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In vitro evaluations have shown that moxalactam, cefoperazone, and cefotaxime, three new beta-lactam antibiotics, have certain potency and antibacterial spectral characteristics in common. Results of parallel tests of these antibiotics against routine clinical isolates have suggested that these compounds could be tested with one disk that is representative of this spectral class. The key requirement for this class concept in disk testing is that there be no bacterial resistance mechanism that can operate against one, but not all, members of the proposed class. The results of an 11-center study of approximately 500 isolates of multiple-antibiotic-resistant Enterobacteriaceae responsible for nosocomial infections illustrated that cross-resistance to moxalactam, cefoperazone, and cefotaxime is highly variable from center to center. Thus, the spectral class concept of disk susceptibility testing would be inappropriate for this group of drugs.

By an agar-dilution procedure, the minimal inhibitory concentrations of R, S, and R + S epimers of moxalactam were determined for 23 commonly isolated organisms. Generally the R epimer was twice as active as the S epimer; however, against Pseudomonas aeruginosa the two were equally active. The stability of the epimers and of the R + S mixture in saline and serum was studied by high-pressure liquid chromatography. Each epimer was stable at -20 C. The interconversion half-life in serum at 37 C, 22 C, and 4 C was 1.5, 4.8, and 13 hr, respectively, for R and 1.5, 11, and 43 hr for S. In buffer both epimers were more stable. In buffered saline the final mixture of R:S was 50:50, if one started with either the R or the S epimer. In serum, however, the R:S ratio of the mixture at equilibrium was 45:55. In patients with normal renal function the ratio of R:S in serum at 2 hr was 0.69 and at 8 hr, 0.55. In patients with severe renal failure the R:S ratio at 2 hr was approximately 0.9 and at 6 hr, 0.85. Probably, in renal failure, time is sufficient for re-equilibration of the epimeric mixture, and hence there is little alteration in the R:S ratio with time.

The activity of cefotaxime was compared with that of ampicillin, moxalactam, and cefoperozone against 50 isolates of Haemophilus influenzae and with that of ampicillin, carbenicillin, cephalothin, cefoxitin, cefamandole, cefazolin, and several other established and investigational beta-lactam antibiotics against several hundred isolates of gram-negative aerobic enteric bacilli. Minimal inhibitory concentrations of the drugs were determined by the agar plate dilution technique for H. influenzae and by the microtiter broth dilution technique for the other pathogens. Cefotaxime was the most active agent against H. influenzae; it was 20 times more active than ampicillin. It was also the most active agent against Escherichia coli, Klebsiella pneumoniae, nontyphoid Salmonella species, and Yersinia enterocolitica. Cefotaxime was among the most active agents against Enterobacter cloacae, Citrobacter species, Shigella species, Proteus mirabilis, and Acinetobacter calcoaceticus. None of the new cephalosporins or penicillin inhibited greater than 90% of the isolates of Pseudomonas aeruginosa at concentrations of less than or equal to 16 micrograms/ml; these drugs were, however, more active than carbenicillin.

Moxalactam was tested against 80 isolates of anaerobic bacteria from clinical specimens. The results of this study and a review of other studies, in which comparable susceptibility testing methods were used, demonstrated the susceptibility to moxalactam of members of the Bacteroides fragilis group, Bacteroides melaninogenicus, Fusobacterium species, anaerobic gram-positive cocci, and Clostridium perfringens.

Moxalactam was compared with alternative antimicrobial agents for in vivo activity against Bacteroides fragilis. Mice were challenged with one of 15 strains and evaluated by quantitative bacteriologic analysis of abscess contents after five days of treatment. Optimal results were achieved with clindamycin, moxalactam, and cefoxitin. The mean decrease in bacteria with these three drugs was significantly greater than with chloramphenicol, cefotaxime, carbenicillin, cephalothin, ampicillin, and cefoperazone. The penetration of antimicrobial agents into subcutaneous abscesses was examined. The mean peak level in sterile abscesses of moxalactam was 27% of the mean peak serum level, a result indicating relatively good penetration compared with other beta-lactam antimicrobial agents. Stability of moxalactam to the beta-lactamase of B. fragilis was demonstrated in vivo by comparing levels of biologically active drug in sterile and infected abscesses and in vitro by comparing levels of antibiotic incubated in sterile exudate and exudate infected with B. fragilis. Moxalactam compares favorably with clindamycin and cefoxitin in activity against B. fragilis.

The cephamycins are a family of beta-lactam antibiotics that are produced by actinomycetes and are structurally similar to the cephalosporins. They are characterized by the presence of a 7-alpha-methoxyl group, which confers unusually high resistance to beta-lactamases. Cefoxitin, the first semisynthetic cephamycin, is resistant to almost all beta-lactamases. Cefoxitin retains the 3-carbamoyl group of cephamycin C and thus has excellent metabolic stability. Cefoxitin is bactericidal and almost devoid of any inoculum effect. Active against many cephalothin-resistant gram-negative bacteria, cefoxitin demonstrates a very broad spectrum that includes indole-positive Proteus and many strains of Serratia. In contrast to that of the cephalosporins, cefoxitin's spectrum of activity against anaerobic pathogens includes Bacteroides fragilis. The therapeutic effectiveness of cefoxitin in experimental infections in mice confirms the excellent characteristics of this semisynthetic cephamycin and indicates that it should be a very valuable agent for treatment of bacterial infections.

Bleeding complications have occasionally been reported in clinical trials of moxalactam therapy for debilitated and/or malnourished patients. Complications that occur secondary to hypothrombinemia are readily corrected by administration of 5-10 mg of vitamin K. In a few instances, the bleeding complications occurred secondary to suppression of platelet function. The present studies aim at clarifying the mechanisms by which bleeding problems attributable to moxalactam and other beta-lactam antibiotics occur. Moxalactam in vitro did not inhibit blood coagulation or platelet aggregation at concentrations of 700 micrograms of moxalactam/ml. When administered to five normal male volunteers at a dosage of 3 g of moxalactam four times daily for seven days, the antibiotic did not affect the levels of vitamin K-dependent clotting factors II, VII, IX, and X or vitamin K-independent clotting factors V, VIII, and I. Consistently normal levels of the abnormal prothrombin precursor descarboxyprothrombin, as determined by immunochemical and functional assays, showed that moxalactam did not possess warfarin-like properties. Moxalactam induced a significant suppression of adenosine diphosphate (ADP)-induced platelet aggregation. It appears that moxalactam inhibits ADP-induced platelet aggregation in vivo by perturbing the platelet membrane, thus making ADP receptors unavailable to the agonist. Of 33 additional beta-lactam antibiotics tested, 27 were found to suppress ADP-induced aggregation at high concentrations in vitro. It is concluded that moxalactam, as well as many newer and older broad-spectrum antibiotics, causes bleeding complications in debilitated patients by elimination of vitamin K-producing gut microorganisms. However, the clinical implications of the observed suppression of platelet function by many beta-lactam antibiotics are unclear.

Forty-eight case report forms for patients with cultures positive for intraabdominal infection treated with moxalactam were reviewed. The infections included abscess or peritonitis due to appendicitis (26); intraabdominal abscess of other causes (7); peritonitis due to bowel perforation (6), bowel infarction (5), or salpingitis (3); and gangrenous cholecystitis (1). Cultures of peritoneal fluid or abscess contents were performed for all patients. Seventy-eight aerobes and 118 anaerobes were isolated from the 48 patients. Thirty-eight patients (79.2%) were cured, therapy failed in nine (18.8%), and one (2%) developed fatal superinfection with Candida. The nine patients for whom treatment failed had a higher frequency of resistant anaerobes in their initial cultures (59%) than did the patients who were cured (29%; P = 0.036). An enterococcal isolate appeared to play a role in at least one treatment failure. There were no serious adverse reactions; eosinophilia (greater than 500 eosinophils/mm3) occurred in 17.4% of the patients, and phlebitis at the intravenous administration site occurred in one patient. Thus moxalactam shows promise as a single agent for the treatment of intraabdominal infections.

Moxalactam was evaluated in vitro against 600 nosocomial isolates of gram-negative bacteria and was compared with cephalothin, cefoxitin, and cefotaxime. Moxalactam was superior to the other compounds, with minimal inhibitory concentrations of less than or equal to 4 micrograms/ml for 95% of the Enterobacteriaceae isolates and less than or equal to 8 micrograms/ml for 85% of the Bacteroides fragilis isolates; 70% of the Pseudomonas aeruginosa isolates were inhibited with less than or equal to 16 micrograms/ml. Moxalactam at doses ranging from 1 g every 12 hr to 2 g every 8 hr was given to patients with serious infections of the respiratory (14) or urinary (13) tract, abdominal abscess (4), osteomyelitis (4), meningitis (5), soft-tissue phlegmon (3), malignant external otitis (2), peritonitis (1), and panophthalmitis (1). The clinical response was excellent in 35 (74.5%) and improved in 12 (25.5%) of the 47 patients. The pathogen was eradicated in 29 (61.7%) patients, two patients had relapses, and bacteria persisted but in decreased numbers and without development of resistance in 16 patients. The half-life of moxalactam was 146 (+/- 21) and 125 (+/- 34) min after 2-g intravenous and 1-g intramuscular doses, respectively. Kinetic studies in sputum, bile, bone, aqueous humor, prostatic fluid, and cerebrospinal fluid showed moxalactam concentrations several times higher than the required MICs. No appreciable adverse effects or toxicity were observed.

Moxalactam is not significantly susceptible to the majority of beta-lactamases produced by bacteria of clinical relevance. However, two types of enzyme--PSE2 and PSE3--from Pseudomonas aeruginosa can hydrolyze this antibiotic at a significant rate. In this respect moxalactam is similar to 7-alpha-methoxy cephem compounds, such as cefoxitin, which are also susceptible to these enzymes. Moxalactam, like other beta-lactam antibiotics having an acid function in the side chain, is a potent inhibitor of the cephalosporinase from Enterobacter cloacae (type Ia beta-lactamase).

Moxalactam, a new synthetic beta-lactam antibiotic, was evaluated for in vitro and in vivo antibacterial activity and was found to have a broad spectrum of activity against gram-positive and gram-negative bacteria. Moxalactam showed more potent activity than did the cephalosporins tested against clinical gram-negative isolates, including cefazolin-resistant Enterobacteriaceae, glucose-nonfermenting bacteria, and Bacteroides fragilis. Moxalactam was the only beta-lactam antibiotic of those tested (including nine penicillins and 15 cephalosporins) that was not affected by beta-lactamase produced by 15 strains of 10 gram-negative species. The potent in vitro activity and high stability to beta-lactamase of moxalactam corresponded to lower ED50 (50% effective doses) required against intraperitoneal infections in mice due to various bacteria resistant to cefazolin, cefoxitin, or cefotiam. Furthermore, moxalactam showed the greatest therapeutic activity among the nine beta-lactam antibiotics tested in models of intraperitoneal mixed infection in mice with Escherichia coli and Pseudomonas aeruginosa.

Adverse reactions similar to disulfiram reactions observed in volunteers given moxalactam prompted an investigation to determine whether moxalactam, like disulfiram, leads to an accumulation of acetaldehyde during ethanol metabolism. Concentrations of ethanol and acetaldehyde in blood of male Wistar rats given test compounds and ethanol were determined by gas chromatography. Moxalactam, like disulfiram, had no effect on concentrations of ethanol but increased the concentrations of acetaldehyde. However, the effect after treatment with moxalactam was less than after treatment with disulfiram. The interval between pretreatment with moxalactam and administration of ethanol that gave the maximal effect ranged from 3 to 24 hr. When ethanol was given before or at the same time as moxalactam, no effect was observed. Cefamandole and cefoperazone, which, like moxalactam, have a methyltetrazolethiol side chain, increased concentrations of acetaldehyde, but penicillin G, carbenicillin, cephalothin, cephradine, cefoxitin, cefazolin, and cefotaxime had no effect. For prevention of a disulfiram-like reaction, physicians should caution patients to avoid alcoholic beverages for several days after treatment with moxalactam, cefamandole, or cefoperazone.

Moxalactam, like cefoxitin, cefuroxime, and cefotaxime, shows little or no interaction with penicillinases. Resistance of moxalactam to cephalosporinases, however, appears to be considerably greater than that of these other recently discovered beta-lactam antibiotics. Moxalactam is a beta-lactamase inactivator and inactivates most of the cephalosporinases produced by gram-negative bacteria. The process of inactivation is specific and follows time-dependent or progressive kinetics, as is the case for a class of enzyme inhibitors called "suicide substrates." Moxalactam is the first beta-lactam antibiotic shown to possess this property of inactivation of beta-lactamases, a property that explains its excellent resistance to beta-lactamases.

Moxalactam is the first member of a new class of beta-lactam antibiotics to be evaluated clinically. Although structurally related to cephalosporins, moxalactam has an oxygen atom where the cephalosporin nucleus has a sulfur atom. The substitution of oxygen for sulfur in moxalactam provides it with greater antibacterial activity than that of its cephalosporin analog. Moxalactam has three other structural elements that affect biologic activity: the methyltetrazolethio moiety, which maximizes in vitro activity; the 7-alpha-methoxy substituent, which confers beta-lactamase stability; and the p-hydroxyphenylmalonyl group, which positively influences not only beta-lactamase stability and the antibacterial spectrum of moxalactam, but also its pharmacokinetics, and leads to a long half-life without high serum binding.