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 elect