In vitro antimicrobial activity evaluation of cefodizime (HR221), a new semisynthetic cephalosporin

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HR810 (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new, cyclical-pyridinium cephalosporin that appeared superior to numerous comparison drugs against 658 strains of aerobic and facultative anaerobic bacteria. Seventeen Enterobacteriaceae spp. were tested by broth microdilution methods, and the 50% MICs (MIC50s) and 90%o MICs (MIC90s) were 0.03 to 0.12 and 0.03 to 2.0 jxg/ml, respectively. Only one strain had an MIC >8.0 ,ug/ml (99.6% is considered susceptible). HR810 inhibited 98% of Pseudomonas aeruginosa isolates at <16 ,ug/ml, and the MIC90 for Acinetobacter spp. was 4.0 ,ug/ml. It was also very active against Pseudomonas spp. and Staphylococcus aureus (MIC90, 0.5 jLg/ml) but marginally active against methicillin-resistant staphylococcal strains (MICgo, 16 1Lg/ml) and enterococcus (MIC90, 32 jig/ml).Non-enterococcal streptococci had MIC50s ranging from 0.008 ,ug/ml for Streptococcus pyogenes to 0.12 tg/ml for pneumococci. All MICs of HR810 against I-Jaemophilus and Neisseria spp. were s0.03 jig/ml (MIC50, 0.002 to 0.008 ,ug/ml). HR810 poorly inhibited ,B-lactamases and was very stable against 11 tested P-lactamases of plasmid (TEM, OXA, SHV-i, and PSE) and chromosomal (Kl, K14, P99) types.HR81O (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new 3'-pyridinium-substituted cephalosporin (Fig. 1). It has a 2,3-cyclopentenopyridine instead of the 3'-acetoxy group found on cefotaxime sodium, and the compound is produced as a sulfate salt. Preliminary reports by the manufacturers, Hoechst AG (Frankfurt, Federal Republic of Germany) and Roussel-tJCLAF (Paris, France), indicate that the compound has marked antimicrobial activity against Pseudornonas aeruginosa, Staphylococcus aureus, enterococci, and members of the family Enterobacteriaceae;it is stable to P-lactamases and penetrates to penicillinbinding protein target sites, with binding comparable to that of ceftazidime; and it is bactericidal, is primarily excreted in the urine, and has a prolonged serum half-life in the early animal studies (2,4,14,22 574, 1983).In this in vitro evaluation, we compare the antimicrobial activity of HR810 with that of new ,B-lactams and also compare these results with those previously published for chemically similar drugs (1, 5-7, 10, 12, 20, 21). We also report the results of studies of P-lactamase stability, 1B-lactamase inhibition by HR810, and the effect of salt content in the medium on the HR810 MICs against methicillinresistant S. aureus strains.

Section: Resultsmentioning

confidence: 99%

Section: H2s04mentioning

confidence: 99%

Section: H2s04mentioning

confidence: 99%

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In vitro evaluation of HR810, a new wide-spectrum aminothiazolyl alpha-methoxyimino cephalosporin

Jones¹,

Thornsberry²,

Barry³

1984

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“…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 Bacterial isolates were obtained from patients recently hospitalized at the Columbia-Presbyterian Medical Center, New York, N.Y.…”

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confidence: 99%

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

Scully¹,

Jules²,

Neu³

1983

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.

“…It inhibited all isolates at a concentration of <0.016 ,ug/ml. Cefodizime, ceftazidime, and aztreonam (formerly azthreonam) are new parenteral P-lactam antimicrobial agents which are highly active in vitro against a broad spectrum of microorganisms (2,3,5). This study was Table 2.…”

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confidence: 99%

Comparative in vitro activity of cefodizime, ceftazidime, aztreonam, and other selected antimicrobial agents against Neisseria gonorrhoeae

Khan¹,

Gruninger²,

Nelson³

et al. 1983

The in vitro activities of three new P-lactam antimicrobial agents, cefodizime, ceftazidime, and aztreonam (formerly azthreonam), were compared with those of cefotaxime, cefuroxime, cefoxitin, and penicillin against 100 3-lactamase-negative and 42 13-lactamase-positive Neisseria gonorrhoeae strains. The three new antimicrobial agents showed excellent activity against N. gonorrhoeae regardless of P-lactamase production. Cefodizime