Cephamycins, a New Family of β-Lactam Antibiotics. IV. In Vivo Studies

Cephamycin A was found to be more active in vivo than cephamycin B. In comparison with cephamycin C, cephamycin A was more active against gram-positive organisms but less active against gram-negative organisms. Given subcutaneously, cephamycin C had good in vivo gram-negative activity, comparing favorably with cephalothin and cephaloridine against cephalosporin-susceptible organisms. In general, against the gram-negative organisms, it was more active than cephalothin or cephalosporin C and about as active as cephaloridine. In addition, cephamycin C protected mice against beta-lactamase-producing Proteus cultures, including clinically isolated strains. The compound is remarkably nontoxic. Cephamycin C was detected in the serum and recovered from the urine of treated mice to about the same extent as cephaloridine. Like cephaloridine and cephalosporin C, cephamycin C must be excreted mainly by glomerular filtration, because the use of probenecid did not enhance the therapeutic effectiveness nor concentrations of these agents in the sera of treated mice.     

Cephamycins, a New Family of β-Lactam Antibiotics II. Isolation and Chemical Characterization

Cephamycins A and B were isolated from the same fermentation broth of various actinomycetes by adsorption and ion-exchange methods. The antibiotics were separated from each other by column chromatography on a dextran-based ion-exchange resin. Cephamycin C was isolated from a different fermentation broth by ion-exchange and gel-filtration methods. The chemical characteristics of these new antibiotics were determined.     

Cephamycins, a New Family of β-Lactam Antibiotics: Antibacterial Activity and Resistance to β-Lactamase Degradation

The susceptibility to some cephalosporin antibiotics and to cephamycin C, a member of a new family of beta-lactam antibiotics, was evaluated for 466 cultures representing 11 different genera or species of gram-negative clinical isolates. The susceptibility of 39 gram-negative cultures known to produce beta-lactamase was also determined. The beta-lactamase activity of a representative group of the clinical isolates and the 39 enzyme producers was studied with the cephalosporins (cephalothin and cephaloridine) and cephamycin C as substrates and was related to the in vitro disc susceptibility to these same antibiotics. The significant resistance to beta-lactamase displayed by the cephamycins is reflected in the kinetics of enzyme activity (K(m) and V(max)) that are reported for the cephalosporins and the cephamycins. Resistance to beta-lactamase is probably one of the reasons that many cephalosporin-resistant cultures are susceptible to cephamycin C.     

Cephamycins, a New Family of β-Lactam Antibiotics I. Production by Actinomycetes, Including Streptomyces lactamdurans sp. n

A number of actinomycetes isolated from soil were found to produce one or more members of a new family of antibiotics, the cephamycins, which are structurally related to cephalosporin C. The cephamycins were produced in submerged fermentation in a wide variety of media by one or more of eight different species of Streptomyces, including a newly described species, S. lactamdurans. These antibiotics exhibit antibacterial activity against a broad spectrum of bacteria which includes many that are resistant to the cephalosporins and penicillins.     

Yersinia enterocolitica: Comparative In Vitro Activities of Seven New β-Lactam Antibiotics

Minimum inhibitory concentrations of seven new β-lactam derivatives were determined against 35 isolates of Yersinia enterocolitica. Ceftizoxime and ceftriaxone were the most active of the antimicrobial agents tested.     

In Vitro Activities of Thirteen β-Lactam Antibiotics Against Chlamydia trachomatis

The in vitro activity (minimal inhibitory concentration and minimal lethal concentration) of 13 β-lactam antibiotics against two laboratory strains of Chlamydia trachomatis was compared. No useful activity could be detected.     

Inhibition of β-Lactamases by β-Lactam Antibiotics

The inhibitory properties of a selected number of beta-lactam antibiotics were studied, with the use of three distinct types of beta-lactamases. The three enzymes were found to be distinguishable on the basis of their susceptibility to inhibition. Not one of the potential inhibitors tested was found to be a potent inhibitor of all three enzymes, but nafcillin possessed the broadest inhibitory activity. The enzyme isolated from Enterobacter cloacae was found to be the most susceptible. In some cases, the degree of inhibition varied with the time of incubation, and, depending upon the time chosen, widely different observations could be made. It is suggested that, in studies such as these, every consideration should be given to the period of incubation and to the concentration of inhibitor employed. Mixtures of inhibitor and cephaloridine did not always act synergistically against growing bacteria, and a number of reasons for failure are suggested.     

Comparative Stability of Newly Introduced β-Lactam Antibiotics to Renal Dipeptidase

Renal dipeptidase purified from swine kidney hydrolyzed N-formimidoyl thienamycin, carpetimycins A and B, and Sch29482, but not azthreonam, penicillin G, or cephaloridine.     

In Vitro Susceptibility of Haemophilus influenzae and Neisseria gonorrhoeae to Ro 13-9904 in Comparison with Other β-Lactam Antibiotics

Ro 13-9904 has high in vitro activity, as does cefotaxime, against 57 Haemophilus influenzae and 60 Neisseria gonorrhoeae strains, including 5 and 11 beta-lactamase-producing strains in each group, respectively.     

Correlation Between the Binding of β-Lactam Antibiotics to Staphylococcus aureus and Their Physical-Chemical Properties

The rate of ¹⁴C-benzylpenicillin (penicillin G) binding to Staphylococcus aureus Oxford cells increased with increasing hydrogen ion concentration. The extent of inhibition of ¹⁴C-penicillin G binding caused by a competing ¹²C-β-lactam antibiotic is a function of hydrogen ion concentration and can be correlated both with net charge of a competing ¹²C-molecule and net charge of the S. aureus cell at a given pH. The ability of a β-lactam antibiotic to compete for ¹⁴C-penicillin G-binding sites can generally be correlated with its hydrophobic nature. It is proposed that, although semisynthetic cephalosporins are chemically less reactive than penicillins, they are superior to benzylpenicillin in their ability to permeate the outer surface of the Staphylococcus cell wall and irreversibly bind to reactive sites.     

In Vitro and In Vivo Activities of Syn2190, a Novel β-Lactamase Inhibitor

Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.     

Joint Tolerance to β-Lactam and Fluoroquinolone Antibiotics in Escherichia coli Results from Overexpression of hipA

The basis of joint tolerance to β-lactam and fluoroquinolone antibiotics in Escherichia coli mediated by hipA was examined. An antibiotic tolerance phenotype was produced by overexpression of hipA under conditions that did not affect the growth rate of the organism. Overexpressing hipA probably decreases the period in which bacteria are susceptible to the antibiotics by temporarily affecting some aspect of chromosome replication or cell division.     

Contribution of β-Lactamases to β-Lactam Susceptibilities of Susceptible and Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates

The β-lactamases in 154 clinical Mycobacterium tuberculosis strains were studied. Susceptibilities to β-lactam antibiotics, their combination with clavulanate (2:1), and two fluoroquinolones were determined in 24 M. tuberculosis strains susceptible to antimycobacterial drugs and in nine multiresistant strains. All 154 M. tuberculosis isolates showed a single chromosomal β-lactamase pattern (pI 4.9 and 5.1). M. tuberculosis β-lactamase hydrolyzes cefotaxime with a maximum rate of 22.5 ± 2.19 IU/liter (strain 1382). Neither amoxicillin, carbenicillin, cefotaxime, ceftriaxone, nor aztreonam was active alone. Except for aztreonam, β-lactam combinations with clavulanate produced better antimycobacterial activity.     

Cefepime-Aztreonam: a Unique Double β-Lactam Combination for Pseudomonas aeruginosa

An in vitro pharmacokinetic model was used to determine if aztreonam could enhance the pharmacodynamics of cefepime or ceftazidime against an isogenic panel of Pseudomonas aeruginosa 164, including wild-type (WT), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achieved in serum with 1- or 2-g intravenous doses, elimination pharmacokinetics were simulated, and viable bacterial counts were measured over three 8-h dosing intervals. In studies with cefepime and cefepime-aztreonam against the PD strain, samples were also filter sterilized, assayed for active cefepime, and assayed for nitrocefin hydrolysis activity before and after overnight dialysis. Against WT strains, the cefepime-aztreonam combination was the most active regimen, but viable counts at 24 h were only 1 log below those in cefepime-treated cultures. Against PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 logs of killing by 24 h. Hydrolysis and bioassay studies demonstrated that aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular environment. In contrast to cefepime-aztreonam, the pharmacodynamics of ceftazidime-aztreonam were not enhanced over those of aztreonam alone. Further pharmacodynamic studies with five other P. aeruginosa strains producing increased levels of cephalosporinase demonstrated that the enhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreonam can enhance the antibacterial activity of cefepime against derepressed mutants of P. aeruginosa producing increased levels of cephalosporinase. This positive interaction appears to be due in part to the ability of aztreonam to protect cefepime from extracellular cephalosporinase inactivation. Clinical evaluation of this combination is warranted.