with log k12 . The electronic properties at the C-2 position had no effect on the isomerization reaction . On the other hand, the logarithm of the isomerization rate back to the delta 3 ester (log k21) correlated with the van der Waals volume (MV) of the 3-substituent . These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated pi-bond system (C3 = C4 - C4 = O) and consequently affects the feasibility of isomerization to the delta 2 ester, i.e., the stability to degradation.

Chem Pharm Bull (Tokyo), 1989 Sep, 37(9), 2369 - 74
Studies on orally active cephalosporin esters . II . Chemical stability of pivaloyloxymethyl esters in phosphate buffer solution; Miyauchi M et al.; The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH 6-8) were investigated . The degradation of the starting delta 3 cephalosporin ester proceeded mainly via isomerization to the delta 2 ester and subsequent hydrolysis to the delta 2 acid . Hydrolysis to the delta 3 acid (the parent acid) was very slow . Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the delta 3 ester kdeg, and slower than the hydrolysis rate of the delta 2 ester k24 . The isomerization process to the delta 2 ester was found to be the rate-determining step in the degradation of cephalosporin esters . The substituent at the C-3 position of the cephalosporins affected the degradation kinetics . The degradation was accelerated by increase of pH, buffer concentration and added protein.

J Gen Microbiol, 1989 Sep, 135 ( Pt 9), 2475 - 82
Isolation and characterization of nitrogen-deregulated mutants of Streptomyces clavuligerus; Bascaran V et al.; Two screening methods for isolation of mutants of Streptomyces clavuligerus with altered control of nitrogen metabolism enzymes are described . Thirty-eight prototrophic mutants with simultaneous deregulation of urease and glutamine synthetase were isolated . Nine mutants were examined in more detail and they also showed deregulated formation of arginase and ornithine aminotransferase . Different patterns of altered control of all four enzymes were observed . Inactivation of glutamine synthetase after ammonium shock took place to different extents in these nine strains, and seven of them had a thermosensitive glutamine synthetase activity . It is concluded that a system of nitrogen control, in which glutamine synthetase has a key role, is present in S . clavuligerus . Cephalosporin production was depressed by ammonium in all the mutants, irrespective of the alterations in nitrogen control of primary metabolism.

Jpn J Antibiot, 1989 Aug, 42(8), 1713 - 9
{Treatment with sulbactam/cefoperazone of severe infections in patients with hematological disorders}; Ohno R et al.; Infectious episodes in 90 patients with hematological disorders were treated with sulbactam/cefoperazone (SBT/CPZ), a new combination drug of a potent beta-lactamase inhibitor, sodium sulbactam, and a third generation cephalosporin, sodium cefoperazone . Clinical responses to the SBT/CPZ regimen were excellent in 23 cases, good in 30 cases, fair in 11 cases, and poor in 26 cases . The overall efficacy rate (percentage of cases showing excellent or good responses) was 58.9% . Efficacy rates classified according to different infections were: 80% in documented sepsis, 57.6% in suspected sepsis, 61.1% in pneumonia and 50% in other infections . One episode of side effect was encountered with redness and itching of skin . Hepatic disorders were observed in 3 cases . These adverse reactions, however, were not serious . These results indicate that SBT/CPZ has a high therapeutic efficacy to severe infections in patients with hematological disorders.

Antimicrob Agents Chemother, 1989 Aug, 33(8), 1326 - 8
Cephalosporin penetration into soft tissue of paralyzed limbs; Darouiche R et al.; Poor penetration of antibiotics into paralyzed tissue may contribute to the difficulty of curing soft tissue infections in paralyzed limbs . A novel model of spinal cord hemisection was used to induce paralysis of one hind leg in mice . Five, 10, or 20 days after induction of paralysis, six groups of 10 mice were injected intravenously with a single dose or with four sequential doses of cefepime, a new broad-spectrum cephalosporin, and then sacrificed . High-performance liquid chromatography was used to compare cefepime levels in soft tissue homogenates of paralyzed and normal hind legs; no significant differences were found in any group . Factors other than antibiotic delivery may be responsible for difficulty in curing infections in paralyzed soft tissue.

Arch Otolaryngol Head Neck Surg, 1989 Aug, 115(8), 940 - 2
The ototoxicity of ceftazidime in the chinchilla middle ear; Brown OE et al.; Ceftazidime (Tazicef) is a broad-spectrum cephalosporin antibiotic that may be useful as a topical agent in the treatment of otorrhea . To test the potential ototoxicity of the drug, 0.5 mL of a 10% solution of ceftazidime was introduced into the bullae of 22 chinchillas . The organ of Corti was normal in 20 temporal bones examined at 1 week after administration of the ceftazidime solution . Only 2 of 24 temporal bones examined after 4 weeks showed minor outer hair cell loss of the basal turn of the organ of Corti . Focal hemorrhage and occasional serous effusions were found in the middle ears of all animals after 1 week; these findings had mostly cleared after 4 weeks . Our results indicate that ceftazidime causes reversible middle ear inflammation, and may have some minor ototoxic potential under these experimental conditions.

J Pharm Sci, 1989 Jul, 78(7), 535 - 40
Age-related change in tissue-to-plasma partition coefficient of cefazolin for noneliminating organs in the rat; Tsuji A et al.; Age-related changes in tissue distribution characteristics of cefazolin, a cephalosporin antibiotic, were examined for noneliminating organs of rats . The in vivo tissue-to-plasma partition coefficients (Kp,vivo) varied markedly among different ages and organs . In particular, muscle and skin acted as reservoirs for cefazolin distribution . There were also marked differences in interstitial fluid space (IS), determined using {14C}inulin, among different ages and organs . For muscle and bone, the magnitude of the age-related changes in Kp,vivo of cefazolin and IS was in the order of 1-week-old greater than 7-week-old = 100-week-old greater than 50-week-old rats . This is well correlated with the age-related changes in the volume of distribution at the steady state of cefazolin per body weight (Vdss/BW) and the extracellular fluid volume per body weight (Vecw/BW) determined previously using {14C}inulin . The predicted Kp value (Kp,pred) was estimated by incorporating the serum protein binding parameters of cefazolin, the IS values, and an interstitial-to-plasma albumin concentration ratio (AR) into equations derived from an extracellular fluid model . The Kp,pred values exhibited a fairly good correspondence with the Kp,vivo values determined for various organs, except gut, in rats of all four ages . These results suggest that the determinant of the age-related change in Vdss/BW is the difference in the IS value of muscle and bone, while the age-related change in serum protein binding plays only a modest role.

Therapie, 1989 Jul-Aug, 44(4), 285 - 9
{Influence of surgical biliary pathology on the diffusion of ceftriaxone in the biliary tract}; Guyot L et al.; Ceftriaxone is a third generation cephalosporin remarkable for its wide distribution in the biliary tract . The purpose of this study was to determine whether biliary tract pathology, as observed during surgery, had an influence on this distribution . 52 patients about to be operated upon and presenting with a high risk of bile infection received a single 1 or 2 g dose of ceftriaxone administered intravenously over 20 min during the hour that preceded surgery . Samples of blood and of bile from the gallbladder (GB) and the common bile duct (CBD), as well as specimens of the GB wall were taken during the operation . In patients whose GB was normal at laparotomy (apart from stones) ceftriaxone concentrations in bile and GB wall were 10-25 and 2 times respectively higher than in plasma . In patients with a grossly distended but not infected GB (hydrocholecystis) ceftriaxone levels were high in CBD bile but null in GB bile and only one-quarter to one-half of plasma levels in GB wall . In patients with stones in the CBD or inflamed GB wall ceftriaxone levels were high in bile (although lower than in cases with normal GB) and similar to plasma levels in GB wall . When malignant pancreatic lesions were present ceftriaxone concentrations could not be measured in both GB and CBD bile but reached 50% of plasma concentrations in GB wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Science, 1989 Jun 16, 244(4910), 1313 - 7
Genetic engineering of filamentous fungi; Timberlake WE et al.; Filamentous fungi are important in medicine, industry, agriculture, and basic biological research . For example, some fungal species are pathogenic to humans, whereas others produce beta-lactam antibiotics (penicillin and cephalosporin) . Industrial strains produce large amounts of enzymes, such as glucoamylase and proteases, and low molecular weight compounds, such as citric acid . The largest and most economically important group of plant pathogens are fungi . Several fungal species have biological properties and genetic systems that make them ideally suited for basic biological research . Recently developed techniques for genetic engineering of filamentous fungi make it possible to alter their detrimental and beneficial activities in novel ways.

Int J Artif Organs, 1989 Jun, 12(6), 379 - 83
Removal of cephalosporins by continuous arteriovenous ultrafiltration (CAVU) and hemofiltration (CAVH); Lau AH et al.; Cephalosporins are used with increasing frequency for sepsis treatment in patients receiving CAVU and CAVH . The different cephalosporins share the same basic molecular structure, yet they exhibit varied extent of plasma protein binding . Different amounts of the antibiotics may be removed by the ultrafiltration procedure because of these variations of physicochemical properties . We evaluated the sieving of eight new cephalosporins across the hemofilter membrane using an in vitro model . Bovine blood was perfused through polysulfone membranes at blood and ultrafiltrate flow rates of 100 and 20 ml/min respectively . Arterial plasma, venous plasma and ultrafiltrate drug concentrations were used to determine sieving coefficients . The sieving coefficients correlated well with the ultrafiltrate-arterial plasma drug concentration ratio (r = 0.679-0.972) but poorly with the extent of protein binding . Factors other than protein binding may therefore affect the drug sieving . Based on the findings, it was predicted that 0.2-21.9% of the daily cephalosporin dose may be removed by the CAVU and CAVH treatment . The need to alter drug dosages depends on the techniques of the ultrafiltration and hemofiltration procedure, the kinetics of the cephalosporins in patients, the sensitivity of the pathogen and the nature of the infection.

J Mol Graph, 1989 Jun, 7(2), 87 - 92
Studying enzyme-beta-lactam interactions using X-ray diffraction; Kelly JA et al.; The interaction of representative beta-lactam antibiotics with a bacterial enzyme target has been mapped in three dimensions using X-ray diffraction data to 2.25 A resolution . Examination of complexes of cephalosporin C, benzylmonobactam, and alpha-(2,3)-methylenepenicillin G with the D-alanyl-D-alanine transpeptidase-carboxypeptidase from Streptomyces R61 shows that the enzyme's reactive serine has acylated the beta-lactam ring of each inhibitor . The known half-lives of the three acyl complexes can be correlated with the distance of the drug's carboxylate (or sulfonate) group from complementary groups on the DD-peptidase.

Gene, 1989 May 30, 78(2), 331 - 8
An electrophoretic molecular karyotype for an industrial strain of Cephalosporium acremonium; Skatrud PL et al.; An electrophoretic molecular karyotype has been established for an industrial strain of Cephalosporium acremonium using transverse alternating field electrophoresis . Eight chromosome bands were detected in gently prepared DNA samples . The size of the chromosomes ranged from approx . 1700 kb up to greater than 4000 kb . The total genomic content for this strain of C . acremonium is at least 22,500 kb . Hybridization analyses revealed that two key genes involved in cephalosporin C biosynthesis are not physically linked to one another . The isopenicillin N synthetase gene (pcbC) resides on chromosome (chr.) VI while the deacetoxycephalosporin C synthetase/deacetylcephalosporin C synthetase gene (cefEF) resides on chr . II . The ribosomal RNA genes were located on chr . VII, while the beta-isopropylmalate dehydrogenase gene (LEU2) was found to be linked to the pcbC gene on chr . VI.

Pathol Biol (Paris), 1989 May, 37(5), 418 - 23
{Cefpiramide, a new cephalosporin with high hepatic elimination; experimental evaluation of its biliary passage and disposition in the liver}; Brogard JM et al.; The biliary elimination and hepatic disposition of cefpiramide were studied using an isolated and perfused rabbit liver model . Five experiments were performed, each lasting 3 hours . After addition of 10 mg of cefpiramide to the circulating blood, the biliary concentration reached a mean peak of 741 +/- 15 micrograms/ml between the 30th and 60th minute; the cumulated biliary elimination of the drug amounted 4042 +/- 1099 micrograms, corresponding to 40.4% of the injected dose . The hepato-biliary clearance was 54.5 ml/hr and the biliary elimination rate constant 0.2019(hr-1) . At the end of the perfusion, 21.7% of the dose was still present in the circulating blood and 1.4% is found in the liver . Control experiments showed that 36.2% of the cefpiramide added into the experimental device was submitted to degradation . Thus, it was possible to calculate the rate of liver biotransformation of cefpiramide, which accounted for 0.3% . These experimental results confirm the major role of the liver in the elimination of cefpiramide and prove that the drug is not submitted to hepatic metabolisation.

J Chromatogr Sci, 1989 May, 27(5), 235 - 9
Drug stability testing by monitoring drug and degradate levels by liquid chromatography; Hayward DS et al.; A cephalosporin antibiotic and its primary degradation product can be separated by a mixed retention mechanism using an ion exchange column and a mobile phase containing acetonitrile and aqueous sodium phosphate . Assay ruggedness, specificity, linearity of response, and standard-sample stability are evaluated and found to be adequate for the desired application . Drug degradation at room temperature in formulations containing citrate and dextrose is found to be roughly first order; fit of the first order rate expression model is better when gain in degradate levels is used as opposed to the direct measurement of drug loss, especially when the magnitude of drug loss is small . The greater accuracy of projections based on the measurement of degradate gain is related to the effect of the imprecision of the analytical measurement on the accuracy of the model.

Pathol Biol (Paris), 1989 May, 37(5), 350 - 2
{Modification of aerobic digestive flora in patients in intensive care during and after treatment with cefmenoxime}; Poisson DM et al.; To evaluate the resistant strains selection during treatment with cefmenoxime, a 3rd generation cephalosporin, 10 adult inpatients of an intensive-care unit had quantitative stool cultures, before the treatment, on the 7-10th day of therapy, and 7-10 days after the end of the antibiotic course . The results show that the selecting effect of cefmenoxime is not different from the effect previously observed for cefotaxime.

Mol Microbiol, 1989 May, 3(5), 689 - 95
Cloning and characterization of beta-lactam biosynthetic genes; Miller JR et al.; Seven genes coding for two different enzymes of the penicillin/cephalosporin biosynthetic pathway have been cloned from fungal and bacterial sources . Using amino acid sequences derived from the purified enzymes, oligonucleotide probes were designed to hybridize to their cognate genes in a genomic library . The high degree of similarity (57%) between enzymes of bacterial and fungal origin suggests a horizontal transfer of a primordial beta-lactam pathway, probably from a bacterial cell to a fungal cell . Overproduction of the proteins in Escherichia coli has allowed further study of the mechanism of action of these important enzymes.

J Oral Maxillofac Surg, 1989 Apr, 47(4), 327 - 30
Pediatric maxillofacial infections: a retrospective study of 113 patients; Dodson TB et al.; This is a retrospective review of 113 hospitalized children with maxillofacial infections . The upper face (orbits, paranasal sinuses, maxillary teeth, and cheeks) was affected most frequently in younger children (mean age = 4.03 years), and the source of infection was often unknown . The patients were treated empirically with a second-generation cephalosporin . Lower-face infections (mandibular teeth, submental, sublingual, and submandibular structures) occurred more frequently in older children (mean age = 5.56 years) and were likely to be of odontogenic origin . Empiric therapy in lower face infections usually consisted of penicillin.

Br J Clin Pract, 1989 Apr, 43(4), 140 - 3
A general practice comparative study of a new third-generation oral cephalosporin, cefixime, with amoxycillin in the treatment of acute paediatric otitis media; Leigh AP et al.; A total of 325 eligible paediatric patients were entered into an open, randomised, multicentre general practice study to assess the comparative efficacy of a new third-generation oral cephalosporin, cefixime, with respect to that of amoxycillin in the treatment of acute otitis media . The dose of cefixime was 100 mg once daily (six months to five years), 200 mg once daily (five to 10 years) and 300 mg once daily (10 to 16 years) . The dose of amoxycillin was as currently used by the participating general practitioners: 62.5 mg tds (six months to one year), 125 mg tds (one to seven years) and 250 mg tds (seven to 16 years) . Both were in the form of an oral suspension . The two groups (160 patients on cefixime and 165 on amoxycillin) were comparable at study entry with respect to all parameters assessed . Overall there was a 95 per cent favourable clinical response seen in both groups (95 per cent confidence limits: 92 and 98 per cent respectively) . Adverse events were comparable in both groups, except that there were more gastrointestinal side effects seen with cefixime (13 per cent) compared with amoxycillin (4 per cent), but only three patients in each group had to be withdrawn because of side effects . These results demonstrate that cefixime given once daily is a safe and effective alternative to amoxycillin in the treatment of acute otitis media in children, and also has the advantage of less frequent dosing.

Jpn J Antibiot, 1989 Apr, 42(4), 930 - 7
{Ceftriaxone as a single agent in empirical therapy of infection in patients with hematologic disorders . Hanshin Infection Study Group}; Kuyama J et al.; For seventy episodes of infection in hematologic disorders mostly during the phase of severe granulocytopenia, a trial was designed to evaluate the efficacy of a new third-generation cephalosporin, ceftriaxone (CTRX) . The regimen consisted mainly of drip infusion of CTRX 2 g every 12 hours . The overall response rate achieved was 54.3 percent . Two episodes of an outpatient with malignant lymphoma were effectively treated by CTRX at a dose of 2-4 g once a day, reflecting its long biological half-life . Gastrointestinal symptoms, hypersensitivity reactions and elevation of hepatic enzyme levels occurred rarely (6.4 and 5.1 percent of the patients, respectively), and these abnormalities were mild and reversible . Thus, CTRX may be recommended as an effective monotherapy in the treatment of infections in immunocompromised patients with hematologic disorders.

J Pharmacobiodyn, 1989 Mar, 12(3), 182 - 5
Facilitated transport of benzylpenicillin through the blood-brain barrier in rats; Suzuki H et al.; The unidirectional influx of benzylpenicillin through the blood-brain barrier was examined with an in situ rat brain perfusion technique using purified {3H}benzylpenicillin . The major transport system of benzylpenicillin through the blood-brain barrier was via a saturable process with a one-half saturation concentration of approximately 8-30 microM . This transport system was significantly inhibited by probenecid (100 microM) and ceftriaxone (2 mM), indicating that the transport system may be shared by some organic anions including third generation cephalosporin antibiotics . These findings suggest that concomitant administration of beta-lactam antibiotics could produce a drug interaction to alter the drug penetration into the central nervous system.

Toxicol Lett, 1989 Mar, 46(1-3), 77 - 82
Potential involvement of renal transport mechanisms in nephrotoxicity; Berndt WO; Among the various physiological factors involved in the development of a nephrotoxic insult, certain renal transport systems may be important . The movement of exogenous organic anions and cations from the blood to the tubular fluid is well recognized . The anion transport system, which has been extensively characterized for the transport of p-aminohippuric acid, may have particular relevance . The nephrotoxic effect of citrinin, certain cephalosporin antibiotics and cysteine conjugates in rats and in isolated renal cells can be blocked by probenecid, a drug known to block the organic anion transporter competitively . The reduction in toxic response is correlated with the renal and cellular content of the nephrotoxic chemical.

Analyst, 1989 Feb, 114(2), 237 - 9
Spectrophotometric determination of certain cephalosporins using molybdophosphoric acid . Part II . Determination of cefadroxil, cefapirin, ceforanide and cefuroxime; Issopoulos PB; The use of molybdophosphoric acid as an oxidising agent for the spectrophotometric determination of four cephalosporin derivatives, viz., cefadroxil monohydrate (I), cefapirin sodium (II), ceforanide L-lysine (III) and cefuroxime sodium (IV), either in the pure form or in pharmaceutical formulations is described . Beer's law is obeyed up to 100 micrograms ml-1 for I, up to 60 micrograms ml-1 for II and IV and up to 80 micrograms ml-1 for III . The molar absorptivities were 4.58 X 10(3), 11.3 X 10(3), 9.8 X 10(3) and 10.9 X 10(3) l mol-1 cm-1 and the Sandell sensitivities were 83.3, 39.3, 53.0 and 41.0 ng cm-2 for I, II, III and IV, respectively . The slopes and intercepts of the equations of the regression line were calculated for each of these drugs with the following correlation coefficients: I, 0.9993; II, 0.9999; III, 1.000; and IV, 0.9999 . These antibiotics were determined successfully both in the pure form and in pharmaceutical preparations . The results demonstrated that the proposed procedure is at least as accurate, precise and reproducible as the official methods, while being simpler and less time consuming . A statistical analysis indicated that there was no significant difference between the results obtained by the proposed procedure and those of the official methods.

J Bacteriol, 1989 Feb, 171(2), 754 - 60
Cloning, characterization, and expression in Escherichia coli of the Streptomyces clavuligerus gene encoding deacetoxycephalosporin C synthetase; Kovacevic S et al.; Biosynthesis of cephalosporin antibiotics involves an expansion of the five-membered thiazolidine ring of penicillin N to the six-membered dihydrothiazine ring of deacetoxycephalosporin C by a deacetoxycephalosporin C synthetase (DAOCS) enzyme activity . Hydroxylation of deacetoxycephalosporin C to form deacetylcephalosporin C by a deacetylcephalosporin C synthetase (DACS) activity is the next step in biosynthesis of cephalosporins . In Cephalosporium acremonium, both of these catalytic activities are exhibited by a bifunctional enzyme, DAOCS-DACS, encoded by a single gene, cefEF . In Streptomyces clavuligerus, separable enzymes, DAOCS (expandase) and DACS (hydroxylase), catalyze these respective reactions . We have cloned, sequenced, and expressed in E . coli an S . clavuligerus gene, designated cefE, which encodes DAOCS but not DACS . The deduced amino acid sequence of DAOCS from S . clavuligerus (calculated Mr of 34,519) shows marked similarity (approximately 57%) to the deduced sequence of DAOCS-DACS from C . acremonium; however, the latter sequence is longer by 21 amino acid residues.

J Pharm Pharmacol, 1989 Feb, 41(2), 136 - 7
Determination of cephalosporin-C amidohydrolase activity with fluorescamine; Reyes F et al.; A spectrophotometric procedure for the assay of cephalosporin-C amidohydrolase activity, based on the determination of the 7-aminocephalosporanic acid (7-ACA) produced in the hydrolysis of cephalosporin-C by the enzyme, is described . This procedure can be used to detect 7-ACA over a range of 10 to 200 micrograms mL-1 . The same method can be used as a fluorometric procedures with a 100-fold greater sensitivity . At pH 4.5 7-ACA produces a strong fluorophor with fluorescamine, detectable spectrophotometrically at 378 nm and fluorometrically at an excitation of 378 nm and emission of 495 nm . At this pH the fluorophors formed with cephalosporin-C, proteins and aminoadipic acid present minimal absorbance values . The conditions for maximal detection of 7-ACA in the presence of proteins, cephalosporin-C and aminoadipic acid have been determined.

Biochim Biophys Acta, 1989 Jan 30, 978(2), 313 - 8
Carrier-mediated transport system for cephalexin in human placental brush-border membrane vesicles; Kudo Y et al.; The uptake of cephalosporin antibiotics, cephalexin, was studied with brush-border microvillous plasma membrane vesicles prepared and purified from human full-term placental syncytiotrophoblasts . The uptake of cephalexin by the membrane vesicles was not stimulated in the presence of an Na+ gradient from the outside to the inside of the vesicles, whereas alpha-(methylamino)isobutyrate uptake into the vesicles of the same preparation was stimulated by an Na+ gradient . The equilibrium level of cephalexin uptake decreased with increasing osmolarity of the medium, which indicates that cephalexin is transported into the membrane vesicles . When cephalexin concentrations were varied, the initial rate of uptake obeyed Michaelis-Menten kinetics with Km and Vmax values of 2.29 mM and 2.98 nmol/mg of protein per 60 s, respectively . The uptake of cephalexin was inhibited by structural analogues and sulfhydryl modifying reagents . These results indicate the existence of a carrier-mediated transport system for cephalexin in the human placental brush-border membranes.

FEMS Microbiol Lett, 1989 Jan 15, 48(2), 145 - 50
Phosphate regulation of ACV synthetase and cephalosporin biosynthesis in Streptomyces clavuligerus; Jhang J et al.; Cephalosporin production by Streptomyces clavuligerus was reduced sharply by 60 mM phosphate added to a chemically-defined medium . All the four synthetases in the pathway examined, i.e., ACV synthetase, cyclase, epimerase and expandase, were repressed by phosphate, with ACV synthetase being the main repression target and expandase the next . ACV synthetase activity was inhibited by phosphate to a lesser extent than expandase and cyclase, and this inhibition could be reversed by adding Fe2+ . Fe2+ itself was inhibitory to ACV synthetase action.

Arthroscopy, 1989, 5(3), 172 - 5
Penetrating knee injuries: the nail gun; Barber FA; Since the development of the nail gun in the 1950s, various reports cite injuries to the head, chest, abdomen, and extremities . Few of these reports mention any nail gun injuries to the knee joint . A total of 33 patients with penetrating injuries to the knee was identified . Of these, 13 had penetrating wounds caused by power nail guns or staplers . The average age was 25 years (range, 17-40) . In 10 of the 13 patients, bone involvement (femur in 6, patella in 2, tibia in 1, and both femur and patella in 1) occurred . Treatment consisted of arthroscopy with irrigation of the knee and nail removal in 10 patients . The other 3 patients underwent arthrotomy in conjunction with nail removal and irrigation . No drains were used postoperatively . I.v . cephalosporin antibiotics were given initially in all cases and were continued orally after hospital discharge . Immediate post injury follow-up varied from a few days to 3 months . Six of the 13 patients were found for follow-up 10-33 months (average 19 months) post injury . All of these returned to full duty in the home construction industry . None developed an infection or needed additional surgery . Based on this series, power nail gun knee joint wounds should have tetanus prophylaxis, arthroscopic evaluation, and irrigation of the knee joint in conjunction with nail removal, i.v . antibiotics for 12-48 h, followed by a 10-day course of oral antibiotics . Unless cultures indicate differently, a first-generation cephalosporin is recommended.

Eur Surg Res, 1989, 21 Suppl 1, 19 - 24
A long-acting cephalosporin in short-term prophylaxis in obstetric and gynecologic surgery; Mancuso S et al.; The efficacy of single-dose (1 g i.v.) ceftriaxone (Rocephin) was evaluated in 175 patients undergoing emergency cesarean section (62 patients) or elective cesarean section (113 patients) . The overall rate of postoperative infectious morbidity was 8% (14/175), with 9.6% (6/62) of the group undergoing emergency surgery and 7.0% (8/113) of the patients choosing elective cesarean section.

Pharmacol Res, 1989 Jan-Feb, 21(1), 51 - 7
Experience with a drug formulary in a large Italian city hospital; Zaccara A et al.; The preparation and distribution of a drug formulary, providing some 377 pharmacological entities together with significant general information, in a large city hospital, enabled the collection of data on the pattern of drug use in this setting . Out of the 377 selected drugs, 27 were never used in the course of one year: most notable among these were the cephalosporin cephalothin, the antifungal griseofulvin, piperazine and the leading anti-H1-blocker terfenadine . Thirteen pharmaceutical preparations were used in over 50,000 doses; among these were the amiloride + hydrochlorothiazide combination, co-trimoxazole and lorazepam . Examination of specific drug series, e.g . of cephalosporins, showed a clear preference for the longer acting ceftriaxone versus a minor use for oral agents, e.g . cefadroxil . There was a wide choice of cardiovascular agents and a relative stability in the preference for major and minor antipsychotics . Outside of the formulary list, only a small number of preparations were requested, among these some traditional analgesic combinations and some extractive products . The provision of a hospital formulary may, in some way, modify drug choice in the hospital, although some established patterns of use are difficult to change . On the other hand, some interesting information was provided on the criteria of choice of hospital physicians.

Fortschr Ophthalmol, 1989, 86(1), 44 - 6
{Retinotoxicity of intravitreous injection of cefmenoxime}; Duncker G et al.; The semisynthetic third generation cephalosporin cefmenoxime was injected through the pars plana into the mid-vitreous in seven rabbit eyes . The drug dosage varied between 0.5 and 15 mg . Seven control eyes were injected only with 0.9% NaCl-solution . Electroretinography was performed before injection and 1 week post injection . The rabbits were anesthetized by intramuscular application of ketanine (Ketanest) . Immediately after the second ERG the eyes were enucleated and prepared for both light and electron microscopy . Light microscopy showed only slight retinotoxic effects . Electron microscopy revealed beginning toxic necrosis of the outer segments of the photoreceptors following drug doses equal to or greater than 2 mg . Significant changes in the ERG were not noted in any of the treated eyes . The toxicity of cefmenoxime and other cephalosporins reported in the literature is discussed together with the clinical relevance of the findings.

Drugs Exp Clin Res, 1989, 15(6-7), 315 - 20
Cefotetan versus piperacillin in the prophylaxis of abdominal and vaginal hysterectomy: a prospective randomized study; Regallo M et al.; A prospective randomized study was carried out on a total of 686 patients who underwent vaginal or abdominal hysterectomy . Of these, 338 were given prophylactic cefotetan (2 g) and 348 piperacillin (2 g) . Both drugs were administered as i.v . bolus 30 min before operation . Findings confirm the higher risk of infection with abdominal hysterectomy and the advantages of the long half-life cephalosporin, cefotetan.

Adverse Drug React Acute Poisoning Rev, 1989 Summer, 8(2), 63 - 72
The nephrotoxicity of cephalosporins; Quin JD; Used alone, the most recently developed cephalosporins are remarkable for their effectiveness and safety . They have a low incidence of relevant nephrotoxicity . All cephalosporins are thought to be potentially nephrotoxic at high doses, and the usual site of damage is the renal tubule . Interstitial nephritis would appear to be much less common . The pathogenesis of nephrotoxicity is therefore thought to be directly dose-related rather than due to hypersensitivity . It is prudent that this be considered when new cephalosporins are evaluated and when the clinician prescribes a cephalosporin, especially when renal function is already compromised.

Eur Surg Res, 1989, 21 Suppl 1, 14 - 8
Ceftriaxone single dose versus ceftazidime multiple doses in the prophylaxis of infection in colorectal surgery; Palla Garcia J et al.; Sixty patients admitted to the hospital for colorectal surgery were randomly assigned to prophylaxis either with a single dose of ceftriaxone (Rocephin) i.v . plus metronidazole given 30 min prior to induction of anesthesia or with multiple doses of ceftazidime plus metronidazole given repeatedly every 8 h up to 24 h after surgery . The overall number of infections observed with the long-acting cephalosporin ceftriaxone was 4 (2 local and 2 remote), with the short-acting ceftazidime the number was 9 (5 local and 4 remote) . Neither regimen was associated with adverse reactions.

Proteins, 1989, 6(3), 275 - 83
Substrate specificities in class A beta-lactamases: preference for penams vs . cephems . The role of residue 237; Healey WJ et al.; Site saturation mutagenesis has been carried out at Ala-237 in RTEM-1 beta-lactamase to assess the role of this site in modulating differences in specificity of beta-lactamases for penams vs . cephems as substrates . (An Ala-237 Thr mutation had previously been shown to increase activity on cephems by about 30-80%.) Screening of all 19 possible mutants on penams and cephems revealed the even more active Ala-237 Asn mutant . Detailed kinetic analysis shows that this mutant has about four times the activity toward cephalothin and cephalosporin C as the wild-type enzyme . Both mutations reduce the activity toward penams to about 10% that of RTEM-1 beta-lactamase and lower by about 5 degrees C the temperature at which the enzyme denatures . Functional properties of the other mutants have also been surveyed . The most interesting aspect of these results is that two quite disparate amino acids, threonine and asparagine, when introduced for Ala-237, cause such similar changes in enzyme specificity while more similar residues do not alter the catalytic properties of the enzyme to such a significant degree.

Rev Laryngol Otol Rhinol (Bord), 1989, 110(1), 123 - 6
{Efficacy and tolerability of cefuroxime-axetil in infections of the upper respiratory tract . Comparative study with cefadroxil}; Dupuis G et al.; Cefuroxime-axetil is the first oral broad spectrum cephalosporin to be naturally stable in the presence of beta-lactamases . The aim of this randomized trial was to evaluate the efficacy and safety of cefuroxime-axetil (250 mg twice daily after meal) with cefadroxil (1 g twice daily during meal) for the treatment of upper respiratory tract infection . In this study 150 patients were enrolled . Before treatment, the two groups were comparable . Clinical success was achieved for 94.3% of the patients treated with cefuroxime-axetil versus 90.4% for cefadroxil . Statistical significance was reached (p less than 0.05) concerning the number of days with facial pain for sinusitis (3 days for the cefuroxime-axetil treated group versus 4 days), the rate of normal tympanum at the second examination (58.3% vs 20% respectively) for otitis, and the number of day with painful dysphagia for tonsillitis (2.6 vs 3.8 days respectively) . Cefuroxime-axetil was safe (a few advers events occurred, almost all gastro-intestinal) . Cefuroxime-axetil is a safe and effective treatment of upper respiratory tract infections.

Hosp Pharm, 1989 Jan, 24(1), 33 - 8
Changing physician prescribing habits through a cost-effective first generation cephalosporin formulary; Cramer R et al.; Cephalosporin antibiotics account for a significant portion (approximately 10%) of our institution's drug budget . A 1985 survey demonstrated that 64% of our first generation injectable cephalosporin (FGIC) orders were for cefazolin . Of the cefazolin orders, approximately 77% used an "every 6 hour" dosage interval . It was thought that this dosage interval was associated with "physician habit" of prescribing similar agents "every 6 hours." By using an "every 8 hour" cefazolin dosage interval in most cases, significant cost savings in the hospital's drug budget could be realized . The Department of Pharmacy and the Pharmacy and Therapeutics (P&T) Committee developed and instituted an FGIC formulary procedure designed to promote the use of cefazolin with an "every 8 hour" dosing interval . Following presentation of literature guidelines to the P&T Committee, measurement of staff physician support through a written survey and presentation of extensive educational programs by the Department of Pharmacy, and FGIC formulary was implemented . The formulary policy included the automatic changing of every 6 hour cefazolin dosing intervals to every 8 hour intervals, with a physician option of "NO SUBSTITUTION." After implementation of the formulary policy, physician prescribing habits for FGIC's changed dramatically . Six months post-formulary, cefazolin accounted for 94% of FGIC prescriptions . Approximately 76% of cefazolin doses were being administered on an "every 8 hour" dosing interval as opposed to 21% prior to formulary implementation . Approximately $45,000 was saved during the first twelve months following formulary implementation . Physicians, pharmacists and nurses have supported the formulary policy.

Pharm Weekbl Sci, 1988 Dec 9, 10(6), 259 - 66
A study of the metal complexation behaviour of some penicillins, cephalosporins and their derivatives; Van Krimpen PC et al.; The metal complexation behaviour of several beta-lactam antibiotics and derivatives is explained, based on the results of potentiometric titrations . The (organo)metal ions used were (organic derivatives of) transition elements and elements with a filled d-subshell . The emphatic class b (organo)metal ions Ag(I), Hg(II) and C6H5Hg(I) form the most stable complexes with the studied ligands: Hg(II) is the most suited ion . The alkaline degradation products and hydroxamic acid derivatives of penicillins and cephalosporins are very similar to penicillamine in their complexation behaviour . This emphasizes the dominant role of the thiol group as site of complexation . A scheme for stepwise complex formation with Hg(II) and Ag(I) is presented . The availability of the thiol group is used to explain small differences in complexation behaviour between penicillin derivatives on the one hand, and cephalosporin derivatives and penicillamine on the other.

Br J Haematol, 1988 Dec, 70(4), 423 - 6
Cefotetan-induced immunologic thrombocytopenia; Christie DJ et al.; Profound thrombocytopenia accompanied by a severe coagulopathy developed in an elderly female patient being treated with cefotetan while undergoing surgery for closure of a perforated gastric ulcer . During the acute phase of the bleeding diathesis, the patient had a platelet count of 12 x 10(9)/l, a prothrombin time of 88 s (normal 10.0-11.8 s) and a PTT of 105 s (normal 23.0-37.0 s) . Potent IgG cefotetan-dependent anti-platelet antibodies, which also were weakly reactive with ampicillin, were detected in the patient's serum using immunofluorescence and a recently developed protein A-agarose rosette forming assay . Unlike typical cephalosporin- and penicillin-induced antibodies that react with cells pretreated with drug, this antibody only reacted with platelets in the presence of exogenous drug . Failure of the antibody to react with drug-coated platelets suggests the possibility that, in this patient, sensitization to cefotetan involved mechanisms other than formation of typical hapten-carrier complexes normally described for members of the cephalosporin family of antibiotics . This appears to be the first definitive report that cefotetan, or any other cephalosporin derivative, can induce immunologic thrombocytopenia.

J Assoc Off Anal Chem, 1988 Nov-Dec, 71(6), 1123 - 30
Reverse-phase liquid chromatographic analysis of cephalosporins; Ting S; A simple and rapid reverse-phase liquid chromatographic method was developed for the qualitative and quantitative analysis of 13 cephalosporin compounds . A mixture of cefaclor, cefadroxil, cefamandole nafate, cefamandole sodium, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftizoxime, cephalothin, cephalexin, cephapirin, and cephradine was resolved into its components in raw material and dosage form samples by using a C18 column, a methanol-water-acetic acid (30 + 70 + 0.1) mobile phase, and a UV detector set at 254 nm . The proposed method is suited both for the determination of cephalosporins in a wide variety of commercial dosage forms and for the investigation of related compounds and other impurities in samples of 7 of the cephalosporins.

Antiviral Res, 1988 Nov, 10(1-3), 59 - 70
Inhibition of HSV-1 and vaccinia virus replication by cephalosporin derivatives; Cottagnoud P et al.; Derivatives of beta-lactam antibiotics of the cephalosporin type at 0.02-1 mM concentrations interfered with in vitro replication of two DNA-containing viruses, herpes simplex I and vaccinia, but showed no effects on two RNA-viruses, lymphocytic choriomeningitis virus and vesicular stomatitis virus, or on cell viability . The exact structure of the active compounds remains unknown, but opening of the beta-lactam ring appears to be a prerequisite for their formation . Whereas cephalosporin derivatives were most active, no active products were obtained from penicillins and monobactams . The potential of these unexpected antiviral effects of widely used beta-lactam antibiotics remains subject of further study.

J Pharm Sci, 1988 Oct, 77(10), 847 - 9
Absorption enhancement of rectally infused cefoxitin by medium chain monoglycerides in conscious rats; Watanabe Y et al.; The enhancing effect of the medium chain monoglycerides glyceryl-1-monoctanoate (GMO), glyceryl-1-monodecanoate (GMD), and glyceryl-1-monododecanoate (GMDD) on rectal absorption of the cephalosporin antibiotic cefoxitin {(6R,7S)-3-hydroxymethyl)-7-methoxy-8-oxo-7-{2-(2-thienyl)acetamido}-5- thia-1-azabicyclo{4.2.0}oct-2-ene-2-carboxylic acid carbamate (ester)} was investigated in unanesthetized rats . Rectal infusion of 3 mg of cefoxitin sodium without monoglyceride resulted in a mean bioavailability of 31 +/- 18% and a mean residence time (MRT) of 134 +/- 44 min . Coadministration with 53% (w/w) GMO significantly enhanced cefoxitin absorption, resulting in a mean bioavailability of 84 +/- 11% and a mean MRT of 75 +/- 8 min . In a lower concentration, GMD (13% w/w) also significantly promoted cefoxitin bioavailability to 68 +/- 14% and reduced MRT to 70 +/- 11 min . With GMDD only, a trend of increasing bioavailability with increasing monoglyceride concentration was observed, which may be explained by its limited aqueous solubility . Concerning the action of GMO and GMD, the longer monoglyceride is, in terms of effective concentration, more potent in enhancing the extent and rate of cefoxitin absorption . However, a further increase in chain length results in a loss of effect, indicating that the effect of monoglycerides on drug absorption may be determined by their intrinsic absorption enhancing action and solubility.

Chemioterapia, 1988 Oct, 7(5), 317 - 9
Ceftizoxime concentrations in human aqueous humor following intravenous administration; Martinelli D et al.; The aqueous humor penetration of the third-generation cephalosporin, ceftizoxime, was determined in 21 patients awaiting cataract extraction, after an intravenous bolus injection of 2 g . The beta-lactam compound achieved a mean peak aqueous humor concentration of 7.8 mg/l two hours after administration with a serum/humor percent ratio ranging between 7 and 16% during the four-hour sampling interval . Therefore, ceftizoxime levels in this extravascular fluid were above the minimum inhibitory concentrations for the majority of sensitive organisms.

Fundam Appl Toxicol, 1988 Oct, 11(3), 450 - 63
Cephalosporin-induced alterations in erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) colony-forming capacity in canine bone marrow; Deldar A et al.; Cephalosporins are among the safest antibiotics . Nevertheless, hematologic abnormalities ranging from mono- to pancytopenia do occur, albeit infrequently, following their therapeutic use . Similar abnormalities to those reported in people have been seen in dogs given high doses of cephalosporins . As part of a study to define the latter thoroughly, we explored the effects of long-term, high-dose cephalosporin administration on canine marrow erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells . Cefazedone (Refosporen, E . Merck, Darmstadt) was administered intravenously at doses of 540 to 840 mg/kg daily to 14 healthy beagle dogs for up to 4 months, or less if hematologic effects were evident earlier . Within 6 to 10 weeks, treated dogs developed pancytopenia (5/14), thrombocytopenia (11/14), moderate to severe neutropenia (8/14), and/or normocytic anemia (8/14) . There was evidence of immune-mediated destruction of peripheral blood cells . All treated dogs exhibited a significant reduction in marrow colony-forming capacity, irrespective of whether peripheral cytopenia was present, with 12/14 showing decreased CFU-GM and 14/14 decreased CFU-E activity . Within a week following cessation of dosing, all affected dogs achieved hematologic remission as defined by restoration of the peripheral blood counts . However, despite this apparent recovery, both CFU-E and CFU-GM activities of the bone marrow remained depressed for at least another 8 months . We conclude that in dogs prolonged administration of high doses of cefazedone induced a persistent deficit of CFU-E and CFU-GM progenitor cells . The clinical relevance of this, if any, remains to be established.

J Pharmacol Exp Ther, 1988 Oct, 247(1), 235 - 41
H+ coupled transport of p.o . cephalosporins via dipeptide carriers in rabbit intestinal brush-border membranes: difference of transport characteristics between cefixime and cephradine; Inui K et al.; We demonstrated previously that aminocephalosporins, such as cephradine, possessing a alpha-amino group and a carboxyl group, are transported via H+/dipeptide carrier system in the intestinal brush-border membranes . The present study examined the transport characteristics of cefixime, a new p.o . cephalosporin with two carboxyl groups, by the rabbit intestinal brush-border membrane vesicles in comparison with those of cephradine . With an intravesicular pH of 7.5, apparent optimum extravesicular pH was 6.0 for cephradine uptake and more acidic (pH 4.5-5.0) for cefixime uptake . An inward H+ gradient {( pH}i = 7.5, {pH}o = 5.0) induced overshoot uptake of cefixime, and this uptake was reduced in the presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, a protonophore . Cefixime uptake at pH 5.0 was trans-stimulated (countertransport effect) and cis-inhibited by dipeptides and aminocephalosporins but not at pH 7.5 . Cephradine uptake at pH 7.5 was stimulated by the countertransport effect of dipeptide but not by cefixime . Cefixime and cephradine uptake at pH 5.0 was greatly inhibited by 4,4'-diisothiocyano-2,2'-disulfonic stilbene . These findings indicate that cefixime is transported by an inward H+ gradient via dipeptide carrier only in an acidic pH region, whereas cephradine is transported via dipeptide carrier in both neutral and acidic pH regions, suggesting the existence of multiple transport systems for dipeptides; a neutral pH preferring system (Type I) and an acidic pH preferring system (Type II).

Biochem Biophys Res Commun, 1988 Sep 15, 155(2), 1082 - 7
Carrier-mediated uptake of cephalexin in human intestinal cells; Dantzig AH et al.; A transport carrier for cephalexin, a cephalosporin antibiotic, was identified in a human intestinal cell line, HT-29 . Uptake via the carrier was inhibited by dipeptides, phe-gly, gly-pro, carnosine, and cefaclor, a close drug analog . Uptake was unaffected by the presence of amino acids . The pH optimum for uptake was 6.2 . Drug uptake was not dependent on the presence of sodium and was insensitive to metabolic inhibitors . The efflux of cephalexin was stimulated by extracellular carnosine, indicating counter-transport . Taken together, drug uptake is mediated by a dipeptide transport carrier and not by an amino acid transport carrier . This is the first demonstration of the carrier in an established cell line.

Aust N Z J Surg, 1988 Sep, 58(9), 733 - 5
Cost-efficiency of a long-acting cephalosporin agent; Hall JC et al.; In a prospective longitudinal study of patients in a general surgical ward, the relative cost-efficiencies of a long-acting third generation cephalosporin (ceftriaxone--mean plasma elimination t 1/2 390 min) and a short-acting second generation cephalosporin (cephamandole: mean plasma elimination t 1/2 32 min) were determined . The total cost of therapy for 24 h was +32.88 for cephamandole and +22.78 for ceftriaxone, that is, a reduction of 31% . Considerable cost containment can be achieved by using third generation cephalosporin agents that only require the administration of one intravenous injection per day.

J Bone Joint Surg Am, 1988 Sep, 70(8), 1221 - 3
High-pressure water-gun injection injuries to the extremities . A report of six cases; Weltmer JB Jr et al.; High-pressure water-gun injection injuries are different from injection injuries that are caused by other agents, in that they are associated with extensive subcutaneous emphysema but only slight soft-tissue inflammation or destruction . The cases of six patients who had such an injury were reviewed . It was found that local irrigation and debridement, together with a short course of penicillin or a broad-spectrum cephalosporin, resulted in complete recovery from this relatively benign variant of high-pressure injection injury.

Ann Thorac Surg, 1988 Aug, 46(2), 172 - 7
Determinants of wound infection incidence after isolated coronary artery bypass surgery in patients randomized to receive prophylactic cefuroxime or cefazolin; Conklin CM et al.; In this open-label, randomized drug study, we compared two cephalosporin prophylactic regimens, one using cefazolin and one using cefuroxime, in 100 patients having coronary bypass surgery . Additional epidemiological data were collected to identify the patient at higher risk for acquiring an infection . Patients were categorized into four groups: (1) no infection; (2) clinically determined infection without a culture or prescription of additional antibiotics; (3) clinical infection with no or negative wound culture and prescription of additional antibiotics; and (4) clinical infection with positive culture and need for additional antibiotics . Seven cefuroxime patients (13.5%) and 9 cefazolin patients (18.8%; p = 0.471) had a wound that became clinically infected (Groups 2-4) . In a univariate analysis, 11 variables were statistically associated with the development of a wound infection . A logistic regression model defined 3 variables at an alpha level of 0.05 and 3 at an alpha level of 0.10 that predicted a wound infection . Patients were identified at high risk of wound infection if they had postoperative weight gain, long operative hospitalization, prolonged use of a Foley catheter, postoperative use of blood products, and operation performed by two specific surgeons . Our results indicated that closer observation of the high-risk patients and a definition of the mechanism of the infections are needed.

Chemioterapia, 1988 Aug, 7(4), 213 - 7
Cephalosporin therapy in intra-abdominal infection: comparative studies of cefotetan, latamoxef and cefoxitin; Wilson SE; Two sequential randomised studies were performed to assess the efficacy of 3 different cephalosporins in the treatment of established intra-abdominal infections . In the first study 102 of 109 (94%) patients given cefotetan 2g iv every 12 hours had a satisfactory clinical response compared to 51 of 56 (91%) patients given latamoxef 2g iv every 8 hours . In the second study cefotetan 2g iv every 12 hours was compared to cefoxitin 2g iv every 6 hours with satisfactory clinical responses in 93 of 95 (98%) cefotetan-treated patients and 41 of 43 (95%) cefoxitin-treated patients . Overall response rates in the two studies were lower in patients with severe peritonitis (82%) or nosocomial infections (70%) . Twelve-hourly dosing with cefotetan appears to be as effective and well tolerated in regional peritonitis as treatment with shorter-acting agents.

J Trauma, 1988 Jun, 28(6), 836 - 9
Popliteal vascular injuries and war: are Beirut and New Orleans similar?
Armstrong K, Sfeir R, Rice J, Kerstein M.
Trauma to the lower extremity associated with fracture and vascular injury has a high reported incidence of limb loss . This study reviews and contrasts the experience at Tulane University affiliated hospitals (TU) and the American University of Beirut (AUB) (1980 to 1984), both of which are surrounded by hostile action . Seventy-six male patients (28--AUB, 48--TU) with an average age of 21.2 (TU) and 24.4 (AUB) years (range, 17 to 42) presented with popliteal artery injuries with (34 {14--AUB; 20--TU} ) and without (42 {14--AUB; 28--TU}) associated fractures . All patients were clinically evaluated, angiogrammed, begun on cephalosporin antibiotics, and operated upon . Fractures were treated with extraskeletal fixation or splinting . Time of initiation of operative therapy varied from less than one to greater than 12 hours . When necessary, contralateral limb reversed saphenous vein was used as an interposition graft . Fasciotomies were done for popliteal artery injuries with greater than 6 hours' ischemic time, and combined popliteal artery and popliteal vein injuries . Nine limbs of 76 at risk were amputated: 5/34 (2/14--AUB; 3/20--TU) with popliteal injuries and fractures, and 4/42 (1/14--AUB; 3/28--TU) with popliteal injuries and without fractures . Five of the amputated limbs had initiation of therapy at greater than 12 hours; three had initiation of therapy at greater than 8 hours . Good communication between surgeons, prompt fracture reduction, antibiotics, angiography, and total repair of the vascular injury resulted in limb salvage in 30/40 patients with popliteal artery injury and fracture, and in 39/42 patients with popliteal artery injury without fracture.(ABSTRACT TRUNCATED AT 250 WORDS)

Jpn J Antibiot, 1988 Jun, 41(6), 641 - 5
{Efficacy of ceftriaxone against infections in the field of obstetrics and gynecology}; Chimura T et al.; Ceftriaxone (CTRX), a newly developed cephalosporin antibiotic, was administered to patients with various bacterial infections in the field of obstetrics and gynecology, and the following results were obtained . 1 . Two grams of CTRX was administered once daily by drip infusion for a total dosage of 6 g to 20 g to each of 3 cases of intrauterine infection, 1 case of adnexitis, 1 case of intrapelvic infection and 2 cases of infection of the external genitalia . 2 . Clinical efficacy of CTRX was good in all cases . No laboratory abnormalities were observed nor subjective or objective adverse reactions occurred during the treatment . The administration of CTRX at a dose of 2 g once daily is a clinically convenient treatment regimen, and its results in satisfactory clinical efficacy.

Am J Surg, 1988 May 31, 155(5A), 61 - 6
Cephalosporin therapy in intraabdominal infections . A multicenter randomized, comparative study of cefotetan, moxalactam, and cefoxitin; Wilson SE et al.; Three broad-spectrum cephalosporins (cefotetan, moxalactam, and cefoxitin) proved effective in this randomized, prospective trial for treatment of 303 surgical patients with moderately severe regional peritonitis.

Biopharm Drug Dispos, 1988 May-Jun, 9(3), 315 - 20
In vitro protein binding interaction studies involving cefixime; Bialer M et al.; Cefixime is a new oral cephalosporin currently undergoing clinical trials . Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man . Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations . In contrast, both salicylic acid and probenecid resulted in concentration-dependent increases in the free fraction of cefixime (up to 2.5-fold) . These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.

Vet Pathol, 1988 May, 25(3), 211 - 8
Cephalosporin-induced changes in the ultrastructure of canine bone marrow; Deldar A et al.; Fourteen healthy dogs were given 540 to 840 mg/kg of cefazedone (Refosporen) intravenously for up to 4 months or until peripheral blood cell count were depressed . Within 6 to 10 weeks treated dogs developed pancytopenia (5/14), thrombocytopenia (11/14), moderate to severe neutropenia (8/14), and/or normocytic anemia with erythroblastemia (8/14) . Ultrastructural changes in bone marrow of severely cytopenic dogs included mitochondrial damage in hematopoietic and nonhematopoietic cells, thickening of endosteal bone lining layers, increased adventitial coverage of vascular sinuses, and an increased number of active macrophages . Swollen, ruptured mitochondria were in erythroid, granulocytic, and megakaryocytic cells, and, to a lesser extent, in macrophages, reticular endothelial, and bone lining cells . Maturation arrest was evident in both erythroid and granulocytic cell lines . There was also evidence of ineffective erythropoiesis and granulopoiesis . None of these changes were observed in bone marrow of controls, treated dogs that did not develop cytopenia, or dogs allowed to recover after cessation of dosing.

J Bacteriol, 1988 May, 170(5), 2319 - 27
Identification of two new cell division genes that affect a high-molecular-weight penicillin-binding protein in Caulobacter crescentus; Nathan P et al.; Penicillin-binding proteins (PBPs) are membrane proteins associated with the synthesis of the bacterial cell wall . We report the characterization of 14 PBPs in Caulobacter crescentus, using in vivo and in vitro penicillin-binding assays and experiments to determine their possible role in cell division . New conditional cell cycle mutants were isolated by selecting cephalosporin-C-resistant mutants of the beta-lactamase strain SC1107 at 30 degrees C that are also defective in cell division at 37 degrees C . They fall into two classes, represented by strains PC8002 and PC8003 . Strain PC8002 produced short cells arrested at all stages of cell division at 37 degrees C and was found to contain a high-molecular-weight PBP 1B which was temperature sensitive when assayed in vivo and in vitro . Strain PC8003 was blocked at an early stage of cell division and formed tightly coiled, unpinched filaments . This cephalosporin-C-resistant strain was also defective in PBP 1B, but only when assayed in vivo . PBP 1B behaved like a high-affinity PBP, and in competition assays, beta-lactams that induced filamentation bound preferentially to PBP 1B . These results and the phenotype of mutant PC8002 suggest that PBP 1B is required for cell division, as well as for cell growth, in C . crescentus . The behavior of strain PC8003 suggests that it contains a conditionally defective gene product that interacts in some way with PBP 1B at an early stage of cell division . None of the mutants showed an allele-specific PBP pattern when assayed in vitro at the nonpermissive temperature, but all of them displayed temperature-sensitive PBP 1C (102 kilodaltons) activity . Thus, it appears that PBP 1C is inhibited at 37 degree C as a consequence of filamentous growth.

J Int Med Res, 1988 May-Jun, 16(3), 197 - 200
A double-blind clinical comparison of two dosage schedules of cefatrizine in children; Careddu P et al.; A double-blind, randomized clinical trial was carried out to compare the effectiveness of twice daily versus once daily administration of the cephalosporin, cefatrizine, in paediatric outpatients with bacterial infection of the respiratory tract . Thirty children were studied, aged 7 years 2 months (range, 4-12 years) . They were given 75 mg/kg.day cefatrizine either once daily or twice daily at 12 h intervals for 8 days . Fever, clinical symptoms, bacterial eradication and overall tolerance were evaluated . No significant differences were observed between once daily or twice daily administration . This is in agreement with other studies carried out on adults . It is concluded that cefatrizine may be given to paediatric out-patients for the treatment of bacterial infection of the respiratory tract only once daily with good clinical and overall results.

Pathol Biol (Paris), 1988 May, 36(5), 511 - 2
{Do imipenem and cilastatin interfere with the determination of serum creatinine?}; Dauchy F; Some cephalosporin antibiotics increase the concentration of serum creatinine . This phenomenon could be due to the interference on the method of dosage, in particularly when the Jaffe reaction is used . This interaction could be present with imipenem, an antibiotic of thienamycins group having a chemical structure similar to that of cephalosporins, (associated with cilastatin in the tienam), in which we find the structure common to creatinine (Formula: see text) considered to be responsible of this interference . Our work indicates that with serum concentration of 100 mg/l, superior to those obtained in therapeutic, neither imipenem nor cilastatin interact on the creatinine dosage using either the Jaffe reaction of the enzymatic technic.

Antibiot Khimioter, 1988 May, 33(5), 327 - 30
{Pathways of the synthesis of glutamic acid by cephalosporin C-producing Acremonium chrysogenum}; Krakhmaleva IN et al.; There were observed two pathways of glutamic acid formation in two strains of Acremonium chrysogenum differing in the production levels of cephalosporin C . The pathway involving glutamate dehydrogenase is known . The other pathway involved amination catalyzed by glutamine synthetase . Activity of both the enzymes during intensive synthesis of the antibiotic was higher in the highly productive strain . Under conditions of limited nitrogen content in the medium production of glutamate during the antibiotic biosynthesis depended on glutamine synthetase . When there was an excess of nitrogen in the medium the main role in production of glutamic acid at the phase of cephalosporin synthesis was played by the other enzyme i . e . glutamate dehydrogenase . By the dynamics the curve of the glutamate dehydrogenase activity correlated with that of the antibiotic production.

J Pharm Pharmacol, 1988 May, 40(5), 329 - 32
Rate-controlled absorption enhancement of rectally administered cefazolin in rats by a glyceride mixture (MGK); van Hoogdalem EJ et al.; The enhancing effect of the medium chain glyceride preparation MGK on the rectal absorption of the cephalosporin antibiotic cefazolin sodium was evaluated in relation to the rate of delivery . Cefazolin sodium proved to be absorbed to a small extent (15 to 27%) after rectal administration without MGK . Bolus administration with MGK enhanced rate and extent of cefazolin sodium absorption, resulting in a bioavailability of 57 +/- 26% . Linear infusion of 3 mg cefazolin sodium with MGK in 32 min produced complete absorption of the antibiotic (102 +/- 7%), but absorption occurred slower in comparison with bolus delivery . The rate of administration proved to be an important variable of the absorption enhancing effect of MGK.

Can J Hosp Pharm, 1988 Apr, 41(2), 73 - 4, 83-4, 96
Methods of controlling cephalosporin use in Canadian hospitals; Godin JP et al.; Cephalosporin antibiotics contribute significantly to hospital antibiotic costs . A survey was conducted to determine cephalosporin use and prescribing control in Canadian hospitals over 300 beds . Of the 125 hospitals surveyed, 84 responses were received; 76 were included in data analysis . Thirty-two percent of hospitals had no restriction policies for intravenous cephalosporins and 88 percent had none for oral cephalosporins . Restrictions were more common for the second and third generation agents . The most common method of restricting cephalosporins was by requiring consultation with an infectious disease service . The yearly cost of cephalosporins varied considerably and was unrelated to the number of beds in the hospital . The data provided allows hospitals to compare their use of cephalosporin antibiotics with other institutions in Canada.

Infection, 1988 Mar-Apr, 16(2), 105 - 8
Platelet function and coagulation in patients with hepatobiliary disorders receiving cefotetan prophylaxis; Triger DR et al.; Eighteen patients with hepatobiliary disorders undergoing invasive biliary tract investigations were given the cephalosporin cefotetan and platelet function and coagulation factors were monitored . No significant changes were observed in the group as a whole, although marked alterations were seen in three patients in association with clinical complications unrelated to the antibiotic . Although cefotetan is structurally similar to cephalosporins which have been associated with bleeding disturbances, it does not appear to induce such abnormalities in a high risk group of patients with normal renal function when given for five days intravenously at a dose of 1 g twice daily.

J Clin Pharmacol, 1988 Mar, 28(3), 253 - 8
Phase I clinical studies of 7432-S: effect of 7432-S on platelet aggregation and blood coagulation; Nakashima M et al.; The effects of 7432-S, a new oral cephalosporin antibiotic, on platelet functions and vitamin K-dependent blood coagulation parameters were studied in human volunteers and animals . Although the ADP- and collagen-induced aggregations of human and animal platelets were inhibited in vitro by extremely high concentrations of 7432-S, the inhibitory effect of 7432-S was weaker than that of latamoxef or cefotaxime . When administered orally to human volunteers or animals, 7432-S caused no inhibition of platelet aggregation . Its administration also caused no change in prothrombin time and activated partial thromboplastin time both in human volunteers and in rats . The conclusion reached was that the new oral antibiotic 7432-S does not affect platelet functions and blood coagulation.

Jpn J Antibiot, 1988 Feb, 41(2), 216 - 24
{Pharmacokinetic and clinical studies on ceftriaxone in the perinatal period}; Hirabayashi K et al.; Ceftriaxone (CTRX), a new cephalosporin antibiotic, was studied for its pharmacokinetic features and clinical efficacy in the perinatal period and the obtained results are summarized below . 1 . Following a one shot intravenous injection of 1 g of CTRX into each of 29 parturient women, CTRX levels were between 4.5 and 19.5 micrograms/ml at 6 hours postdose and between 4.5 and 4.7 micrograms/ml at 24 hours postdose in the amniotic fluid and between 11.7 and 22.7 micrograms/ml at 6 hours postdose and between 4.5 and 4.7 micrograms/ml at 24 hours postdose in the umbilical cord serum . It was shown that CTRX was maintained there at high levels for a long time and the transfer of CTRX into the umbilical cord serum was better than that of other antibiotics . 2 . Following a one shot intravenous injection of 1 g of CTRX into each of 12 cases of puerpera, CTRX was detected in the mother's milk until 10 hours postdose, though at a very low level averaging 0.32 to 0.79 microgram/ml . It was considered, however, that CTRX affected little infants through the mother's milk . 3 . CTRX was evaluated to be very effective in 2, effective in 5 and ineffective in 1, of 8 cases of infections during the perinatal period . From the above results, CTRX appeared to be effective against infections during the perinatal period.

Vet Hum Toxicol, 1988 Feb, 30(1), 66 - 7
The effects of penicillin and cephalosporin ingestions in children less than six years of age; Swanson-Biearman B et al.; Oral antibiotic ingestions account for 1-2% of all pediatric exposures reported to regional poison information centers . The majority of these pediatric exposures involve the ingestion of penicillin or cephalosporin derivatives . How much can be ingested before gastric emptying is necessary is a controversial issue in the management of these cases . A study was designed to determine if children less than 6 years of age could safely ingest a maximum of 250 mg/kg of a penicillin or cephalosporin derivative without significant adverse effects . Sixty-one cases were prospectively collected . The average antibiotic amount ingested was 113.3 mg/kg (17.8-250.0 mg/kg) . Each patient was evaluated for symptoms at the time of the initial call and at 6-12 degrees, 24 degrees, 48 degrees, and 72 degrees . Eighty-four percent of the children remained asymptomatic during the evaluation period . Eight of 13 symptomatic patients developed 1 or 2 episodes of diarrhea; 2 developed a rash . Amoxicillin suspension was involved in 70% of the cases, followed by cefachlor suspension 11%, and amoxicillin tablets 5% . Liquid preparations accounted for 90% of the cases and solid dosage forms, the remainder . The data strongly suggests that ingestions of less than 250 mg/kg of these products are not associated with significant outcomes and do not require gastric emptying.

J Pharmacol Exp Ther, 1988 Feb, 244(2), 520 - 5
Mechanisms of the bacterial endotoxin-cephaloridine toxic synergy and the protective effects of saline infusion in the rabbit kidney; Tune BM et al.; To examine the mechanisms of the nephrotoxic synergy of bacterial cell wall lipopolysaccharide (LPS) (or endotoxin) and the cephalosporin antibiotics, we have studied: 1) the effects on mean arterial blood pressure and the clearances of inulin, p-aminohippurate and cephaloridine (Cld) of a 12%-lethal dose of Escherichia coli 0111-B4 LPS (0.05 mg/kg b.wt.i.v.), with both low and high rates of saline infusion (0.1 ml/min vs . a 7.5-ml/kg load followed by 0.4 ml/min, respectively, in approximately 2-kg rabbits); 2) the separate and combined effects of LPS and saline infusion on the concentrations of Cld in renal cortex and serum; and 3) the separate and combined effects of LPS and saline infusion on the nephrotoxicity of Cld, quantified by acute tubular necrosis scoring and serum creatinine concentrations 48 hr after treatment with 90 mg/kg of Cld i.v . and by mitochondrial respiratory toxicity, depletion of reduced glutathione and production of lipid peroxidation products in renal cortex 1 hr after treatment with 90 to 360 mg/kg of Cld i.v . The following was found: 1) the increased saline infusion (saline) largely prevented an LPS-induced fall of inulin clearance and partially prevented a fall of blood pressure and p-aminohippurate and Cld clearance; 2) as a result, saline prevented slightly elevated late serum and cortical Cld concentrations in LPS-treated animals; 3) the tubular necrosis and elevation of serum creatinine caused by Cld alone was reduced slightly and that produced by the combination of LPS plus Cld was reduced greatly by saline; 4) the comparable mitochondrial respiratory toxicity found after Cld and LPS-plus-Cld was prevented by saline infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Vet Rec, 1988 Jan 2, 122(1), 15 - 7
Pharmacokinetics of cephalexin in dogs and cats after oral, subcutaneous and intramuscular administration; Silley P et al.; A three-way crossover study was carried out in 10 dogs and nine cats to establish the pharmacokinetic parameters of the semi-synthetic cephalosporin antibiotic, cephalexin sodium, when administered orally, subcutaneously or intramuscularly . Ten dogs received a subcutaneous or intramuscular injection of 10 mg/kg bodyweight cephalexin or an oral dose of three 50 mg cephalexin tablets; the peak serum concentrations achieved were 24.9, 31.9 and 18.6 micrograms/ml, respectively, and the times taken to reach these peak levels were 1.2, 0.9 and 1.8 hours . Nine cats received either a subcutaneous or intramuscular dose of 0.25 ml cephalexin suspension (approximately 20 mg/kg bodyweight) or an oral dose of one 50 mg tablet; the peak serum concentrations achieved were 54.0, 61.8 and 18.7 micrograms/ml for the subcutaneous, intramuscular and oral administrations respectively, with times to peak concentrations of 1.1, 0.7 and 2.6 hours.

Pharmazie, 1988 Jan, 43(1), 18 - 9
The comparative stability of different types of penicillin and cephalosporin N-pyrryl derivatives; Arin MJ et al.; The kinetics of the decomposition of potassium salts of 4-thia-1-azabicyclo{3.2.0.}heptane-3,3-dimethyl-6-amino-7-oxo-N- {2(1H-pyrrolyl)acetyl} -2-carboxylic acid (6R, trans), 4-thia-1-azabicyclo{3.2.0}heptane-3,3-dimethyl-6-amino-7-oxo-N-{2-phenyl - 2(1H-pyrrolyl)acetyl}-2-carboxylic acid (6R, trans), 5-thia-1-azabicyclo{4.2.0.}oct-2-ene-3- {(acetyloxy)methyl}-7-amino-8-oxo-N-{2(1H-pyrrolyl)acetyl}-2-ca rbo xylic acid (6R, trans), 5-thia-1-azabicyclo{4.2.0.}oct-2-ene-3- {(acetyloxy)methyl}-7-amino-8-oxo-N-{2-phenyl-2(1H-pyrrolyl)acetyl }- 2-carboxylic acid (6R, trans), 5-thia-1-azabicyclo{4.2.0.}oct-2-ene-7-amino-3-methyl-8-oxo-N- {2(1H-pyrrolyl)-acetyl}-2-carboxylic acid (6R, trans) and 5-thia-1-azabicyclo{4.2.0.}oct-2-ene-7-amino-3-methyl-8-oxo- N-{2-phenyl-2(1H-pyrrolyl)acetyl}-2-carboxylic acid (6R, trans), in aqueous solution at 37 degrees C and at ionic strength of 0.5 mol.l-1 have been studied over the 2.3-11.5 pH range . In all cases, the hydrolysis of these compounds is subject to acid-base catalysis and, in some instances, to a general catalysis by various species present in the buffer solutions . The experimental results have been analyzed and discussed in relation to the hydrolytic mechanisms.

J Clin Chem Clin Biochem, 1988 Jan, 26(1), 15 - 24
{A kinetic method for the direct determination of creatinine in serum with 3,5-dinitrobenzoic acid without deproteinization}; Sabbagh M et al.; A kinetic method is reported for the determination of creatinine in serum without deproteinization, using alkaline 3,5-dinitrobenzoate solution . The increase in absorbance at 546 nm due to the formation of an orange-red complex is measured . The relationship between the creatinine concentration and absorbance was linear up to a tested concentration of 8840 mumol/l in the aqueous standard solution . Recovery of added creatinine was 98-102% . Compared with the procedure of Jaffe, as modified by Helger et al . (Z . Klin . Chem . Klin . Biochem . 12, 344-349 (1974}, the present method shows less interference by pseudo-creatinine chromogens, and no interference by high serum concentrations of bilirubin or triacylglycerols . The measured serum concentration of creatinine was not affected by cephalosporin therapy . Interferences and side reactions have been minimized or eliminated by optimization of the concentrations of all reactants and of the measurement time . The described procedure can, however, only be performed in an instrument, which permits the measurement of absorbance changes in short time intervals after the start of the reaction . In comparative studies on 212 sera, the dinitrobenzoate method and the enzymic UV-test gave similar results, whereas the Jaffe method as modified by Helger et al . gave significantly higher values.

J Clin Pharmacol, 1988 Jan, 28(1), 88 - 95
Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status; Shearer MJ et al.; The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status . Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not . The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon . Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested . Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy . Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes . Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days . The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.

Drug Intell Clin Pharm, 1988 Jan, 22(1), 54 - 7
Compatibility of clindamycin phosphate with aztreonam in polypropylene syringes and with cefoperazone sodium, cefonicid sodium, and cefuroxime sodium in partial-fill glass bottles; Marble DA et al.; The stability and compatibility of clindamycin phosphate admixed with four beta-lactams, an experimental monobactam (aztreonam), and three cephalosporins (cefoperazone sodium, cefonicid sodium, and cefuroxime sodium), were studied . Aztreonam alone and the combination of clindamycin phosphate-aztreonam were prepared in duplicate polypropylene syringes . Each cephalosporin antibiotic as well as the three clindamycin phosphate-cephalosporin combinations were admixed in duplicate 100 ml partial-fill glass bottles containing either dextrose 5% in water or NaCl 0.9% . All solutions were examined, antibiotic concentrations were determined, and pH was measured at the time of admixture and 1, 4, 8, 12, 24, and 48 hours later . The solutions were maintained at room temperature under fluorescent lighting for the length of the study . Antibiotic concentrations were determined by drug-specific high performance liquid chromatographic assays . Significant instability or incompatibility was defined as a decrease in concentration of greater than ten percent relative to the initial concentration measured at the time of admixture . All antibiotics were stable for 48 hours . In the combination studies, clindamycin was stable for 48 hours, both in partial-fill glass bottles and syringes . Aztreonam, cefoperazone, cefonicid, and cefuroxime were also stable for 48 hours.

Life Sci, 1988, 42(19), 1809 - 16
Biochemical mechanisms of cephaloridine nephrotoxicity; Goldstein RS et al.; Large doses of the cephalosporin antibiotic, cephaloridine, produce acute proximal tubular necrosis in humans and in laboratory animals . Cephaloridine is actively transported into the proximal tubular cell by an organic anion transport system while transport across the lumenal membrane into tubular fluid appears restricted . High intracellular concentrations of cephaloridine are attained in the proximal tubular cell which are critical to the development of nephrotoxicity . There is substantial evidence indicating that oxidative stress plays a major role in cephaloridine nephrotoxicity . Cephaloridine depletes reduced glutathione, increases oxidized glutathione and induces lipid peroxidation in renal cortical tissue . The molecular mechanisms mediating cephaloridine-induced oxidative stress are not well understood . Inhibition in gluconeogenesis is a relatively early biochemical effect of cephaloridine and is independent of lipid peroxidation . Furthermore, cephaloridine inhibits gluconeogenesis in both target (kidney) and non-target (liver) organs of cephaloridine toxicity . Since glucose is not a major fuel of proximal tubular cells, it is unlikely that cephaloridine-induced tubular necrosis is mediated by the effects of this drug on glucose synthesis.

J Antibiot (Tokyo), 1988 Jan, 41(1), 113 - 22
Role of the cephalosporinase gene in the resistance of the clinically isolated cephem-resistant Escherichia coli; Aramori I et al.; A small number of highly cephem-resistant strains was found in extensive susceptibility testing of clinical isolates of Escherichia coli to the new cephalosporin derivatives . The cephem-resistance of these clinical isolates appeared to be due to the increased cephalosporinase activities . To clarify the mechanism of the resistance, we cloned the cephalosporinase genes from two typical cephem-resistant clinical isolates as well as from an E . coli K-12 strain . The following two lines of evidence indicated that the cephem-resistance resulted from hyper production of the cephalosporinase due to the up-mutation of the regulatory sequence of the cephalosporinase gene . 1) Reciprocal exchange of the regulatory sequence including a short segment of N-terminal coding sequence and the rest of the coding sequence between the cephalosporinase genes from E . coli K-12 and the cephem-resistant clinical isolate showed that the higher cephalosporinase activity was accompanied by the regulatory sequence of the cephalosporinase gene from the clinical isolate . 2) The promoter activities of the cephalosporinase genes were determined by cloning the regulatory sequences into a promoter analysis vector . The promoter activities of the cephalosporinase genes from the clinical isolates were 23-33-fold higher than that of the cephalosporinase gene from E . coli K-12.

Arch Toxicol, 1988, 62(6), 458 - 64
Nephrotoxic potential of first-, second-, and third-generation cephalosporins; Cojocel C et al.; First-, second-, and third-generation cephalosporins were investigated for their peroidative and nephrotoxic potential . Renal cortical slices from male Wistar rats were incubated at 37 C for 1 h in a phosphate-buffered medium containing the cephalosporin (1.25, 2.5, 5 or 10 mg/ml) . In another series of experiments 5 mg/ml cephalosporin was incubated under the same conditions for 30, 60, 90 and 120 min . Subsequently, slices were incubated for 60 or 90 min in a bicarbonate- or phosphate-buffered medium containing pyruvate or tetraethylammonium (TEA) to determine gluconeogenesis and TEA accumulation, respectively . The peroxidative potential was determined at the end of the first incubation by measuring the increase in the malondialdehyde (MDA) content in renal cortical slices . The nephrotoxic potential was determined at the end of the second incubation by measuring the decrease in accumulation of the organic ion (TEA) and decrease of pyruvate-stimulated gluconeogenesis in renal cortical slices . First-generation cephalosporins, cephaloridine and cephalothin showed a time- and concentration-dependent increase in MDA content and a decrease in TEA accumulation and gluconeogenesis by renal cortical slices . Cefazolin, another first generation cephalosporin, showed a weak peroxidative and practically no nephrotoxic potential . In the group of second-generation cephalosporins, cefotiam showed a weak peroxidative potential comparable to that of cefoxitin but had a much greater nephrotoxic potential which was similar to that of cephaloridine . The third-generation cephalosporins, cefotaxime and cefoperazone showed a low peroxidative and no nephrotoxic potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Drugs Exp Clin Res, 1988, 14(8), 519 - 27
Experimental and clinical evaluation of the biliary pharmacokinetic profile of cefpiramide, a new cephalosporin with high hepatic elimination; Brogard JM et al.; Biliary elimination of cefpiramide was studied experimentally and in human subjects using chromatography (HPLC) . During a 3-h perfusion of five isolated rabbit liver preparations, 40.4% of cefpiramide added to the circulating blood was eliminated in the bile and only 0.3% was metabolized in the liver . In five healthy subjects, after a single intravenous administration of 1 g of cefpiramide, a maximal concentration of 339 +/- 107 micrograms/ml was reached during the 2nd hour in the collected duodenal fluid, and 1.23 +/- 0.20% of the given dose was recovered within 4 h . In ten cholecystectomized patients provided with a T-tube, intravenous injection of 1 g of cefpiramide resulted during the 2nd hour in a biliary peak concentration of 1161 +/- 392 micrograms/ml . The total amount of antibiotic eliminated in the bile over 24 h averaged 231.5 +/- 39.1 mg, corresponding to 23.2 +/- 3.9% of the administered dose . Hepatic clearance was 3.13 ml/h . Intraoperative specimens sampled simultaneously 1 h after intravenous administration of 1 g of the antibiotic in ten patients undergoing cholecystectomy showed cefpiramide concentrations of 157 +/- 21 micrograms/ml in serum, 1726 +/- 501 micrograms/ml in choledocal bile, 84 +/- 33 micrograms/ml in gall-bladder bile and 22.6 +/- 4.2 micrograms/g in gall-bladder wall . These data emphasize the excellent biliary tropism of cefpiramide, and compare favourably with results concerning 19 other beta-lactams previously studied under the same conditions . They constitute a good prerequisite for possible beneficial treatment of biliary tract infections.

J Ocul Pharmacol, 1988 Winter, 4(4), 345 - 9
Toxicity and pharmacokinetics of cefepime (BMY-28142) following intravitreal injection in pigmented rabbit eyes; Jay WM et al.; We delineated the dose- and time-dependent retinal toxicity of cefepime (BMY-28142), a new third generation cephalosporin, using electroretinography in pigmented rabbit eyes . Toxicity was evaluated following intravitreal doses ranging from 0.5 to 20mg/0.1ml (N = 18) . Electroretinographic patterns at one and two weeks indicated a toxic response to 20 mg of cefepime . B-waves were normal at one and two weeks for rabbits receiving doses of 0.5 to 10mg . Pharmacokinetic analysis after single intravitreal injection of 1 mg of cefepime (N = 3 rabbits/dose) disclosed the following vitreous fluid levels (ug/ml): 645 at Oh, 431 at 8h, 235 at 24h and 23 at 72h . Peak aqueous humor levels (56 ug/ml) were observed at 8h after injection . At 72h, ug/ml was detected in the aqueous fluid.

Clin Neurol Neurosurg, 1988, 90(4), 369 - 71
Myoclonic activity associated with cefmetazole, with a review of neurotoxicity of cephalosporins; Uchihara T et al.; We reported a case of a 66-year-old female with uremia who developed myoclonic activity after administration of cefmetazole (4g/2 days) . Curiously, the level of the antibiotics (236 micrograms/ml) in the cerebrospinal fluid (CSF) was higher than that in the blood (103 micrograms/ml) . Myoclonic activity faded away after cessation of the antibiotics . This is the first case reported developing neurotoxicity associated with intravenous administration of cefmetazole . In addition, the curious pharmacokinetic dynamics of cephalosporin in uremia is discussed.

Nephrol Dial Transplant, 1988, 3(2), 221 - 4
Cefodizime: a new cephalosporin with apparent immune-stimulating properties in chronic renal failure; Vanholder R et al.; In vitro experiments suggest that cefodizime, a new cephalosporin, causes an increase in phagocytic capacity . We therefore evaluated the effect of cefodizime on the phagocytic system in haemodialysis patients by an estimation of the 14CO2 production during glucose metabolisation by phagocytic cells, in the resting state, and after zymosan and latex . The production of 14CO2 after latex increased in five of six patients (mean +/- SD: from 17,932 +/- 11,859 before to 21,183 +/- 7849 d.p.m . at the end of treatment) . The corresponding data after zymosan were 48,381 +/- 24,891 and 70,176 +/- 15,140 d.p.m . The improved 14CO2 production after stimulation persisted for 2 further weeks . These results suggest a stimulation in vivo of the depressed phagocytic system of the uraemic patient by cefodizime.

Drug Nutr Interact, 1988, 5(4), 195 - 203
Drug and nutrient interactions in the elderly diabetic; Roe DA; Elderly diabetics take more drugs than other groups of elderly patients . Their multiple drug use is largely explained by the drugs that they take for complications of their primary disease; these include cardiovascular drugs for macrovascular disease and antibiotics for secondary infections . They also take more drugs for control of other conditions that are etiologically associated with the development and progression of their diabetes, including antihypertensive agents, antilipemic agents and steroids, and nonsteroidal antiinflammatory drugs (NSAIDs), which are taken for relief of joint pain that is intensified by arthritic joints bearing excess weight . Drugs taken by elderly diabetics that contribute to the high prevalence of drug-nutrient interactions include those taken as antidiabetic agents, including both insulin and sulfonylureas as well as calcium channel blockers; they also include thiazides, loop diuretics, sulfa drugs, cephalosporin antibiotics, tetracyclines, antifungal agents, cholestyramine and colestipol, niacin, prednisone and other corticosteroids, and NSAIDs . These drugs and drug combinations contribute to the risk of hyperglycemia, which can cause nonketotic hyperglycemia in the elderly; to the risk of hypoglycemia, which in the elderly carries the risk of inducing pseudo-stroke; to the risk of drug-induced nutritional deficiencies from antilipemics and cephalosporins, which can induce vitamin K deficiency; to the risk of acute incompatibility reactions, including flush reactions from chlorpropamide, niacin, and calcium channel blockers; and to the risk of edema, anemia, and hyperkalemia from NSAIDs.(ABSTRACT TRUNCATED AT 250 WORDS)

Dermatologica, 1988, 177(5), 292 - 4
Generalized eruptive pustular drug rash due to cephalexin; Jackson H et al.; A 38-year-old woman developed a generalized pustular eruption 18 h after taking an oral cephalosporin (cephalexin) . After having excluded other possible pustular dermatoses, we concluded that our patient's eruption was drug-induced.

Drug Metab Dispos, 1988 Jan-Feb, 16(1), 130 - 4
Disposition of cefixime in the pregnant and lactating rat . Transfer to the fetus and nursing pup; Halperin-Walega E et al.; The disposition of cefixime, a potent, third generation, orally active cephalosporin, was characterized in the pregnant and lactating rat . After a single iv dose of 17.8 mg/kg 14C-cefixime to day 18 pregnant rats, the half-life for elimination of radioactivity from both maternal serum and placentas was 6.9 hr . Elimination from fetal plasma and tissues was somewhat longer, 12.5 and 13.7 hr, respectively . However, comparison of areas under the curve indicated that exposure of the fetuses to cefixime was far less than that of placentas . Whole body autoradiography showed the greatest radioactivity in maternal liver, kidney, and intestines . In the lactating rat, steady state plasma concentrations of 14C-cefixime were achieved by continuous ip infusion of 2.54 mg/kg/day via Alza osmotic Mini-pumps from days 10 to 14 postpartum . Plasma concentrations of radioactivity in the dams were, on the average, 70 times greater than in their nursing pups throughout the study . After 102 hr of drug infusion, total radioactivity in the body of the pups, including the stomach and intestinal contents, was 1% of the 14C-cefixime estimated to be in the mother's body at steady state . Overall, these data indicate that exposure of the developing rat fetus and nursing pup to cefixime after maternal drug administration is quantitatively small.

Drug Metabol Drug Interact, 1988, 6(3-4), 317 - 26
Mechanism of thioamide antithyroid drug associated hypoprothrombinemia; Lipsky JJ et al.; The thioamide class of antithyroid drugs has been associated with the development of hypoprothrombinemia . Two drugs in this class, propylthiouracil and methimazole, resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics . Both were found in vitro to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid with 50 per cent inhibitory concentrations of 2 mM for propylthiouracil and 0.1 mM for methimazole . Methimazole was also found to inhibit vitamin K epoxide reductase, an enzyme related to the carboxylation reaction, with a 50 per cent inhibitory concentration of 25 uM . In vivo methimazole, administered twice at a dose of 500 mg/kg to rats on a vitamin K deficient diet produced hypoprothrombinemia . These results suggest that the mechanism of hypoprothrombinemia associated with thioamide antithyroid drugs may be similar to the mechanism of hypoprothrombinemia associated with cephalosporins which contain the methyltetrazole-thiol leaving group.

FEBS Lett, 1987 Dec 10, 225(1-2), 218 - 22
The importance of the negative charge of beta-lactam compounds for the inactivation of the active-site serine DD-peptidase of Streptomyces R61; Varetto L et al.; The interaction between the Streptomyces R61 penicillin-sensitive DD-peptidase and deacetyl-cephalosporin C or its lactone derivative has been studied at different pH values . The results show the importance of an enzyme group of pK approximately equal to 9 which might form an ion pair with the free carboxylate of the former compound . This electrostatic interaction is shown to contribute to the formation of the first, non-covalent enzyme-inactivator complex by a factor of at least 50.

Tex Heart Inst J, 1987 Dec, 14(4), 374 - 81
Cefamandole prophylaxis for cardiovascular surgery: a dosage comparison; Zeluff BJ et al.; For more than a decade, studies have indicated that antibiotic dosing immediately before and for a short time after surgery is effective in reducing the incidence of infectious complications of open-heart operations . At our institution we have used cefamandole, because of its broad spectrum of activity against bacteria common to the skin and respiratory system and its low toxicity . However, in response to more recent studies that threw doubt on the ability of the recommended dosing regimen (1.0 g given intravenously every six hours for three days) to maintain adequate intraoperative levels of cefamandole in heart tissue, we undertook an evaluation of a dosage of 2.0 g given intravenously every 6 hours for two days . This was a randomized study of 211 successive, evaluable, open-heart surgery patients who had no concurrent infections or cephalosporin allergy . Postoperatively, there were eight surgery-related infections (3.9%) and eight nosocomial infections in the 2.0-g dose group, compared with seven surgery-related infections (3.5%) and seven nosocomial infections in the 1.0-g dose group . These differences were not statistically significant . Tissue levels and cardiopulmonary bypass pump time were not risk factors for infection . We conclude that the 2.0-g doses over two days are no more effective than the 1.0-g doses over three days . However, when administration fees are considered, in a cost comparison, the 2.0-g dosing regimen is more economical than the 1.0-g regimen . (Texas Heart Institute Journal 1987; 14:374-381)

Chemioterapia, 1987 Dec, 6(6), 417 - 9
Influence of ceftizoxime on the immune system; Leonardi MS et al.; In the last few years the interest about the influence on host/parasite relations exerted by antibiotics has increased . In this study we have studied the effect of ceftizoxime, a third generation cephalosporin, on some functional parameters of human macrophages and granulocytes . Ceftizoxime does not seem to exert any stimulatory effect on phagocytosis and chemotaxis, but at the same time it allows these cells to explicate their functions during an infective process . A separate series of experiments was designed in order to investigate the immunogenicity of ceftizoxime and its immunological cross-reactivity versus other beta-lactam antibiotics . The low ELISA title of ceftizoxime indicates its weak immunogenic power . Cross-reactivity was also very low (title 1:25) when ceftizoxime was tested against the other antibiotics.

J Antimicrob Chemother, 1987 Dec, 20(6), 913 - 8
Absence of disulfiram-type reactions to single and multiple doses of cefonicid: a placebo-controlled study; McMahon FG et al.; Disulfiram-type reactions after ingestion of alcohol have been reported in patients treated with a number of cephalosporin antibiotics; predominantly with agents containing the methylthiotetrazole side chain, although other similar configurations have also been implicated . Since cefonicid has a sulphonic acid thiotetrazole substitution, we investigated the possibility of a cefonicid-ethanol interaction in 15 healthy volunteers . During the first two crossover phases of the study, single 1 g doses of cefonicid followed by ethanol challenges were compared to placebo followed by ethanol challenges . In the third phase, all volunteers received three consecutive 1 g doses of cefonicid given at 24 h intervals followed by an ethanol challenge . At no time did any of the subjects experience a disulfiram-type reaction, and their blood aldehyde concentrations did not increase throughout the study.

J Reprod Med, 1987 Dec, 32(12), 907 - 10
Cefonicid vs . cefoxitin for cesarean section prophylaxis; Hartert RA Jr et al.; A randomized, prospective study compared a long-acting, second-generation cephalosporin, cefonicid (Monocid), with a short-acting, second-generation cephalosporin, cefoxitin (Mefoxin), for cesarean section prophylaxis . One hundred thirty-nine patients were enrolled, with 81 receiving a 1-g intravenous dose of cefonicid after cord clamping and 58 receiving a 2-g dose of intravenous cefoxitin after cord clamping and at 6, 12 and 18 hours postpartum . In those patients receiving cefonicid prophylaxis, endometritis incidence was 17.3% (14 of 81) . This finding was not statistically significant (P less than .397) when compared to the 12.1% incidence of endometritis (7 of 58) with cefoxitin . In addition, the febrile morbidity incidence for cefonicid prophylaxis was 23.5% (19 of 81) as compared to 15.5% (9 of 58) for cefoxitin (P less than .25) . Because the two drugs appear to be equally efficacious, cefonicid may be the better choice because of its markedly lower cost.

J Antibiot (Tokyo), 1987 Dec, 40(12), 1746 - 50
Effect of ammonium as nitrogen source on production of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase by Cephalosporium acremonium C-10; Zhang JY et al.; Cephalosporin production by Cephalosporium acremonium strain C-10 was suppressed when the organic nitrogen source (1.2% L-asparagine) was replaced by 1.2% (NH4)2SO4 . A higher level of (NH4)2SO4 (3.5%) led to even greater suppression . Ammonium repression was exerted on formation of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase, together with that of expandase; a lesser effect by ammonium was observed on cyclase production . Inhibition of ACV synthetase activity byammonium was also observed (ca . 50% inhibition at 250 mM NH4+).

Pathol Biol (Paris), 1987 Dec, 35(10 Pt 2), 1450 - 3
{Action of cephalosporins on T lymphocytes: the role of mediators}; Rouveix B et al.; The in vitro effect of various cephalosporins on T lymphocyte functions was studied . These antibiotics directly stimulated lymphokine production and significantly suppressed mitogen-stimulated lymphocyte transformation responses . Penicillin had no effect . Suppression of blastogenesis could be mediated through suppressor cell enhancement as indicated by: i) the significant suppressed lymphocyte transformation observed while using the dialyzed supernatant of cephalosporin-stimulated and cultured lymphocytes, ii) the enhanced blastogenesis, commonly ascribed to suppressor cell depletion, blunted by pre-incubation with cephalosporins, iii) the suppressed blastogenesis of allogenic responder cells in MLR by cephalosporin pre-incubated, mitomycin treated cells . An indirect effect through PgE2 release by macrophages cannot ruled out . The enhancement of suppressor activity by most of the cephalosporins might explain the smaller incidence of late hypersensitivity reactions observed with these antibiotics compared with penicillins.

Biochim Biophys Acta, 1987 Nov 27, 905(1), 65 - 74
Identification of identical binding polypeptides for cephalosporins and dipeptides in intestinal brush-border membrane vesicles by photoaffinity labeling; Kramer W; The uptake of a photolabile derivative of the orally effective cephalosporin cephalexin, N-(4-azidobenzoyl)cephalexin, was investigated in brush-border membrane vesicles . The compound was taken up into the intravesicular space and inhibited the active uptake of cephalexin in a concentration-dependent manner . Therefore, this probe interacts with the transport system shared by alpha-aminocephalosporins and dipeptides . Photoaffinity labeling of brush-border membrane vesicles from rat small intestine with N-(4-azido{3,5-3H}benzoyl) derivatives of the cephalosporin cephalexin and the dipeptide glycyl-L-proline resulted in the covalent incorporation of radioactivity into membrane polypeptides with apparent molecular weights of 127,000, 100,000, 94,000 and 86,000, the polypeptide of molecular weight 127,000 being predominantly labeled . The specificity of labeling was demonstrated by a decrease in the labeling of the polypeptide of apparent molecular weight 127,000 in the presence of beta-lactam antibiotics and dipeptides, whereas glucose, taurocholate or amino acids had no effect on the labeling pattern . These data demonstrate an interaction of cephalosporins and dipeptides with a common membrane protein of molecular weight 127,000, which could be a component of the intestinal transport system(s) responsible for the uptake of orally effective cephalosporins and dipeptides.

Transfusion, 1987 Nov-Dec, 27(6), 460 - 3
'Immune complex' mediated intravascular hemolysis due to IgM cephalosporin-dependent antibody; Salama A et al.; Immune hemolytic anemia (IHA) related to cephalosporins is rare and generally considered to be the result of a drug-adsorption mechanism . In previously reported cases, the hemolysis was usually extravascular and the causative antibodies were IgG, incapable of activating complement, and demonstrable by the direct or indirect antiglobulin test using red cells (RBCs) pretreated in vitro with cephalosporin . The authors report a patient in whom acute intravascular hemolysis developed while she was receiving cefotaxime (a cephalosporin as yet not reported to cause IHA) . The patient's RBCs were coated only with complement fragments (C3d), even at the peak of the hemolytic episode . Her serum and eluates repeatedly yielded negative results when tested against normal or cephalosporin-coated RBCs . However, strong hemagglutination and C5b-9-mediated hemolysis were observed if the patient's serum was tested against RBCs in the presence of the drug, its ex vivo antigen and, to a lesser degree, cephalothin and ceftriaxon, but not in the presence of penicillin and other related cephalosporins . The positive reactions were not changed by preincubating the serum with different amounts of the drugs . All of these findings reflect the typical picture of drug-induced IHA by the so-called "immune complex" mechanism and not by the drug-adsorption mechanism . The authors conclude that cephalosporin can cause immune hemolysis in two ways: the drug-adsorption mechanism and, as described here, the "immune complex" mechanism.

Gut, 1987 Nov, 28(11), 1467 - 73
An epidemic of pseudomembranous colitis: importance of person to person spread; Nolan NP et al.; Twenty three cases of pseudomembranous colitis (PMC) occurred in three hospitals in 10 months . Retrospective analysis shows that they represented a single epidemic with a readily traceable chain of person-to-person contact within and between hospitals . Most patients had severe pre-existing illness and all had broad spectrum antibiotics, including either ampicillin/amoxycillin, a broad spectrum cephalosporin (particularly cefotaxime), or both . All patients had severe diarrhoea and all responded to vancomycin, but relapse occurred in five . Ten patients eventually died, principally because of underlying disease rather than from PMC . Failure to find fibrin thrombi in blood vessels in biopsies and the scanty distribution of non-invasive bacteria supports the concept of mucosal damage by bacterial toxin, rather than by direct infection, or ischaemia . Although environmental colonisation cannot be excluded, the observed pattern of spread suggests a major role for direct person-to-person crossinfection in the spread of disease in this outbreak.

Antimicrob Agents Chemother, 1987 Nov, 31(11), 1675 - 82
Purification to homogeneity and characterization of acyl coenzyme A:6-aminopenicillanic acid acyltransferase of Penicillium chrysogenum; Alvarez E et al.; The acyl coenzyme A (CoA):6-aminopenicillanic acid (6-APA) acyltransferase of Penicillium chrysogenum AS-P-78 was purified to homogeneity, as concluded by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric focusing . The enzyme is a monomer with a molecular weight of 30,000 +/- 1,000 and a pI of about 5.5 . The optimal pH and temperature were 8.0 and 25 degrees C, respectively . This enzyme converts 6-APA into penicillin by using phenylacetyl CoA or phenoxyacetyl CoA as acyl donors . The pure enzyme showed a high specificity and affinity for 6-APA and did not accept benzylpenicillin, 7-aminocephalosporanic acid, cephalosporin C, or isocephalosporin C as substrates . The enzyme converted isopenicillin N into penicillin G, although with a lower efficiency than when 6-APA was used as the substrate . It did not show penicillin G acylase activity . The acyl CoA:6-APA acyltransferase required dithiothreitol or other thiol-containing compounds, and it was protected by thiol-containing reagents against thermal inactivation . The acyltransferase was inhibited by several divalent and trivalent cations and by p-chloromercuribenzoate and N-ethylmaleimide . The activity was absent in four different mutants that were blocked in penicillin biosynthesis.

Schweiz Med Wochenschr, 1987 Oct 3, 117(40), 1549 - 59
{Ceftriaxone, a cephalosporin with high hepatic elimination . Evaluation of its biliary clearance in man . Therapeutic value}; Brogard JM et al.; The biliary elimination of ceftriaxone, a cephalosporin derivative, was quantitatively studied in man with the help of high pressure liquid chromatography (HPLC) . In 6 healthy volunteers a mean peak concentration of 565 +/- 347 (SEM) micrograms/ml was observed in the aspirated duodenal fluid within the first hour after i.v . administration of 2 g ceftriaxone, and 1.4 +/- 0.5% of the dose was recovered during the 4 hours investigation period . In 10 cholecystectomized patients provided with a T-drain, the biliary concentration peak (1078 +/- 158 micrograms/ml) was reached within 1 hour after administration and the total 24 hours recovery amounted to 9.5 +/- 2.9% of the dose given . In 12 patients undergoing cholecystectomy, serum, and choledochal (CB) and gallbladder bile (GB) were peroperatively collected 1 hour after i.v . administration of 2 g ceftriaxone; the respective concentrations were: 199 +/- 10 (serum), 5259 +/- 1085 (CB), and 4533 +/- 809 (GB) micrograms/ml . These data point to excellent biliary elimination of ceftriaxone compared with the other beta-lactams previously studied, and afford evidence of its high therapeutic potential in biliary tract infections.

Xenobiotica, 1987 Oct, 17(10), 1139 - 45
Plasma protein binding of ceftriaxone; Popick AC et al.; 1 . The plasma protein binding characteristics of ceftriaxone, a new cephalosporin antibiotic, were determined in human, baboon, rabbit, dog and rat plasma . 2 . The protein binding of ceftriaxone was similar and concentration-dependent in human, baboon, rabbit and rat plasma, being highly bound (90-95%) at low concentrations (less than 100 micrograms/ml) but considerably less bound (approx . 60%) at high concentrations (greater than 400 micrograms/ml) . Binding in dog plasma was also concentration-dependent but much lower (approx . 25%) at lower concentrations (30 micrograms/ml) and virtually unbound (2%) at high concentrations (1 mg/ml) over a similar concentration range . 3 . Binding of ceftriaxone to human plasma involved two sites: a high affinity-low capacity (saturable) site and a low affinity-high capacity site . Binding to dog plasma apparently was at a single, high affinity-low capacity site . 4 . The pharmacokinetics of ceftriaxone in an animal species with binding characteristics similar to man (baboon), appear to be non-linear when based on total drug concentration and linear when based on the free drug concentration . In the dog, pharmacokinetic parameters did not change appreciably if calculated from total or free drug concentrations, due to the low protein binding.

Am Fam Physician, 1987 Sep, 36(3), 185 - 92
Cephalosporin therapy for childhood meningitis; Smith MA et al.; Ampicillin and chloramphenicol have been used for initial empiric therapy of childhood meningitis since the mid-1970s . Problems associated with these drugs include the possibility of chloramphenicol-associated aplastic anemia and the existence of Hemophilus influenzae type b resistance to both ampicillin and chloramphenicol . Several second- and third-generation cephalosporins have been shown to be as effective as ampicillin and chloramphenicol in the treatment of childhood meningitis.

Biochem Int, 1987 Sep, 15(3), 653 - 8
Biliary secretion of cefoperazone and its inter-relationship with bile acid transport in the rat; Pattinson NR et al.; Cefoperazone is a third generation cephalosporin which is secreted predominantly in bile . This study set out to examine the effect of stimulating bile choleresis on the biliary secretion of cefoperazone . Stimulation of both bile acid-dependent and independent bile flow (phenobarbitone pretreatment) hastened the peak appearance of a pulse of cefoperazone into bile . Although the biliary secretion rate of cefoperazone was enhanced by bile acid infusion, the % recovery and maximal biliary concentration were reduced . The reciprocal effect of continuous cefoperazone infusion on the rate of biliary transport of a pulse of bile acid was examined . Cefoperazone infusion hastened the biliary transport of glycocholate . Net recovery of glycocholate was unaffected.

J Antimicrob Chemother, 1987 Aug, 20(2), 273 - 82
Alterations of pharmacokinetic properties of gentamicin, penicillin G and two cephalosporins in septicaemic rabbits; Haslberger AG et al.; The pharmacokinetics of gentamicin, penicillin G, latamoxef and CPW 86-363, a novel third generation cephalosporin, were studied in healthy and septicaemic rabbits . Elevation of body temperature in infected animals was paralleled by statistically significant decreases in serum drug levels during the early stages of the distribution phase for penicillin G, latamoxef and CPW 86-363 whereas gentamicin showed increased serum drug levels during the early period . No significant differences were seen in tissue fluid levels (STIF) or normal and septicaemic rabbits for the four antibiotics used . Haemodynamic alterations and an increased permeability of blood vessel walls are presumed to contribute to changes in distribution properties of various drugs during experimental septicaemia . The qualitative differences among the antibiotics tested seem to be related to their physico-chemical characteristics.

Toxicol Appl Pharmacol, 1987 Aug, 90(1), 143 - 55
The hematopathology of cefonicid- and cefazedone-induced blood dyscrasias in the dog; Bloom JC et al.; Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized . A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months . Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias . Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology . Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals . The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue . The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible . These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.

Toxicol Appl Pharmacol, 1987 Aug, 90(1), 135 - 42
The hematologic effects of cefonicid and cefazedone in the dog: a potential model of cephalosporin hematotoxicity in man; Bloom JC et al.; Cephalosporin antibiotics cause a variety of hematologic disturbances in man, the pathogeneses and hematopathology of which remain poorly characterized . There is a need for a well-defined animal model in which these blood dyscrasias can be studied . In four subacute toxicity studies, the intravenous administration of cefonicid or cefazedone to beagle dogs caused a dose-dependent incidence of anemia, neutropenia, and thrombocytopenia after 1-3 months of treatment . A nonregenerative anemia was the most compromising of the cytopenias and occurred in approximately 50% of dogs receiving 400-500 mg/kg cefonicid or 540-840 mg/kg cefazedone . All three cytopenias were completely reversible following cessation of treatment; the time required for recovery of the erythron (approximately 1 month) was considerably longer than that of the granulocytes and platelets (hours to a few days) . Upon rechallenge with either cephalosporin, the hematologic syndrome was reproduced in most dogs tested; cefonicid (but not cefazedone)-treated dogs showed a substantially reduced induction period (15 +/- 5 days) compared to that of the first exposure to the drug (61 +/- 24 days) . This observation, along with the rapid rate of decline in red cell mass parameters of affected dogs, suggests that a hemolytic component complicated the red cell production problem and that multiple toxicologic mechanisms contributed to the cytopenia . We conclude that the administration of high doses of cefonicid or cefazedone to dogs can induce hematotoxicity similar to the cephalosporin-induced blood dyscrasias described in man and thus provides a useful model for studying the mechanisms of these disorders.

J Pharmacol Exp Ther, 1987 Aug, 242(2), 660 - 5
Transport of benzylpenicillin by the rat choroid plexus in vitro; Suzuki H et al.; To characterize the transport system by which benzylpenicillin, an organic anion, is accumulated by the isolated rat choroid plexus, kinetic analysis of benzylpenicillin transport was performed . Accumulation of benzylpenicillin was against an electrochemical potential gradient via a saturable process (Km = 58 microM and Vmax = 84 nmol/ml of tissue per min) that was inhibited by sulfhydryl reagents (p-hydroxymercuribenzoate and N-ethylmaleimide), metabolic inhibitors (KCN and 2,4-dinitrophenol) and anion exchange inhibitors (4-acetamide-4'-isothiocyanatostilbene-2,2'-disulfonic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid), but is major transport system did not require the inward Na+ gradient . Organic anions, such as 5-hydroxyindoleacetic acid, homovanillic acid, p-aminohippuric acid and probenecid inhibited the accumulation of benzylpenicillin, whereas dipeptides did not affect it . Kinetic analysis of the accumulation of benzylpenicillin suggests that both phenoxymethylpenicillin and cefpiramide are also transported via the benzylpenicillin transport system . Other penicillin and cephalosporin derivatives inhibited the accumulation of benzylpenicillin with different affinities . Penicillin derivatives without dissociating groups in the side chain had the higher affinity for the benzylpenicillin transport system than other beta-lactam antibiotics did . Among penicillin derivatives examined, a good correlation (r = 0.92) was observed between the lipophilicity and the affinity for the benzylpenicillin transport system, whereas no correlation was observed among the cephalosporin derivatives . These findings suggest that the major transport system of benzylpenicillin in the rat choroid plexus is via a carrier-mediated active anion transport process which is distinct from that of dipeptides, and does not require the inward Na+ gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

J Clin Microbiol, 1987 Aug, 25(8), 1380 - 3
Detection of beta-lactamase activity among clinical isolates of Branhamella catarrhalis with six different beta-lactamase assays; Doern GV et al.; A total of 74 different clinical isolates of Branhamella catarrhalis were examined for their ability to produce beta-lactamase by six different beta-lactamase assays . These included a conventional tube and disk test, in which the chromogenic cephalosporin nitrocefin was used as a substrate; a disk procedure, in which pyridinium-2-azo-p-dimethylanaline cephalosporin was used as a substrate; broth and disk acidometric methods; and a conventional tube iodometric assay . A total of 58 of the study isolates produced beta-lactamase . In all cases, positive results were obtained with the nitrocefin tube and disk assays after 1 min . With the pyridinium-2-azo-p-dimethylanaline cephalosporin disk test, 57 of the 58 beta-lactamase-producing strains yielded a positive reaction in 1 min; the remaining strain was positive after 10 min . None of the beta-lactamase-producing strains produced positive reactions by either the broth or disk acidometric methods after 1 min . With the broth test, 10 min was required for positive test results for 42 strains; 30 min was necessary for 16 strains . By the disk acidometric procedure, all 58 strains were positive after 10 min . Of 58 beta-lactamase-producing strains, 30 were positive by the iodometric assay after 1 min, 13 strains required 10 min, and 4 strains were detected as being beta-lactamase positive only after 30 min . One beta-lactamase-producing strain remained negative by the iodometric method . Among the 16 strains of B . catarrhalis that lacked beta-lactamase that were examined in this study, no false-positive results were obtained by any of the six assays.

J Pediatr, 1987 Aug, 111(2), 293 - 9
Recreational use of psychoactive drugs by patients with cystic fibrosis; Stern RC et al.; We assessed unprescribed psychoactive drug use in 173 adults with cystic fibrosis . Twenty (11%) regularly smoked tobacco . Cigarette smoking ranged from 1 to 30 years (2 to 60 pack-years) . Alcohol was used by 60%, and marijuana by 20% of the patients . Pulmonary symptoms were often increased the day after alcohol ingestion . Alcohol occasionally caused nausea, vomiting, and headache if the patient was taking some cephalosporin derivatives (such as cefsulodine) or chloramphenicol . Marijuana often aggravated chronic pulmonary symptoms, although some patients reported transient relief during use . Comparison with a retrospectively selected control group did not show faster short-term pulmonary deterioration in the tobacco smokers . Physicians who deal with cystic fibrosis and other chronic illnesses should be cognizant of interactions of unprescribed and prescribed drugs . Recreational use of unprescribed psychoactive drugs should be considered if unexpected symptoms occur in older patients.

Biochem Pharmacol, 1987 Jul 15, 36(14), 2317 - 24
Purification and partial characterization of rat intestinal cefuroxime axetil esterase; Campbell CJ et al.; An esterase which hydrolyses the cephalosporin antibiotic, cefuroxime axetil has been isolated from rat intestinal washings and purified . Closely related cefuroxime esters were extremely poor substrates, but p-nitrophenyl acetate and alpha-naphthyl acetate were slowly hydrolysed by the purified enzyme . Analysis by gel filtration gave an Mr = 51,000 and on SDS-polyacrylamide gel electrophoresis the esterase resolved into two main bands of Mr = 31,500 and 26,800 . Analytical isoelectric focusing resolved purified esterase into multiple forms active toward alpha-naphthyl acetate, the isoelectric points of which ranged from pH 4.5 to 6.3 . The esterase bound specifically to Con A-Sepharose suggesting it could be a glycoprotein . Esterase activity was unaffected by the presence of dihydroxy bile salts (1-8 mM) and inhibition studies using organophosphates and eserine salicylate have classified the enzyme as a carboxylesterase.

Hosp Formul, 1987 Jul, 22(7), 658 - 63, 673, 676
Application of decision analysis to drug selection for formulary addition; Kresel JJ et al.; Decision analysis (DA) is a quantitative method for making decisions, incorporating both probabilistic data and value judgments, and clinical and economic outcomes . The P & T Committee at the Mary Hitchcock Memorial Hospital used this technique to aid in selection of a third-generation cephalosporin for formulary addition . Cost-specific data from this hospital, together with clinical data derived from the medical literature, and a panel of infectious disease specialists were used to compare costs associated with antibiotic regimens of three infections . Results show that ceftizoxime is the least costly treatment for hospital-acquired pneumonia and sepsis of unknown origin, whereas metronidazole plus gentamicin is the least costly regimen for intra-abdominal infections . This demonstrates that drugs with higher acquisition costs can, in some cases, be less expensive than drugs with lower acquisition costs when the total cost of drug therapy is considered.

Dig Dis Sci, 1987 Jun, 32(6), 615 - 9
Inhibition of biliary phospholipid and cholesterol secretion by cefoperazone; Pattinson NR et al.; The effect of cefoperazone, a third-generation cephalosporin, on biliary lipid secretion in rats was examined . Rats were anesthetized with ether and the mid-lumbar vein and common bile duct cannulated . Bile acid secretion was maintained by intravenous taurocholic acid infusion (28 mumol/hr) . A 1-hr control period was followed by intravenous cefoperazone infusion at either submaximal (20 mumol/hr), or supramaximal (60 mumol/hr) concentrations . At the cefoperazone infusion rate of 20 mumol/hr (biliary secretion of 7.1 +/- 1.6 mumol/hr) phospholipid secretion fell 19% and cholesterol secretion fell 31%; at a cefoperazone infusion rate of 60 mumol/hr (biliary secretion rate of 27.1 +/- 5.1 mumol/hr) phospholipid and cholesterol secretion were further reduced 40% and 56%, respectively, of controls . All changes were significant (P less than 0.01) . Inhibition of both cholesterol and phospholipid secretion paralleled each other, was dose-dependent, and reversible . Cefoperazone's inhibitory action was abolished at a bile acid infusion rate of 108 mumol/hr . Cefoperazone was not found to be associated with bile acid micelles or mixed micelles as determined by ultracentrifugation and gel filtration . Thus, the effect of cefoperazone on biliary lipid secretion is not due to the impairment of mixed micelle formation in the canalicular lumen but rather its inhibitory effect appears to be due to a presecretory event.

Pharm Res, 1987 Jun, 4(3), 214 - 9
Kinetics and mechanism of zinc ion-mediated degradation of cephalosporins in tromethamine solution; Tomida H et al.; Earlier studies of the hydrolysis and aminolysis of penicillin, in the presence of zinc ion and tromethamine (Tris), revealed a very rapid catalysis mediated by a ternary complex in which the metal ion brought the reactants into close proximity in a suitable configuration for reaction . In the present work similar studies with a group of cephalosporins show not only much slower rates of reaction but a different mechanism in which the zinc ion-tromethamine complex functions as a nucleophile in a bimolecular reaction . Evidence for the differences in mechanism includes not only the different dependence of rate upon tromethamine concentration, but comparable rates of reaction of methyl esters of a penicillin and a cephalosporin and the reaction products observed by high-performance liquid chromatography.

Br J Ophthalmol, 1987 Jun, 71(6), 433 - 5
A study of aqueous and serum levels of ceftazidime following subconjunctival administration; Clements DB et al.; Patients undergoing cataract surgery may develop an infective endophthalmitis postoperatively which may result in the loss of an eye . This study was carried out to measure aqueous humour levels and to assess patients' tolerance of ceftazidime, a potent antipseudomonal cephalosporin, given subconjunctivally . Eighteen patients received 125 mg ceftazidime subconjunctivally before they underwent routine cataract surgery . A further two patients received 62.5 mg subconjunctivally . The results show good penetration into the aqueous humour well above the minimum inhibitory concentrations (MICs) of possible pathogens . There were no postoperative infections, no local irritation, and no systemic side effects.

Nature, 1987 May 7-13, 327(6117), 79 - 82
Crystallographic study of a beta-lactam inhibitor complex with elastase at 1.84 A resolution; Navia MA et al.; The continuing discovery and development of beta-lactams as antibiotics has had an unparalleled impact on the overall health and well-being of society . Recently, appropriately substituted cephalosporins were shown to be potent inhibitors of elastase, suggesting a novel therapeutic role for the beta-lactams in the control of emphysema and other degenerative diseases . We have now solved and partially refined at atomic resolution the structure of a complex of porcine pancreatic elastase with the time-dependent irreversible inhibitor 3-acetoxymethyl-7-alpha-chloro-3-cephem-4-carboxylate-1,1-dioxide tert-butyl ester (I), the most potent of the beta-lactam elastase inhibitors yet reported . (Porcine pancreatic elastase is a close relative of the desired drug target, human polymorphonuclear leukocyte elastase.) A mechanism of action is presented, based on the structure and on biochemical evidence (T.-Y.L . et al., in preparation), which clarifies the operational similarities and differences between beta-lactam elastase inhibitors and antibiotics . Features of the reaction include the expulsion of a leaving group at the cephalosporin 3' position and the formation of two covalent bonds with the active site of porcine pancreatic elastase at residues Ser 195 and His 57.

Jpn J Antibiot, 1987 May, 40(5), 1074 - 83
{Fundamental and clinical studies on cefuzonam in the field of obstetrics and gynecology}; Yamamoto T et al.; Fundamental and clinical studies on cefuzonam (CZON, L-105), a new oxime type cephalosporin, were performed and the results obtained are summarized below: 1 . Concentrations of CZON were determined in serum, internal genital organs and retroperitoneal fluid after a single intravenous administration of 1 g dose . The peripheral serum level of CZON was 74.0 micrograms/ml at 15 minutes after the administration . A sufficient transfer of CZON into internal genital organs and retroperitoneal fluid was demonstrated . 2 . In clinical trial, CZON was given to 11 cases with obstetrical and gynecological infections . Efficacies were evaluated as good in 9 cases and poor in 2 cases . No side effects were observed in any of the cases treated with CZON . In laboratory examinations, transient elevation of serum GOT, GPT and alkaline phosphatase was noted in 1 case.

Antimicrob Agents Chemother, 1987 May, 31(5), 799 - 804
Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys; Forgue ST et al.; The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound . Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method . Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen . For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level . After administration of 87 to 1,502 mg/kg by i.v . infusion, CL (12.5 ml/min per kg) was again similar for all dose groups . Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable . No consistent differences among dose group mean Vss values were found . The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose . For the cynomolgus monkey, kinetic parameters for 5-min i.v . infusions were linearly related to dose over the range of 10 to 600 mg/kg . Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg . The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.

Am J Hosp Pharm, 1987 May, 44(5), 1111 - 8
Particulate-matter content of 11 cephalosporin injections: conformance with USP limits; Parkins DA et al.; The particulate-matter content of 11 dry-powder cephalosporin injections was determined using a modified version of the official United States Pharmacopeial Convention (USP) method for particulate matter in small-volume injections (SVIs) . Ten vials of each cephalosporin product were each constituted with 10 mL of Water for Injections BP that had been filtered through a 0.22-micron membrane . The pooled contents of the 10 vials for each product were allowed to stand under reduced pressure to ensure removal of gas bubbles . Particulate-matter content was determined using a HIAC/Royco particle counter on six 10-mL samples obtained from the pooled solutions for each product . All solution preparation and particle counting was performed in a horizontal-laminar-airflow hood . Modifications of the USP method used in this study included the use of six rather than two samples from each pooled solution, the addition of diluent to the injections through the rubber closure with a needle instead of into the open container, and changes in the degassing method . Particle counts for all products examined were lower than USP limits for SVIs . All but two products contained less than 15% of USP limits for particles greater than or equal to 10 microns in effective diameter and particles greater than or equal to 25 microns in effective diameter . The standard USP method for degassing (standing for two minutes) was inadequate . Application of reduced pressure for up to 10 minutes was necessary for thorough degassing of products.(ABSTRACT TRUNCATED AT 250 WORDS)

Int J Clin Pharmacol Ther Toxicol, 1987 May, 25(5), 262 - 78
Distribution properties of cephalosporin in man: pharmacokinetic and experimental approaches; Ganzinger U; The distribution properties of cephalosporin derivatives in man were analysed according to a two-compartment model and several pharmacokinetic approaches were followed to calculate disposition parameters . These calculations resulted in different parameters with the dimension of either volume or time or in relative values . These correlate significantly with experimentally derived disposition data, e.g., the volume of distribution of the peripheral compartment vs . the ratio of intravascular and extravascular AUC-values or the mean residence time vs . absolute drug levels at various extravascular sampling sites . Based on calculated disposition parameters, the various cephalosporin derivatives can be assigned to 4 different clusters with specific distribution properties, which correlate significantly with the daily dose recommended for the treatment of moderate to severe infections . This demonstrates the clinical relevance of mathematically derived distribution parameters for the prediction of drug levels in extravascular sites and for the design of therapeutically effective dose regimens . The usefulness of other pharmacokinetic concepts is discussed together with the graphical computation of experimental data according to kinetic hysteresis analysis.

Transfusion, 1987 May-Jun, 27(3), 266 - 7
Disulphide bonds are a requirement for adsorption of cephalosporins on the red cell membrane; Duran-Suarez JR et al.; The authors studied the behavior of red cells (RBCs), treated with 2-aminoethylisothiouronium bromide (AET), against 100 serums containing cephalothin antibodies and 27 serums with cephapirin antibodies . None of the serums reacted with cephalosporin-coated RBCs that had been exposed previously to AET . The possibility of the Kell system acting as a receptor for cephalosporins was excluded . The authors discuss the significance of cysteine disulphide bonds and the tertiary or quaternary structure of red cell membrane proteins in the binding of cephalosporins to RBCs.

Pathol Biol (Paris), 1987 May, 35(5), 448 - 50
{Comparison of the diffusion of ceftriaxone in digestive surgery after a single administration at doses of one and two grams}; Lokiec F et al.; Twenty patients undergoing gastrointestinal surgery were randomly allocated to receive either 1 or 2 g of ceftriaxone, a long half-life third generation cephalosporin, as a single dose intravenous prophylaxis on induction of anaesthesia . Plasma and tissue samples were taken 2 hours and analysed with an HPLC procedure . The results of plasma and tissue concentrations of ceftriaxone showed that 1 g dosage was enough for preventing the occurrence of postoperative sepsis . No adverse reaction or side-effects were recorded.

Pharm Weekbl Sci, 1987 Apr 24, 9(2), 98 - 103
Influence of protein binding and severity of illness on renal elimination of four cephalosporin drugs in intensive-care patients; Van Dalen R et al.; A pharmacokinetic study after a single dose of ceftriaxone, cefoxitin, cefuroxime and ceftazidime was performed to investigate the influence of protein binding and severity of disease on the renal elimination . In intensive-care patients drug-protein binding was substantially less compared to that in volunteers and patients with less complicated diseases . This did not result in increased elimination but, due to increased apparent volumes of distribution, prolonged half-life times were observed . Consequently, in patients with complicated disease states a dosage regimen should be based on pharmacokinetic studies performed in a similar patient group.

J Pharm Pharmacol, 1987 Apr, 39(4), 272 - 7
Saturable uptake of cefixime, a new oral cephalosporin without an alpha-amino group, by the rat intestine; Tsuji A et al.; The mechanism of intestinal uptake of cefixime, a new oral cephalosporin antibiotic, has been examined using the everted jejunum of rats . The initial uptake rates were apparently pH-dependent with the maximum rate at pH 5.0 and a 3-fold reduction at pH 7.0 . The uptake at pH 5.0 followed mixed-type kinetics involving saturable and non-saturable processes in a manner similar to that for several amino-beta-lactam antibiotics . Cefixime uptake was inhibited significantly by 20 mM permeants such as cyclacillin, cephradine, benzylpenicillin, propicillin, glycyl-L-proline and glycyl-glycine . Replacement of Na+ in the medium with choline produced a slight but significant inhibition of cefixime uptake . In spite of the absence of significant inhibition by the amino acids glycine and proline, the dipeptide, glycyl-L-proline in Na+-free medium showed a marked inhibitory effect . The inhibition kinetics of cefixime uptake by glycyl-L-proline and cyclacillin were consistent with competitive-type inhibition . This study provides the first evidence of saturable intestinal uptake of a cephem antibiotic without an alpha-amino group in the side chain, suggesting transport through the dipeptide carrier system(s).

J Chromatogr, 1987 Mar 13, 389(2), 369 - 77
Investigation of perchlorate, phosphate and ion-pairing eluent modifiers for the separation of cephalosporin epimers; Kennedy JH et al.; The retention behavior of several pairs of 7 alpha- and 7 beta-cephalosporin epimers was investigated using perchlorate, phosphate and ion-pairing eluent modifiers . At pH 2.5, sodium perchlorate, sodium phosphate and sodium pentanesulfonate all provided separation of epimers with free 7-amino groups . When the 7-amino group was blocked, as in cephalexin and cefaclor, sodium perchlorate gave the best separation at pH 2.5 . A tetrabutylammonium ion-pairing system at pH 7.0 provided separation of all epimer pairs containing a free carboxylic acid at the 3 position . Hydrophobic, residual silanol and ionic interactions were factors in the retention mechanism of the cephalosporins under the conditions investigated . An ionic interaction of perchlorate with the protonated amine of the cephalosporin was postulated as an explanation of the retention and selectivity effects observed with perchlorate as an eluent modifier.

J Pharm Sci, 1987 Mar, 76(3), 208 - 14
Degradation kinetics and mechanisms of a new cephalosporin, cefixime, in aqueous solution; Namiki Y et al.; Hydrolysis of cefixime in buffer solutions (pH 1-9) at 25 degrees C and a constant ionic strength of 0.3 was investigated using ion-pair reversed-phase HPLC . Hydrolysis rates followed pseudo first-order kinetics; the rate of hydrolysis of cefixime was very slow at pH 4-7, slightly faster at lower pH, and quite rapid at higher pH . In the early stages of hydrolysis, six major degradation products were isolated and identified: a beta-lactam ring-opened product and a 7-epimer (basic conditions), three lactones derived from intramolecular cyclization between the 2-carboxyl and 3-vinyl groups (acidic conditions), and an aldehyde derivative involving a 7-acyl moiety (neutral conditions) . Principal degradation pathways for cefixime were found to involve initial cleavage of the beta-lactam ring.

Antimicrob Agents Chemother, 1987 Feb, 31(2), 292 - 4
Peritoneal transport of cefonicid; Morse GD et al.; The pharmacokinetic characteristics of cefonicid, a highly protein-bound expanded-spectrum cephalosporin, were examined in six noninfected, clinically stable patients undergoing continuous ambulatory peritoneal dialysis . After a 1.0-g intravenous dose of cefonicid, the mean concentrations in serum were 105 +/- 25 and 35.6 +/- 14.4 micrograms/ml at 3 and 72 h, respectively . Despite a prolonged half-life in serum of 49.7 +/- 18 h, the penetration into peritoneal fluid was low . The average concentration in dialysate over the 72-h study period was 2.7 micrograms/ml . The serum clearance was 2.6 +/- 1.0 ml/min, and the distribution volume was 0.14 +/- 0.02 liter/kg . Dosage recommendations and clinical considerations for cefonicid use in continuous ambulatory peritoneal dialysis patients are discussed.

Fundam Appl Toxicol, 1987 Feb, 8(2), 280 - 9
Testicular toxicity of N-methyltetrazolethiol cephalosporin analogs in the juvenile rat; Comereski CR et al.; The testicular toxicity of 10 antibiotics was evaluated in juvenile rats . Three of the antibiotics, cefbuperazone, cefamandole, and cefoperazone, contain the N-methyltetrazolethiol group as the 3-substituent; ampicillin, cefazolin, cephalothin, cefoxitin, piperacillin, and ceforanide do not contain this moiety . Testicular degeneration, partially irreversible in nature, was observed with those antibiotics which contain the N-methyltetrazolethiol substituent . Further, free N-methyltetrazolethiol also produced testicular degeneration in the juvenile rat . This substituent is most likely responsible for the testicular toxicity observed with cefbuperazone, cefamandole, and cefoperazone in the juvenile rat . The implications of these findings to man are undetermined.

Pharm Res, 1987 Feb, 4(1), 33 - 7
Dose-dependent pharmacokinetics of a new oral cephalosporin, cefixime, in the dog; Bialer M et al.; Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin . To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted . In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered . In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs . A period of 1 month separated the two studies . When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose . The oral systemic bioavailability in the dose range 6.25-50 mg/kg was 55% . It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg . The average peak serum concentrations ranged from 15.8 micrograms/ml at 6.25 mg/kg to 119 micrograms/ml at 200 mg/kg . Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25% . This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.

Am J Emerg Med, 1987 Jan, 5(1), 40 - 1
Pneumoparotitis: an unusual manifestation of hay fever; Garber MW; This case concerns bilateral parotitis apparently caused by increased intraoral pressure generated by sneezing and forceful clearing of the nares during an attack of hay fever . This was accompanied by painful anterior cervical lymphadenopathy . The condition responded well to an oral cephalosporin and increased fluid intake along with an analgesic agent . The patient recovered without sequelae.

Infection, 1987, 15(5), 348 - 50
Hemostasis in patients with normal and impaired renal function under treatment with cefodizime; Andrassy K et al.; Ten patients (two with normal, eight with impaired renal function) on their usual diet were treated with cefodizime (HR 221) for seven days . The dosage was 4 g/day, adapted to renal function as appropriate . Platelet function, plasma coagulation and vitamin K metabolism were investigated before and on day 7 of therapy . Platelet function and plasma coagulation remained unchanged, regardless of the size of the serum antibiotic trough levels, in both normal and impaired renal function . Vitamin K1 metabolism remained unaffected, since no increase in vitamin K1 2,3 epoxide in the circulation was observed during the therapy . Cefodizime (HR 221), a parenteral aminothiazole cephalosporin, does not affect hemostasis.

Int Orthop, 1987, 11(1), 61 - 3
Bone levels of cephradine and cefuroxime after intravenous administration in patients undergoing total hip replacement; Cain TJ et al.; A randomised, comparative study is reported of single intravenous doses of cephradine 2 g or cefuroxime 1.5 g given as prophylactic cover for total hip replacements in 40 patients . The serum and bone levels of cephalosporin achieved were higher in the cephradine treated group in proportion to the higher dose employed . Both agents provided adequate bone levels on average, cephradine 25.34 mcg/g, cefuroxime 17.39 mcg/g, although bone penetration was more variable with cefuroxime.

Adv Ophthalmic Plast Reconstr Surg, 1987, 7, 171 - 80
Orbital and periorbital dog bites; Gonnering RS; Although periorbital and orbital dog bites are rare, they most frequently occur in young children and commonly involve significant associated adnexal injuries . In most cases, the dog is either the family pet or is otherwise known to the victim . The exact precipitating event is usually unknown . Most victims are treated by a physician soon after injury, and can be reconstructed primarily following meticulous local wound care, including adequate irrigation . Infection is rare, but because of its potentially disastrous consequences, prophylactic treatment with penicillinase-resistant penicillin or cephalosporin seems indicated . Serious, potentially fatal consequences due to underlying intracranial injury in children under aged 2 years, fatal septicemia in splenectomized individuals, tetanus, and rabies must be considered by ophthalmologists who treat such patients.

Arch Intern Med, 1987 Jan, 147(1), 44 - 7
Effect of an educational intervention on oral cephalosporin use in primary care; Ives TJ et al.; The prescribing of oral cephalosporin antibiotics in an ambulatory setting was evaluated before and after an educational intervention . A drug utilization review used previously developed criteria to study the indications, processes, complications, and outcome for oral cephalosporins in the outpatient setting . Baseline data were collected for one year in the initial phase of the study . Only one prescription (1.4%) in the initial phase (0.96% of the total) met the criteria for appropriate use . However, during the year after an educational intervention by a clinical pharmacist explaining the proper use of oral cephalosporins, the prescribing of these agents decreased substantially . Educational strategies in medical schools and residency programs that seek to improve drug-prescribing behavior should combine drug utilization review programs with specific education about the appropriate use of pharmacologic agents.

Pharmacotherapy, 1987, 7(5), 185 - 7
Acute bacterial endocarditis due to Hemophilus parainfluenzae . Response to ceftizoxime in an ampicillin-allergic patient; da Camara CC et al.; Endocarditis secondary to Hemophilus parainfluenzae is an uncommon entity that appears to be increasing in frequency, perhaps due to improved laboratory isolation techniques . Although controversial, most of the published literature recommends a penicillin, with or without concomitant gentamicin, as definitive therapy . We report the first successful use of the third-generation cephalosporin ceftizoxime in an ampicillin-allergic patient . A 55-year-old white female was hospitalized after 5 days of experiencing fever, chills, nausea, and vomiting . A cardiac echocardiogram revealed a large mitral valve vegetation, and the patient was treated with intravenous ampicillin, gentamicin, and clindamycin . Two weeks after emergency mitral valve replacement the patient developed spiking fevers and a macular, erythematous rash while receiving ampicillin . Ceftizoxime was initiated and continued to complete a 4-week period of intravenous antibiotics . Follow-up at 14 months showed no further evidence of infection . Ceftizoxime appears efficacious in eradicating H . parainfluenzae in patients allergic to penicillin.

Antibiot Med Biotekhnol, 1987 Jan, 32(1), 6 - 11
{Effect of lysine on cephalosporin biosynthesis and morphogenesis in Acremonium chrysogenum}; Bartoshevich IuE et al.; The effect of exogenic lysine on production of cephalosporin by auxotrophic and prototrophic strains of A . chrysogenum and their development was studied . It was shown that lysine added to the medium at a concentration of 0.5 or 1 mg/ml partially eliminated the effect of catabolic repression by glucose and had a stimulating effect on production of cephalosporin in the presence of sucrose . Both phenomena were most pronounced in the prototrophic strain 309-A . High concentrations of lysine (10 mg/ml) inhibited cephalosporin biosynthesis more intensively in the auxotrophic strain 291-A than in the prototrophic strain 309-A . Marked differences in the character of the culture development in media supplemented with 1 or 10 mg/ml of lysine were also observed.

Drug Intell Clin Pharm, 1986 Dec, 20(12), 975 - 80
Is there cost reduction potential for extended half-life cephalosporins?
Scalley RD, Stuart CC Jr.
Two new second-generation cephalosporin derivatives with extended half-lives, ceforanide and cefonicid, have recently entered the U.S . marketplace . Because longer dosing intervals require fewer daily doses, potential exists for overall cost reduction if pharmacy and nursing time can be effectively saved . Reduction in personnel costs, however, must be sufficient for these more expensive products to be truly cost effective . We studied the impact of substituting these newer agents for older, less expensive products with formulary status at our 200-bed community hospital . Results show that no nursing expenses could be recovered, and there is little chance of consistently reducing pharmacy compounding expenses . Within the constraints of these studies, particularly physician prescribing habits, the GRASP (Grace Reynolds Application and Study of PETO) system of determining nurse staffing, and our drug acquisition costs, we find that the newer extended half-life products have very limited usefulness and may only increase the cost of antibiotic utilization.

FEBS Lett, 1986 Nov 10, 208(1), 43 - 7
Effects of magnesium and sodium ions on the outer membrane permeability of cephalosporins in Escherichia coli; Yamaguchi A et al.; Both Mg2+ and Na+ stimulated the outer membrane permeation of negatively charged cephalosporins in Escherichia coli without any significant alteration of the permeation of a zwitterionic cephalosporin . Such stimulation was not observed in an E . coli mutant lacking porins . The stimulation was caused by the direct interaction between the cations and the porin pores, which resulted in a decrease in cation selectivity of both the Omp F and Omp C porin pores.

Surg Gynecol Obstet, 1986 Nov, 163(5), 421 - 7
A comparison of piperacillin, cephalothin and cefoxitin in the prevention of postoperative infections in patients undergoing vaginal hysterectomy; Benigno BB et al.; A randomized, double-blind, multicenter trial was initiated to compare the safety and efficacy of piperacillin, cephalothin and cefoxitin in the prophylactic treatment of patients undergoing vaginal hysterectomy . The total dose of each antibiotic was 6 grams given in three equally divided doses . A satisfactory prophylactic response was obtained in 143 of 151 (95 per cent) patients treated with piperacillin, in 82 of 87 (94 per cent) patients treated with cephalothin and in 57 of 60 (95 per cent) patients treated with cefoxitin . The pooled data indicated that the piperacillin treatment group did not differ from the combined cephalosporin treatment groups with respect to prophylactic response, presence of febrile morbidity, fever index, duration of postoperative hospitalization and incidence of reported adverse experiences.

J Clin Pathol, 1986 Nov, 39(11), 1245 - 9
Effects of N-methyl-thiotetrazole cephalosporin on haemostasis in patients with reduced serum vitamin K1 concentrations; Mackie IJ et al.; Two patients with low random serum vitamin K1 concentrations but with normal prothrombin times and normal biological assays of the vitamin K dependent coagulation proteins were treated with an N-methyl-thiotetrazole cephalosporin (cefotetan) postoperatively . Four to six days later both patients developed a prolonged prothrombin time and a noticeable and specific lowering of the clotting activities of factors II, VII, IX and X, though the serum vitamin K1 concentrations remained unchanged . Crossed immunoelectrophoresis of prothrombin showed the appearance of a second peak corresponding to descarboxyprothrombin (PIVKA II) . These abnormalities corrected after vitamin K administration . These data are consistent with the hypothesis that cephalosporins with an N-methyl-thiotetrazole side chain inhibit the hepatic utilisation of vitamin K but that this only causes hypoprothrombinaemia when liver reserves of vitamin K are low.

Am J Med, 1986 Oct, 81(4), 709 - 12
Hemophilus influenzae type B cellulitis in adults; McDonnell WM et al.; Cellulitis due to Hemophilus influenzae type B is a rare but treatable event in adults . Herein is described a 67-year-old woman with anterior neck cellulitis caused by H . influenzae type B, documented by positive blood culture results . Six additional cases reported in the literature are reviewed . The following clinical syndrome emerges: the patient is usually older than 50 years of age, and pharyngitis develops first, followed by the onset of high fever and rapidly progressive anterior neck swelling, tenderness, and erythema associated with dysphagia . Because the causative organism may be resistant to ampicillin, the early use of chloramphenicol is recommended along with a beta-lactamase-resistant penicillin or cephalosporin (to cover other potential pathogens), or an appropriate third-generation cephalosporin that would also adequately cover all possible pathogens.

Antimicrob Agents Chemother, 1986 Oct, 30(4), 536 - 41
Two-dimensional thin-layer chromatography for simultaneous detection of bacterial beta-lactam acylases and beta-lactamases; Chen KC; A rapid and specific procedure was developed for the simultaneous detection of bacterial acylases and beta-lactamases, using ampicillin and cephalexin as substrates . Bacterial suspensions from agar plates were incubated separately with each beta-lactam substrate for 1 h at 37 degrees C . The supernatant of the reaction mixture was dansylated, and the dansyl derivatives were separated by two-dimensional thin-layer chromatography on polyamide sheets . The end products resulting from acylase hydrolysis, including the intact beta-lactam nucleus, 6-aminopenicillanic acid or 7-aminodeacetoxycephalosporanic acid, and the acyl side chain acid, D-(-)-alpha-aminophenylacetic acid, and the end product resulting from beta-lactamase hydrolysis (D-phenylglycylpenicilloic acid or D-phenylglycyldeacetoxycephalosporoic acid) were separated from each unhydrolyzed substrate and amino acids by this procedure . The presence of the intact beta-lactam nucleus in the reaction mixture is the indication of acylase activity . This method is sensitive and reproducible and has been successfully applied to screening for acylase activity in a variety of bacteria . It may be pharmaceutically useful for identifying organisms capable of removing the acyl side chain from naturally occurring beta-lactam antibiotics such as penicillin G, penicillin V, and cephalosporin C for production of the beta-lactam nuclei which serve as the starting materials for semisynthetic beta-lactam antibiotics.

Arch Microbiol, 1986 Oct, 146(1), 46 - 51
Relationship between nitrogen assimilation and cephalosporin synthesis in Streptomyces clavuligerus; Brana AF et al.; The levels of three enzymes of the beta-lactam antibiotic pathway and overall cephalosporin production were subject to nitrogen source repression in Streptomyces clavuligerus . The specific activities of isopenicillin N synthetase ("cyclase") and deacetoxycephalosporin C synthetase ("expandase") measured during the exponential phase depended on the nitrogen source employed, following a pattern that roughly correlated with the corresponding antibiotic production . The effects on isopenicillin N epimerase ("epimerase") activities were less marked than those on the cyclase and expandase . Production of cephalosporins and enzymatic activities were not related to the growth rate of the cultures . Glutamate, glutamine and alanine inhibited production when added to resting cell systems, while lysine and alpha-aminoadipate were stimulatory . No clear relationship could be drawn between cephalosporin production or beta-lactam synthetase activities and the activities of enzymes of ammonium assimilation (glutamine synthetase, glutamate synthase and alanine dehydrogenase) . The intracellular pools of free glutamine, alanine and ammonium were the only ones markedly affected by the nitrogen source in the wild type and mutants, but these amino acids did not seem to play an obvious role as intracellular mediators of nitrogen control.

Jpn J Antibiot, 1986 Aug, 39(8), 2219 - 24
{Ceftazidime: placental transfer and pharmacokinetic parameters in the third trimester pregnancy}; Fujimoto S et al.; Ceftazidime (CAZ), a newly developed cephalosporin with very high stability to beta-lactamase, was evaluated for its transfer into fetus and amniotic fluid in the third trimester pregnancy, following a single bolus intravenous injection at a dose of 1 g . In subjects with various conditions (background factors) standardized, concentrations of CAZ in maternal venous blood, venous and arterial blood in umbilical cord, and amniotic fluid were determined . High concentration of CAZ (10 micrograms/ml or higher) was found to be maintained in fetal blood and amniotic fluid for ca . 4 hours and ca . 8 hours, respectively, after intravenous injection, showing good placental transfer of CAZ . In view of MICs of CAZ, satisfactory clinical efficacy is expected in perinatal infections.

Cutis, 1986 Jul, 38(1), 58 - 60
Pustular eruption following administration of cephradine; Kalb RE et al.; We report the case of an unusual generalized pustular drug eruption caused by the cephalosporin cephradine . Previously reported pustular drug reactions are briefly reviewed . We suggest that a reaction to an administered drug should be considered in the differential diagnosis when a patient presents with fever and a diffuse pustular eruption.

J Antibiot (Tokyo), 1986 Jun, 39(6), 822 - 6
Synthesis of benzylpenicillin by cell-free extracts from Streptomyces clavuligerus; Jensen SE et al.; Cell-free enzyme concentrates from Streptomyces clavuligerus were found to convert phenylacetyl-L-cysteinyl-D-valine (PCV) directly into benzylpenicillin when incubated under reaction conditions which support the activity of isopenicillin N synthetase . The formation of benzylpenicillin was detected both by biological assay and by high performance liquid chromatography . Supplementation of PCV-containing reaction mixtures with cofactors required for ring expansion activity did not result in the production of cephalosporins . Incubation of phenoxyacetyl-L-cysteinyl-D-valine (PoCV) under the same reaction conditions did not result in the formation of penicillin V or any cephalosporin product.

Antimicrob Agents Chemother, 1986 Jun, 29(6), 1108 - 9
Cephalosporin-induced hypoprothrombinemia: is the N-methylthiotetrazole side chain the culprit?
Agnelli G, Del Favero A, Parise P, Guerciolini R, Pasticci B, Nenci GG, Ofosu F.
The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new beta-lactamase-stable cephalosporins prompted us to evaluate the effect on hemostasis of three cephalosporins (cefamandole, ceftriaxone, and ceftazidime) in 30 patients with serious infections . Cefamandole and ceftriaxone, both containing a sulfhydryl group, induced a significant and similar prolongation of prothrombin time and decrease in factor VII activity . Ceftazidime, in contrast, had no effect on these two parameters.

Biochem Pharmacol, 1986 Jun 1, 35(11), 1781 - 6
H+ gradient-dependent transport of aminocephalosporins in rat intestinal brush-border membrane vesicles . Role of dipeptide transport system; Okano T et al.; The transport of cephalosporin antibiotics in brush-border membrane vesicles isolated from rat small intestine has been studied by a rapid filtration technique, demonstrating a carrier-mediated transport system for aminocephalosporins such as cephradine . In agreement with the transport mechanisms of dipeptides, the uptake of cephradine by brush-border membrane vesicles was Na+-independent and was stimulated in the presence of an inward H+ gradient ({H+}o greater than {H+}i) . Cephradine uptake in the presence of an inward H+ gradient was a saturable process with an apparent Km of 9.4 mM, and was markedly inhibited by dipeptides but not inhibited by amino acids . The present data suggest that aminocephalosporins can be transported by a common carrier-mediated system with dipeptides in the intestinal brush-border membranes and this process may be driven by an H+ gradient.

Pathol Biol (Paris), 1986 Jun, 34(5 Pt 2), 559 - 60
{Hepatic diffusion of ceftriaxone}; Lucht F et al.; We studied the intrahepatic diffusion of ceftriaxone, a new third generation, very potent cephalosporin with a long serum half-life . Sixteen patients had percutaneous liver biopsy for suspected liver disease or protracted fever of unknown origin . Serum samples and liver biopsy specimens were taken simultaneously . Serial determinations of ceftriaxone concentrations showed that the hepatic half-life was significantly shorter than the serum half-life . We suggest that ceftriaxone be used in higher or more closely spaced doses for the treatment of liver infections.

Biochem Biophys Res Commun, 1986 May 29, 137(1), 528 - 35
Cell-free synthesis of delta-(L-alpha-aminoadipyl)-L-cysteine, the first intermediate of penicillin and cephalosporin biosynthesis; Banko G et al.; delta-(L-alpha-aminoadipyl)-L-cysteine synthetase (LL-AC synthetase) activity has been found in extracts of Cephalosporium acremonium C-10 . The enzyme extract carries out a linear synthesis of LL-AC from its constituent amino acids for at least 6 hours . The reaction is dependent on active enzyme, time, L-alpha-aminoadipate, L-cysteine, ATP and Mn2+ or Mg2+ . The activity is stabilized by glycerol.

Neurosurgery, 1986 May, 18(5), 632 - 6
Vancomycin penetration of a brain abscess: case report and review of the literature; Levy RM et al.; A 56-year-old man developed an abscess within a right parietal cystic anaplastic astrocytoma 3 days after removal of iodine-125 sources placed 9 days earlier for interstitial radiation therapy . After treatment with cephalosporin antibiotics proved unsuccessful, the patient was treated with intravenous vancomycin and intermittent percutaneous drainage of the abscess . Vancomycin levels obtained from the brain abscess fluid, both before and during later operative removal of the abscess, were 15 and 18 micrograms/ml, respectively; the serum vancomycin level was 21 micrograms/ml . This is the first report of the excellent penetration of vancomycin into brain abscess fluid.

Cutis . 1986 May;37(5):390.
Cryptogenic drug eruption resulting from cephalosporin lavage; Szylit JA et al.; The actual cause of a drug eruption may not be obvious at times . In such cases, careful review of medication logs, order sheets, and progress notes should be supplemented by nursing notes and verification of treatment given by those responsible for the patient's care.

Pathol Biol (Paris), 1986 May, 34(5), 320 - 4
{In vitro study of ceftriaxone binding to blood}; Brandebourger M et al.; Binding of ceftriaxone, a new third generation cephalosporin, to blood was studied in vitro . Steady state dialysis with 14C-ceftriaxone was used . Percentages of ceftriaxone bound to plasma within the range of therapeutic concentrations (10 to 1,000 microM) varied widely (80 to 50%) . Indicating that the binding process is saturable, investigations performed with various isolated plasma proteins in physiologic concentrations show that ceftriaxone binds mainly to albumin, and marginally or not at all to alpha-1-acid glycoprotein, gammaglobulins, transferrin, haptoglobin, and lipoproteins . Albumin has a single binding site (n = 0.7) with moderate affinity (Ka = 72,000 M-1) for ceftriaxone . The presence of this site explains why ceftriaxone binds to plasma according to a saturable process . Only a small proportion (5%) of ceftriaxone (75-450 microM) binds to red blood cells in whole blood with a 50% hematocrit . A strongly significant inhibition of ceftriaxone (520 microM) binding to plasma was found with high bilirubin levels (230 microM) (24% decrease; p less than 0.01) . A small but significant decrease in ceftriaxone (380 microM) binding to plasma was found with high serum oleic acid (1014 microM) or uric acid (1,800 microM) concentrations (2% decrease; p less than 0.05).

Antimicrob Agents Chemother, 1986 May, 29(5), 849 - 51
Dose ranging study of cefpimizole (U-63196E) for treatment of uncomplicated gonorrhea in men; Sandberg ET et al.; We conducted a two-center dose ranging study to evaluate the efficacy, tolerance, and toxicity of cefpimizole, a new cephalosporin, in the treatment of uncomplicated gonorrhea in 96 males . Twelve patients at each center were treated intramuscularly with single doses of 1.0, 0.5, 0.25, and 0.125 g of cefpimizole . All urethral infections were cured at the highest dose, but lower doses produced progressively decreasing cure rates of 90% (0.5 g), 83% (0.25 g), and 71% (0.125 g) . Treatment failures of rectal and pharyngeal infections occurred at the highest dose level . Geometric mean MICs for cefpimizole for successfully and unsuccessfully treated volunteers were 0.088 and 0.282 micrograms/ml, respectively . A prominent adverse effect was clinically significant pain at the injection site, which occurred in 57 (59%) of 96 patients . Results of the study demonstrate that cefpimizole offers no advantage over currently available antibiotics in the treatment of uncomplicated gonorrhea in men.

Jpn J Antibiot, 1986 Apr, 39(4), 1128 - 37
{Clinical experience with cefixime in the pediatric infections}; Furukawa S et al.; We used cefixime (CFIX), a newly developed oral cephalosporin antibiotic, to treat 21 children with various infections . The results are summarized as follows . The serum half-lives of CFIX after an administration of 6 mg/kg to each of 2 children were 2.56 and 2.79 hours . The serum concentrations were high enough to ensure the therapeutic response . The clinical response was "excellent" in 16 children and "good" in 5, with a 100% efficacy rate . No side effects were recorded . The only abnormal finding was slight eosinophilia in 1 child.

J Antimicrob Chemother, 1986 Apr, 17(4), 471 - 9
Disc diffusion test for the determination of semi-quantitative substrate profiles of beta-lactamases; van de Klundert JA et al.; The incorporation of beta-lactamases from crude, cell-free lysates incorporated into agar plates used for antibiotic sensitivity testing with sensitivity discs results in a characteristic decrease in the inhibition zones . The degree of zone reduction for a particular antibiotic depends on the substrate specificity of the enzyme involved and the concentration of the enzyme in the agar . By using this technique a distinction can be made between cephalosporinases, penicillinases and broad-spectrum enzymes . In a number of cases, the identification of the enzyme subclass is possible, provided that the relevant penicillin and cephalosporin discs are included in the test . For the elucidation of substrate profiles for routine and epidemiological purposes this method can replace other, more elaborate techniques, such as the iodometric, spectrophotometric and acidimetric methods . An analysis by this method is presented for 126, unrelated, consecutive clinical isolates.

Am J Obstet Gynecol, 1986 Apr, 154(4), 955 - 60
Single-dose cefotetan versus multidose cefoxitin for prophylaxis in cesarean section in high-risk patients; McGregor JA et al.; A prospective, randomized, open trial of a single intravenous dose of a new broad-spectrum and long-acting cephalosporin was compared with the effect of three doses of cefoxitin in a group of 70 women undergoing cesarean section who were at high risk for postoperative endomyometritis and wound infection . All patients either had ruptured membranes or were in active labor, or both, without clinically detectable chorioamnionitis at the time of prophylaxis . Forty-six women received a single 2 gm dose of cefotetan and 24 received 2 gm of cefoxitin every 4 hours to complete a three-dose regimen . Outcomes of infectious febrile morbidity due to endomyometritis (15% versus 8%), wound erythema (4% versus 12%), and other parameters were similar for cefotetan and cefoxitin, respectively . Both agents were well tolerated in this high-risk population . Within the limits of this study, single-dose cefotetan chemoprophylaxis appears to be comparable to multidose cefoxitin administration in reducing morbidity in operative site infections after cesarean section.

Am J Obstet Gynecol, 1986 Apr, 154(4), 946 - 50
Cefotetan in the treatment of obstetric and gynecologic infections; Poindexter AN 3rd et al.; The efficacy, tolerance, and safety of cefotetan--a new 7-alpha-methoxy cephalosporin--was assessed in controlled and uncontrolled evaluations involving 131 evaluable patients hospitalized with obstetric and gynecologic infections . The 99% satisfactory clinical response rate obtained with this drug was equivalent to that obtained with either moxalactam or cefoxitin, yet the mean amount of cefotetan given was lower than that of the other two drugs . Cefotetan was well tolerated and produced no major adverse reactions . In this era of Diagnosis Related Groups and cost containment, the twice-daily dosage schedule of cefotetan is a decided cost benefit.

J Lab Clin Med, 1986 Mar, 107(3), 269 - 78
Calcium-specific immunoassays for factor IX: reduced levels of antigen in patients with vitamin K disorders; Bray GL et al.; Polyclonal rabbit anti-factor IX antisera were fractionated to establish solid-phase immunoassays recognizing calcium-dependent and non-calcium-dependent epitopes . The assays were greater than 99.9% specific for factor IX and sensitive to 0.05 U/dl plasma or 2 ng/ml purified factor IX . For the calcium-dependent fraction, an absolute requirement of divalent metal ions was found, and Sr(II), Mn(II), and Mg(II) could substitute for Ca(II) . On immunoblots of reduced, electrophoresed factor IXa, the 125I-calcium-dependent antibody fraction bound to the amino-terminal light chain . Plasma sampled from 13 patients receiving warfarin and one with cephalosporin-related vitamin K deficiency had a mean level of calcium-dependent factor IX antigen of 22 U/dl, comparable to the 24 jU/dl average of factor IX procoagulant activity; these two results were highly correlated . Antigen levels determined by either the polyclonal or a monoclonal, non-calcium-dependent anti-factor IX assays ranged from 1.7-fold to 6.0-fold greater than the corresponding levels of factor IX procoagulant activity or calcium-dependent antigen level for each subject's plasma . The difference reflects inactive, circulating factor IX . In contrast, factor IX antigen levels determined by an assay using a monoclonal, calcium-dependent anti-factor IX were from one half to one thirteenth as much as those measured by the polyclonal, calcium-dependent immunoassay . The disparity between results of calcium-dependent assays suggests that some Gla residues near the amino terminus of factor IX are relatively less important for normal procoagulant function of factor IX than others, are more sensitive to the effects of vitamin K antagonism or deficiency, and are important for the epitope recognized by this particular calcium-dependent, monoclonal antibody.

J Clin Hosp Pharm, 1986 Feb, 11(1), 47 - 54
Stability of cefuroxime sodium in some aqueous buffered solutions and intravenous admixtures; Das Gupta V et al.; Cefuroxime sodium (Zinacef) is a new semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration which is stable to most of the beta-lactamases . The stability of cefuroxime sodium in aqueous solutions, with or without phosphate buffer, and in 5% dextrose and 0.9% sodium chloride injections was studied using a stability-indicating high-pressure liquid chromatographic method developed in our laboratory . The optimum pH range of stability was determined to be approximately 4.5-7.3 . Both buffered and unbuffered solutions followed first-order decomposition . In 5% dextrose and 0.9% sodium chloride injections, cefuroxime was stable for 1 day (more than 90% potent) at 25 degrees C and for at least 30 days at 5 degrees C . At -10 degrees C, there was negligible decomposition after 30 days . The pH values of the solutions stored at 5 degrees C and -10 degrees C remained in the maximum stability range and the solutions were clear even after 30 days of storage . Thawing the frozen solutions in a microwave oven adversely affected the stability.

Am Surg, 1986 Feb, 52(2), 91 - 2
Successful vascular reconstruction . Determinants of disability; Floyd HD et al.; Improvements in limb salvage during the last decade are a reflection of advances in angiography, antibiotics and technique . We report a 100 per cent success rate with vascular repair and a 100 per cent disability outcome in extremity injuries . Ten male patients, with a mean age of 27.3 (range 18 to 41) years, sustained trauma to the extremity with vascular injury . The etiology of injury was gunshot wounds (5), blunt trauma (4), and stab wounds (1) . Time from injury to vascular repair was a mean of 186 (range 60 to 360) min . Vessels injured included popliteal artery and vein (4), tibial artery and vein (2), subclavian artery and vein (2), and axillary artery (1) . Six of the injuries were associated with fracture of the adjacent bone and treated with external skeletal fixation . All patients had an associated nerve injury . Five patients underwent fasciotomy; nine were treated with 500 ml Dextran-40 for 48 hr (each day for 2 days) . All patients received cephalosporin antibiotics pre-, intra-, and post-operatively . All patients had successful vascular repair, as identified by Doppler ultrasound (10 patients) and intra-/post-operative arteriography (5 patients) . The median follow-up period was 22 (range 18 to 30) months . There were no primary amputations (within 30 days); there were four late amputations (2, no function and foot ulcer; 2, causalgia) . The five popliteal/tibial injuries had no dorsiflexion and foot drop, two had no function and leg ulcers; two patients had femoral and sciatic nerve injury at the thigh; and three patients had injuries to the brachial plexus.(ABSTRACT TRUNCATED AT 250 WORDS)

Immun Infekt, 1986 Feb, 14(1), 28 - 9
{Effect of cefodizime on the immune system: in vitro studies}; Limbert M; Cefodizime is a broad-spectrum cephalosporin with high efficacy, especially in experimental infections . The in vivo activity may be partly due to an immunomodulatory effect . Macrophages in cefodizime-treated mice showed enhanced activity (chemiluminescence, IL-1-synthesis, IFN-synthesis) . The number of PFC increased during the treatment with cefodizime . The spleen cells of these mice showed elevated responses to dextransulfate and LPS but not to ConA or PHA.

Ther Drug Monit, 1986, 8(4), 483 - 9
Protein binding of ceftriaxone: comparison of three techniques of determination and the effect of 2-hydroxybenzoylglycine, a drug-binding inhibitor in uremia; Fiset C et al.; Ceftriaxone is a third-generation cephalosporin exhibiting a long half-life and a concentration-dependent protein binding . This study compared three techniques of protein binding determination (equilibrium dialysis chamber, ultrafiltration cones (Centriflo), and ultrafiltration (Centrifree micro-partition system) on human plasma and serum at ceftriaxone concentrations achieved clinically . A second objective was to determine the effect of 2-hydroxybenzoylglycine (HBG) on the protein binding of ceftriaxone . High performance liquid chromatography (HPLC) and liquid scintillation counting assays were used . Equilibrium dialysis was rotated for 12 h . The supplier's recommendations were followed for ultrafiltration techniques . The plasma protein binding of ceftriaxone, as determined by equilibrium dialysis and assayed by HPLC, decreased from 98.6 to 73.5% for drug concentrations varying from 25 to 400 micrograms/ml . Somewhat lower values were obtained with Centrifree, the binding fell from 92.1 to 73.5% for the same concentration range . Serum protein binding was similar to results obtained with plasma samples . Centriflo cones yielded more inconsistent results . A significant difference was seen between the three techniques (p less than 0.0001, three-way analysis of variance) . The addition of HBG, a compound that inhibits drug binding in uremia, resulted in ceftriaxone binding defects similar to those seen in uremic serum . Although equilibrium dialysis remains a classic method of protein binding determination, Centrifree appears to be a better system.

Chemotherapy, 1986, 32(5), 399 - 403
Displacement effect of ceftriaxone on bilirubin bound to human serum albumin; Gulian JM et al.; The effects of ceftriaxone, a 'third-generation' cephalosporin, on bilirubin-serum albumin complexes were investigated . This study was performed on human adult samples at various bilirubin-albumin ratios . Ceftriaxone caused a decrease of unconjugated bilirubin and simultaneously an increase of erythrocyte-bound bilirubin . These variations were proportionally more important for low concentrations of antibiotic, including therapeutic values . It was concluded that ceftriaxone competes with bilirubin and displaces it from albumin-binding sites.

Arch Gynecol, 1986, 239(1), 59 - 62
IUD-associated ovarian actinomycosis causing bowel obstruction; Maroni ES et al.; PIP: This case report presents an unusual case of primary IUD-associated ovarian actinomycosis, which spread to the sigmoid causing intestinal obstruction . A 43-year-old gravida 3, para 2, had her 1st IUD from 1978-80 (Gyne-T) and her 2nd IUD from 1980 to October 1983 (Multiload) . Right lower abdominal pain led to hospitalization in May 1983 . A tender nodular mass was palpated in the left pelvic area . Laboratory results confirmed the presence of inflammation . Rapid improvement followed a course of laxatives and cephalosporin antibiotics, and the patient was discharged with the diagnosis of acute sigmoid diverticulitis . 2 months later, a double contrast examination of the large intestine was done and showed severe narrowing of the sigmoid colon over a distance of 12 cm and occasional sharp recesses . Colonoscopy showed a spastic stricture of the sigmoid with massive edema of the otherwise intact mucosa at 18 cm . Computer tomography of the abdomen showed a large, focally cystic infiltrative mass in the pelvis with congestion and displacement of both ureters as well as bilateral hydronephrosis, predominantly on the right side . The descending colon was congested . The patient was readmitted to hospital with the tentative diagnosis of ovarian cancer when her general condition deteriorated . She complained again of abdominal pain in the right lower quadrant and alternating diarrhea and constipation . Pyrexia and the hematological findings suggested sepsis . The pelvis contained a predominantly leftsided nodular mass and a brown fetid discharge was coming through the cervix . The IUD was removed and treatment with ampicillin and clindamycin was started with rapid improvement in the patient's condition . Obstruction with extreme distention of the colon required emergency laparotomy . An inflammatory mass was found in the pelvis consisting of a right-sided ovarian tumor, bilateral hydrosalpinges, and a tightly encased sigmoid colon . The dilated caecum had a large necrotic area in its wall which necessitated caecostomy and double-current sigmoidostomy after subtotal hysterectomy and bilateral salpingo-oophorectomy . The patient made a good recovery . As recently as the 1950s, primary pelvic actinomycosis was a rarity . In the last 4 years alone, 20% of all reported cases of actinomycosis involved the female genital tract . The percentage of cases found among IUD users has been continuously increasing and in the last 2 years all published cases were IUD users . The presence of actinomyces in vaginal smears always is indicative of the presence of a foreign body, most commonly and IUD .

Chemotherapy, 1986, 32(3), 205 - 8
Azlocillin serum levels on repetitive dosage in patients with normal and abnormal renal function; Wenk M et al.; Azlocillin serum concentrations were followed in 9 severely ill patients with various degrees of renal dysfunction after single and repetitive dosage . All patients were treated concomitantly with a cephalosporin and/or an aminoglycoside antibiotic . Elimination halflives (t1/2 beta) were highly variable (62-1, 194 min), but no significant increase occurred in patients with stable renal function during repetitive dosage due to previously described nonlinear pharmacokinetic behavior of azlocillin . However, drug accumulation was observed in patients with deterioration of renal and hepatic function . The rise in drug accumulation can be disproportionally high if both routes of elimination are affected . In such cases, careful dosage adjustment of azlocillin is required to avoid toxic side effects.

Vutr Boles, 1986, 25(2), 89 - 93
{Noncompartment (model-independent) pharmacokinetic analysis . 1 . The method of statistical moments in evaluating the pharmacokinetic characteristics of cefotiam following its intravenous administration}; Terzinvanov D; The pharmacokinetic analysis was enriched, during the last several years, with the method of statistical moment (MSM)--an alternative for the classical compartment approach, presumed as model-non-dependent . The advantages of MSM presented are: elimination the necessity of constructing a model in advance and as a result--elaboration of complicated computer programmes . The possibilities of MSM in a comparative aspect with the traditional compartment pharmacokinetic analysis are presented in the present paper, making use of the data about cephalosporin antibiotic cefothiam after intravenous administration to patients after cholecystectomy . The values of the pharmacokinetic parameters studied, evaluated via both methods, did not statistically differ, suggesting the possibility of using MSM method as an alternative method for rapid evaluation of the pharmacokinetic parameters necessary for the elaboration of dose regimes.

Jpn J Antibiot, 1986 Jan, 39(1), 109 - 15
Pharmacokinetics of cefotiam in the exudate from wounds of patients with breast cancer operated upon for radical mastectomy; Mizuta E et al.; Cephalosporin antibiotics have been widely used to prevent infections during and after operation . To establish an efficient use of prophylactic antibiotics for patients undergoing surgery, it is important to investigate the drug levels in exudate from wounds of the patients and to elucidate the relation between drug concentration in the blood and that in the exudate . In a previous paper, the present authors (except E.M . and Y.K.) determined cefotiam (CTM) concentrations in serum and exudate from wounds of patients with breast cancer who underwent radical mastectomy and discussed an adequate regimen of CTM prophylaxis after the operation . However, CTM concentrations in serum and exudate from the wounds of the patients were not analyzed pharmacokinetically . In the present paper we report on the disposition kinetics of CTM in serum and exudate from wounds after the administration of CTM following bolus intravenous injection into patients with breast cancer operated upon for radical mastectomy.

Alcohol Clin Exp Res, 1986 Jan-Feb, 10(1), 27 - 32
The effect of 5,5'-dithiobis(1-methyltetrazole) on cytoplasmic aldehyde dehydrogenase and its implications for cephalosporin-alcohol reactions; Kitson TM; Cephalosporin antibiotics with a 1-methyltetrazole-5-thio side chain have the ability to cause an unpleasant flushing reaction if they are taken some time before the drinking of alcohol . It is proposed that the explanation for this is that the side chain becomes liberated in vivo and oxidized to 5,5'-dithiobis(1-methyltetrazole) or to a mixed disulfide analogue which then inactivates aldehyde dehydrogenase . Support for this proposal is given by the results below concerning the interaction in vitro between the disulfides and sheep liver cytoplasmic aldehyde dehydrogenase . 5,5'-Dithiobis(1-methyltetrazole) has a rapid and pronounced inactivatory effect, very similar in many ways (though not identical) to that of disulfiram, to which it has a structural similarity . (Disulfiram is widely used therapeutically to deter alcoholics from drinking.) 1-Methyl-5-methylthiotetrazole (which is a simple model of the antibiotics) and the free 1-methyltetrazole-5-thiol have no effect on the enzyme in vitro, but methyl 5-(1-methyltetrazolyl) disulfide is a potent inactivator; this also supports the proposed pathway.

Drug Metab Dispos, 1986 Jan-Feb, 14(1), 132 - 6
Serum protein binding of a new oral cephalosporin, CL 284,635, in various species; Bialer M et al.; CL 284,635 is a new third generation oral cephalosporin . Its serum protein binding was investigated in the human, monkey, dog, rat, and rabbit . This study was performed by using an equilibrium dialysis and ultrafiltration method, using radiolabeled and cold CL 284,635 . In humans, CL 284,635 was found to have a mean free fraction {fu = concentration of unbound (free) drug divided by total concentration of unbound plus bound to serum proteins} of 31.3 +/- 3.3% with no serum concentration dependency in a range of 0.5 to 26 micrograms/ml . The drug was mainly bound to albumin . In rabbits and monkeys the protein binding profile of CL 284,635 was found to be 36.1 +/- 2.3% and 33.9 +/- 1.5% with no serum concentration dependency . In rats and dogs a non-concentration-dependent fu was observed at serum concentrations ranging from 0.5 to 30 micrograms/ml . A gradual increase in fu values was observed at higher serum concentrations of CL 284,635 . Overall, the protein binding profile of CL 284,635 was found to be different in the five investigated species . The protein binding of CL 284,635 in monkeys and rabbits was most similar to that in humans . These species differences in protein binding may have an impact on the disposition of the drug in different species.

Hosp Formul, 1986 Jan, 21(1), 76 - 8, 83-4
Cephalosporin selection: view from a beleaguered P & T committee member; Talley JH; Formulary decisions in smaller community hospitals are often not made with the same criteria used in large university medical centers . Community hospitals do not have the diagnostic technologies of the tertiary medical centers, nor do they experience the wide variety of bacterial infections . When the P & T Committees of such hospitals make formulary decisions regarding cephalosporins, they must base these choices on their particular needs, such as breadth of coverage and cost-effectiveness . A P & T Committee member from a community hospital offers his views on appropriate cephalosporin selection.

Fundam Appl Toxicol, 1985 Dec, 5(6 Pt 1), 1153 - 60
Cephaloridine nephrotoxicity: strain and sex differences in mice; Pasino DA et al.; Marked species and sex differences have been observed in the nephrotoxicity to the cephalosporin antibiotic cephaloridine (CPH) . Preliminary studies have also indicated significant strain differences in mice to CPH nephrotoxicity . To investigate these findings further, male and female C57BL, BALB/c, CD-1, CFW, CBA/J, and DBA/2 mice were given either 4000 or 6000 mg/kg of CPH, sc . Renal function was assessed 48 hr later by the ability of renal cortical slices to accumulate the organic ions p-aminohippurate (PAH) and tetraethylammonium (TEA), changes in blood urea nitrogen (BUN) and kidney-to-body wt ratios . CPH produced dose-dependent nephrotoxicity in C57BL female mice . After 6000 mg/kg, PAH and TEA slice-to-medium (S/M) ratios were reduced by 70 and 49%, respectively; BUN was elevated 10-fold . The same dose given to CFW females had no effect . BALB/c, CD-1, CBA/J, and DBA/2 females showed intermediate signs of toxicity . Male mice of all strains tested exhibited no nephrotoxicity . CPH nephrotoxicity has been correlated with the concentration of CPH within the tubular cell; and C57BL female mice had relatively greater intracellular accumulation of CPH than C57BL male mice and CFW female mice in vitro and in vivo . Thus, differences in net renal cortical accumulation of CPH suggest possible differences in transport, binding, and/or metabolism of CPH may exist among strains and between sexes of mice.

Surg Gynecol Obstet, 1985 Dec, 161(6), 518 - 22
Comparative clinical evaluation of ceftizoxime with clindamycin and gentamicin and cefoxitin in the treatment of postcesarean endomyometritis; Apuzzio JJ et al.; New third generation cephalosporins have been recommended as single agent antibiotic therapy in the treatment of postoperative infections . This study compares the new third generation cephalosporin ceftizoxime with cefoxitin, clindamycin and gentamicin in the treatment of postcesarean section endomyometritis . The results indicate that the clindamycin and gentamicin regimen is more efficacious in the treatment of severe infection after cesarean section than either ceftizoxime or cefoxitin regimens . Therefore, the results of this study suggest caution in substituting single drug antibiotic therapy with cefoxitin or the third generation cephalosporins for the standard clindamycin and gentamicin regimen in the treatment of postcesarean section endomyometritis until more clinical data are available.

Am J Hosp Pharm, 1985 Nov, 42(11), 2506 - 9
In vitro inactivation of tobramycin by cephalosporins; Spruill WJ et al.; The in vitro inactivation of tobramycin when combined with each of six cephalosporins in samples of human serum was investigated . Each of six cephalosporins (cefazolin sodium, cefoxitin sodium, cefamandole nafate, moxalactam disodium, cefoperazone sodium, and cefotaxime sodium) was added to human serum samples containing tobramycin sulfate 8 micrograms/mL to produce final cephalosporin concentrations of approximately 250 and 1000 micrograms/mL . Duplicate solutions were prepared and stored at either 0 or 21 degrees C . Solutions containing tobramycin 8 micrograms/mL alone and with carbenicillin disodium in four concentrations were prepared as controls . Samples were assayed using a fluorescence polarization immunoassay (TDX) at 0, 2, 4, 8, 12, 24, and 48 hours to determine tobramycin concentration; two of the carbenicillin-tobramycin solutions were frozen immediately for assay 53 hours later . Tobramycin concentrations in the admixtures were compared with those in tobramycin reference samples . At both temperatures, samples containing tobramycin with cefamandole 250 micrograms/mL or cefotaxime 250 micrograms/mL showed less than 10% inactivation of tobramycin for at least 48 hours . At 0 degrees C, tobramycin retained greater than 90% activity when combined with cefoperazone 250 and 1000 micrograms/mL . In samples containing cefazolin 250 micrograms/mL at 0 degrees C and cefoperazone 250 micrograms/mL at 21 degrees C, tobramycin was stable for 24 hours . Only samples containing moxalactam stored at 21 degrees C showed greater than 16% inactivation of tobramycin at 48 hours . Under these study conditions, tobramycin is only moderately inactivated in vitro when combined with clinically achievable concentrations of the tested cephalosporins (excluding moxalactam) and then stored for up to 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Am Rev Respir Dis, 1985 Nov, 132(5), 1093 - 7
Isoelectric focusing of beta-lactamases in Mycobacterium fortuitum . Association of a single enzyme pattern with cefoxitin resistance; Wallace RJ Jr et al.; The uninduced culture supernatants and cell extracts from 58 strains of the 3 biovariants (biovar) of Mycobacterium fortuitum were all positive for beta-lactamase with the chromogenic cephalosporin substrate . By analytical isoelectric focusing (IEF), 29 of 30 strains of biovar fortuitum exhibited an identical beta-lactamase pattern with 1 major band . In contrast, the beta-lactamases of biovar peregrinum and the unnamed third biovar were heterogeneous, with multiple bands and a variety of patterns . The pH range of isoelectric points for the beta-lactamases was relatively narrow, however, with most bands appearing between pH 4.3 and 5.2 . Although additional genetic studies are required, these enzymes appear to be chromosomal, as they are present in all strains including some without detectable plasmids . Repeat isolates from the same patient obtained up to six months apart always had the same beta-lactamase pattern by IEF . Of the third biovar complex, 30% are cefoxitin resistant with minimal inhibitory concentrations greater than 32 micrograms/ml . All 9 cefoxitin-resistant isolates tested had the same unique beta-lactamase pattern by IEF, although this enzyme failed to hydrolyze cefoxitin while hydrolyzing cephalothin and benzylpenicillin . Thus, despite the association of cefoxitin-resistance with a single enzyme pattern, the role of this beta-lactamase in resistance is not known.

J Pharm Pharmacol, 1985 Nov, 37(11), 836 - 9
Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone; Kwon KI et al.; The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated . Caffeine failed to decrease in-vitro protein binding of ceftriaxone . Rabbit plasma concentrations of ceftriaxone (30 mg kg-1 i.v.) were elevated significantly (P less than 0.05 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg-1 i.v . was co-administered compared with ceftriaxone given alone . Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 +/- 38 ml kg-1 (mean +/- s.d., n = 6) to 97 +/- 33 ml kg-1 (caffeine 5 mg kg-1, P less than 0.05), and 94 +/- 8 ml kg-1 (caffeine 10 mg kg-1, P less than 0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 +/- 106 ml kg-1 (mean +/- s.d., n = 6) to 31 +/- 18 ml kg-1 (caffeine 5 mg kg-1, P less than 0.5) and 36 +/- 31 ml kg-1 (caffeine 10 mg kg-1, P less than 0.1) . The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P less than 0.05) after caffeine . The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.

J Pharmacol Exp Ther, 1985 Nov, 235(2), 382 - 8
Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,3,4-thiadiazole-5-thiol; Kerremans AL et al.; Heterocyclic thiol metabolites of cephalosporin antibiotics may play an important role in the pathophysiology of hypoprothrombinemia and hemorrhage in patients treated with these drugs . A heterocyclic thiol metabolite of moxalactam, 1-methyltetrazole-5-thiol (MTT), inhibits the gamma carboxylation of glutamic acid that is required for the formation of active clotting factors . One possible pathway for the biotransformation of thiol compounds such as MTT is S-methylation catalyzed by either thiopurine methyltransferase (TPMT), a soluble enzyme, or by thiol methyltransferase, a microsomal enzyme . Therefore, MTT and 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), a thiol "leaving group" structurally related to MTT that is present in cefazolin, were tested as possible substrates for S-methylation catalyzed by purified human kidney TPMT or by human liver microsomes, a source of thiol methyltransferase . MTT and MTD were methylated by both human kidney TPMT and human liver microsomes . The products of these reactions were shown by high-performance liquid chromatography to be S-methyl MTT and S-methyl MTD . Apparent Km constants for the methylation of MTT and MTD by TPMT were 0.26 and 0.068 mM, respectively . Apparent Km constants for the methylation of MTT and MTD by human liver microsomes were 0.60 and 0.20 mM, respectively . Maximal velocity (Vmax) values for the S-methylation of MTD catalyzed by TPMT and by human liver microsomes were 3.58- and 678-fold greater than were those for the thiol methylation of MTT . Finally, S-methyl derivatives of MTT and MTD were one to two orders of magnitude less potent as inhibitors of the in vitro gamma carboxylation of glutamic acid than were MTT and MTD themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

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