The In Vitro Activity, Human Pharmacology, and Clinical Effectiveness of New beta-Lactam Antibiotics

Cefodizime, an iminomethoxy aminothiazolyl cephalosporin similar to moxalactam and ceftazidime, was less active (minimal inhibitory concentration, 1.6 to 12 p.g) than cefazolin or cefotaxime against Staphylococcus aureus and Staphylococcus epidermidis. It inhibited Haemophilus and Neisseria spp. at <0.5 ,ug/ml. It did not inhibit methicillin-resistant staphylococci, enterococci, or Listeria spp. and was 8-to 32-fold less active than cefotaxime, moxalactam, or ceftazidime against Escherichia coli, Citrobacter spp., Klebsiella pneumoniae, Providencia spp., and Serratia spp. Cefotaxime-resistant Enterobacter cloacae, Citrobacter freundii, and Proteus vulgaris were resistant to cefodizime. Cefodizime was less active than cefoxitin or moxalactam against Bacteroides fragilis. Cefodizime was not hydrolyzed by common plasmid or chromosomal ,-lactamases, and it inhibited type I ,-lactamases.The introduction of the iminomethoxy group on the acyl side chain of the dihydrothiazime ring of the cephalosporine nucleus and the presence of the aminothiazolyl group have provided increased activity against Enterobacteriaceae while retaining much of the gram-positive activity of the earlier cephalosporins (3). Cefodizime is structurally similar to cefotaxime but has a 1-mercapto-1,3-thiazole chain substituted for the acetoxy group at position 3 of the dihydrothiazine ring (J. Bacterial isolates were obtained from patients recently hospitalized at the Columbia-Presbyterian Medical Center, New York, N.Y. In addition, organisms which were known to be multiply resistant to antibiotics and to contain previously characterized ,B-lactamases were used in some experiments. These isolates had been stored frozen for a number of years.Antimicrobial activity was measured by an agar dilution method with Mueller-Hinton agar unless specified otherwise. Fresh dilutions of the compounds were prepared daily in sterile medium or distilled water. A final inoculum of 105 CFU prepared by dilution of a fresh overnight broth culture was applied as a spot to the agar with a replicating device. Broth dilutions were performed in 1-mi (volume) tubes with a final inoculum of 105 CFU. Plates or tubes were incubated at 350C for 18 h. The minimal inhibitory concentration (MIC) was defined as the lowest concentration of antibiotic that inhibited visible growth on agar or in broth. The minimal bactericidal concentration (MBC) was determined by plating 0.1-ml amounts from clear 1-mi broth tubes onto blood agar plates. The MBC was defined as the concentration at which there was no growth after 24 h of incubation at 35C. The susceptibility of streptococci was determined by using Muelier-Hinton agar supplemented with 5% sheep blood. The susceptibility of Neisseria and Haemophilus spp. was determined on chocolate MuellerHinton agar incubated in the presence of 5% CO2.

Section: Resultsmentioning

confidence: 99%

In vitro activity and beta-lactamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin

Scully¹,

Jules²,

Neu³

1983

“…The utility of the combination stems from the broad spectrum of antimicrobial activity of cefoperazone (9,17) and the ability of sulbactam to inhibit some ,B-lactamases (15). Patients who are candidates for treatment with cefoperazone-sulbactam may be physiologically compromised and may therefore not distribute or eliminate these drugs as do healthy subjects.…”

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confidence: 99%

Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients

Schwartz

Jáuregui

Bachmann

et al. 1988

The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean, 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (C..), area under the curve of drug concentration in plasma versus time (AUC), half-life (t112), apparent volume of distribution by the area method (Yarne), apparent volume of distribution at steady state (V.), and total body clearance (CL) for day 1 (day 5) were 297.5 (237.5) ,ug/ml, 1,247 (1,063) ug. h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cm.., AUC, t1/2, Varea, V., and CL were 110.3 (78.0),ug/ml, 228 (217) ug. h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t112. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5.

“…One hypothesis is that these antibiotics, which are secreted in the bile, destroy intestinal bacteria which produce vitamin K, a necessary cofactor in the synthesis offour of the clotting factors (4). Another theory is that the MTT which is released from the intact antibiotic is able to inhibit gamma carboxylation of glutamic acid (7,11), the vitamin K-dependent step in the synthesis of the clotting factors. This hypothesis is supported by the observation that MUT inhibits the gamma carboxylation of glutamic acid in an in vitro rat liver microsomal system (6).…”

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confidence: 99%

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats

Lipsky¹,

Lewis²,

Novick³

1984

To determine whether the hypoprothrombinemia associated with antibiotics containing a 1-methyl-5-thiotetrazole (MUT) group is a result of the presence of the MUT group, rats were maintained on a vitamin K-deficient diet for 10 days and then received either intravenous moxalactam or cefotaxime or oral MUT for two additional days. MUT and moxalactam, which contains the MUT group, prolonged prothrombin time. Cefotaxime, which lacks the MUT group, had no effect.The use of beta-lactam antibiotics which contain a 1-methyl-5-thiotetrazole (MUT) group has been associated with the development of hypoprothrombinemia in humans. These antibiotics include cefamandole (5), cefoperazone (9), and moxalactam (8). The mechanism for the hypoprothrombinemia is in dispute. One hypothesis is that these antibiotics, which are secreted in the bile, destroy intestinal bacteria which produce vitamin K, a necessary cofactor in the synthesis offour of the clotting factors (4). Another theory is that the MTT which is released from the intact antibiotic is able to inhibit gamma carboxylation of glutamic acid (7,11), the vitamin K-dependent step in the synthesis of the clotting factors. This hypothesis is supported by the observation that MUT inhibits the gamma carboxylation of glutamic acid in an in vitro rat liver microsomal system (6). To test the in vivo relevance of this finding, we examined the effects of moxalactam, cefotaxime, and MTT in rats maintained on a vitamin K-free diet. Moxalactam contains the MTT group; cefotaxime does not (Fig. 1) Both moxalactam and MTT produced hypoprothrombinemia in rats maintained on vitamin K-deficient diets for 10days. There was a three-to fourfold prolongation of prothrombin time within 48 h of the first dose of these drugs (Table 1).* Corresponding author. 380The ability of cefotaxime, a drug which does not contain the MTT group, to produce hypoprothrombinemia was examined and compared with that of moxalactam. Cefotaxime was not able to produce a prolongation of the prothrombin time, but under the same conditions, moxalactam again increased the prothrombin time over fivefold (Table 2). Three animals in the moxalactam group died (two of hemorrhage) before the third prothrombin time determination.The results of these experiments indicate that MTT and moxalactam containing MUT in its structure are capable of producing hypoprothrombinemia in vivo. Cefotaxime, which does, not possess an MUT group, did not produce hypoprothrombinemia. Previous studies by others of rats on normal diets given doses of moxalactam up to 2.7 g/kg did not reveal any evidence of hypoprothrombinemia (12). The vitamin K-deficient diet used in our studies was chosen because a lack of vitamin K intake may be a contributing or necessary factor for humans to become hypoprothrombinemic while on MUT-containing antibiotics. Our use of rats on vitamin K-deficient diets may resemble the clinical situation, in which it appears that lack of oral intake of food, and thus possible decreased intake of vitamin K, may be a predisposing condition ...