Paradox between the responses of Escherichia coli K1 to ampicillin and chloramphenicol in vitro and in vivo

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We evaluated the activity of BMY-28142 against a Kl E. coli strain and a type III group B streptococcal strain in vitro and in vivo and compared the results with those of cefotaxime and penicillin G, respectively. In vitro, the MICs and MBCs of BMY-28142 were close to those of cefotaxime (s2-fold difference) for E. coli and fourfold less than those of penicillin G for group B streptococci. In vivo studies with an experimental bacteremia and meningitis model in newborn rats revealed that the mean penetration of BMY-28142 into the cerebrospinal fluid was 15% that of concomitant levels in serum and that significantly greater bactericidal titers were achieved in blood and cerebrospinal fluid for both test organisms with BMY-28142 than with cefotaxime and penicillin G. However, the overall efficacy of BMY-28142 was similar to that of cefotaxime for the E. coli infection and that of penicillin G for the group B streptococcal infection. This was shown by similar rates of bacterial clearance .from blood and cerebrospinal fluid and similar mortality rates. These findings indicate that the activity of BMY-28142 is bactericidal in vitro and in vivo against E. coli and group B streptococci, suggesting that this agent may be a suitable alternative for the therapy of E. coli and group B streptococcal bacteremia and meningitis.Because of the significant morbidity and mortality associated with neonatal bacterial infections, particularly due to E. coli and group B streptococci (GBS), many new beta-lactam antibiotics with expanded in vitro spectra have generated considerable enthusiasm for studies of their activities in vivo.BMY-28142 is a novel cephalosporin with potent in vitro activity against most aerobic and facultatively anaerobic gram-positive and gram-negative organisms (1,4,5).This study was performed to evaluate the activity of BMY-28142 in vitro and in vivo against Escherichia coli and GBS, the two most common bacterial pathogens in newborn infants (14). The results were compared with those of cefotaxime for E. coli and those of penicillin G for GBS. MATERIALS AND METHODSOrganisms. A serum-resistant E. coli Kl strain (C5) and a type III GBS strain (K79) were used in this study. Both organisms were isolated from the cerebrospinal fluid (CSF) of newborn infants with meningitis (6-8).In vitro studies. MICs and MBCs were measured in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) by the standard macrobroth dilution method (17). The antimicrobial agents tested were BMY-28142 (Bristol Laboratories, Syracuse, N.Y.) for both E. coli and GBS, cefotaxime sodium (Hoechst-Roussel Pharmaceuticals, Somerville, N.J.) for E. coli, and potassium penicillin G (Bristol) for GBS. Antimicrobial agent solutions were diluted serially twofold from 4 to 0.008 ,ug/ml in Mueller-Hinton broth. An inoculum of approximately 2 x 105 CFU/ml of the E. coli or GBS strain was prepared as described previously from late-logarithmic-phase cultures (6, 7). Equal volumes (0.5 ml) of antibiotic and bacterial dilutions were mixed and incubated at 37°...

Section: Methodsmentioning

confidence: 99%

Efficacy of BMY-28142 in experimental bacteremia and meningitis caused by Escherichia coli and group B streptococci

Kim¹,

Bayer²

1985

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“…All antibiotic solutions were serially twofold diluted from 16 to 0.03 ,ug/ml in Mueller-Hinton broth. Late logarithmic-phase cultures of strain C5 containing approximately 5 x 105 CFU/ml were prepared as previously described (5). The MIC was defined as the lowest antibiotic concentration exhibiting no visual turbidity, and the MBC (with subculture volume of 0.01 ml) was defined as the lowest concentration of antibiotics which resulted in .99.9% killing of the original inoculum.…”

Section: Methodsmentioning

confidence: 99%

“…It has been shown previously that experimental Escherichia coli bacteremia and meningitis induced in the newborn rat is suitable for evaluating in vivo efficacies of various antimicrobial agents, particular in terms of rates of bacterial clearance from blood and cerebrospinal fluid (CSF) and of mortality (4)(5)(6). In these studies, it has been shown the activity of armpicillin against E. coli Kl is limited (4,5), but that of cefotaxime is excellent.…”

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confidence: 97%

“…In these studies, it has been shown the activity of armpicillin against E. coli Kl is limited (4,5), but that of cefotaxime is excellent. Results of recent studies, however, have shown that the outcome of E. coli infections in this model treated with cefotaxime is not significantly better than that of a conventional therapeutic regimen, ampicillin-gentamicin (K. S. Kim, submitted for publication).…”

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confidence: 99%

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Efficacy of cefmenoxime in experimental Escherichia coli bacteremia and meningitis

Kim¹

1985

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Cefmenoxime, a new semisynthetic cephalosporin structurally similar to cefotaxime, was evaluated for its activities in vitro and in vivo against a Kl Escherichia coli strain in comparison with activities of cefotaxime and ampicillin. In vitro the MICs and MBCs of both cefmenoxime and cefotaxime were the same, 1/16th and 1/32nd those of ampicillin, respectively. The efficacies of cefmenoxime and cefotaxime against experimentally induced E. coli bacteremia and meningitis in newborn rats were similar and significantly better than that of ampicillin as judged by bactericidal titers of blood and cerebrospinal fluid, rapidity of clearance of bacteria from blood and cerebrospinal fluid, and incidence of meningitis in animals with bacteremias. The efficacy of cefmenoxime or cefotaxime measured by impact on mortality was influenced by the size of bacterial populations. The mortality was significantly greater in rats with bacterial counts before therapy of .106 CFU/ml of blood than in animals with lower counts. Overall, the in vivo efficacy of cefmenoxime was similar to that of cefotaxime; thus it could be useful in the therapy of neonatal E. coli infection.It has been shown previously that experimental Escherichia coli bacteremia and meningitis induced in the newborn rat is suitable for evaluating in vivo efficacies of various antimicrobial agents, particular in terms of rates of bacterial clearance from blood and cerebrospinal fluid (CSF) and of mortality (4-6). In these studies, it has been shown the activity of armpicillin against E. coli Kl is limited (4, 5), but that of cefotaxime is excellent. Results of recent studies, however, have shown that the outcome of E. coli infections in this model treated with cefotaxime is not significantly better than that of a conventional therapeutic regimen, ampicillin-gentamicin (K. S. Kim, submitted for publication). Recently, Tsuchiya et al. (12) have shown that cefmenoxime, a new cephalosporin structurally similar to cefotaxime, has greater protective and therapeutic activities than cefotaxime against members of the family Enterobacteriaceae in mice despite their similar activities in vitro. The present study was therefore performed to examine the activity of cefmenoxime in vitro and in vivo against E. coli and to compare the results with those of cefotaxime and ampicillin. MATERIALS AND METHODSOrganisms. A serum-resistant E. coli Kl strain (C5) isolated from the CSF ofa newborn infant with meningitis was used in this study.In vitro studies. The MICs and MBCs were measured in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) by a macrobroth dilution mpethQd (13). Antimicrobial agents tested were cefmenoxime hydrochloride (Abbott Laboratories, TAP Pharmaceuticals, North Chicago, Ill.), ampicillin trihydrate (Bristol Laboratories, Syracuse, N.Y.) and cefotaxime sodium (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.). All antibiotic solutions were serially twofold diluted from 16 to 0.03 ,ug/ml in Mueller-Hinton broth. Late logarithmic-phase cultures of strain C5 c...

“…Our preliminary studies have shown that this inoculum of L. monocytogenes produces bacteremia (with or without meningitis) in 100% of the animals within 18 h of inoculation. At 18 h after inoculation and daily thereafter for 4 days, 0.1 ml of blood and 0.01 ml of cerebrospinal fluid (CSF) were obtained as previously described for quantitative cultures (15,16 …”

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In vitro and in vivo studies of imipenem-cilastatin alone and in combination with gentamicin against Listeria monocytogenes

Kim

1986

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Listeria monocytogenes is an important cause of bacteremia and meningitis in neonates and immunocompromised patients (7,10,12,17,20,22). Although penicillin G and ampicillin (with or without an aminoglycoside) are considered the drugs of choice for the treatment of Listeria infection, there is a need for alternative drugs in cases of penicillin-allergic patients and in therapeutic failures (2, 30).'Imipenem (N-formimidoyl thienamycin), unlike newer cephalosporins, appears to be a promising candidate because of its excellent in vitro activity against L. monocytogenes with an MIC for 90% of strains tested of s 0.12 ,ug/ml (9,13,21,31). In addition, combinations of imipenem-gentamicin have been shown to be synergistic in vitro against L. monocytogenes (9). However, in vivo evaluation of imipenem against L. monocytogenes has not been reported. The present study therefore was performed to examine the in vitro and in vivo activities of imipenem and imipenemgentamicin in comparison with ampicillin and ampicillingentamicin against L. monocytogenes. MATERIALS AND METHODSOrganism. A clinical strain of L. monocytogenes (strain LM2) that was isolated from the blood of an infant with sepsis was used in the in vitro and in vivo experiments.In vitro studies. MICs and MBCs were measured in Todd-Hewitt broth (Difco Laboratories, Detroit, Mich.) by the standard macrobroth dilution method (29). The antimicrobial agents tested were imipenem (Merck Sharp & Dohme Research Laboratories, Rahway, N.J.), ampicillin trihydrate (Bristol Laboratories, Syracuse, N.Y.), and gentamicin sulfate (Schering Corp., Kenilworth, N.J.). Antimicrobial agents were diluted serially twofold from 16 to 0.03 ,ug/ml in Todd-Hewitt broth. An inoculum of approximately 5 x 105 CFUJ of L. monocytogenes per ml was prepared from late logarithmic phase cultures. Equal volumes (0.5 ml) of antibiotic and bacterial dilutions were mixed and incubated at 37°C for 24 h. The MIC was defined as the lowest antibiotic concentration exhibiting no visual turbidity. From each tube, 0.01 ml was transferred to a quadrant of sheep blood agar ahd incubated at 37°C for 24 h to determine the MBC, which was defined as the lowest concentration of antibiotics resulting in -99.9% killing of the original ipoculum.The MICs and MBCs of imipenem-gentamicin and ampicillin-gentamicin were measured in Todd-Hewitt broth (1). Twofold dilutions of each antibiotic were used in a checkerboard fashion. MIC and MBC endpoints were read as described above for each antibiotic alone and in various combinations. The results were expressed as the fractional bactericidal concentration index, which was calculated by the following formula (3, 23): (MBC of drug A in combination with drug B/MBC of drug A) + (MBC of drug B in combination with drug A/MBC of drug B) (for studies of imipenem-gentamicin, drug A was imipenem and drug B was gentamicin, or vice versa; for studies of ampicillingentamicin, drug A was ampicillin and drug B was gentamicin, or vice versa). When the FBC index was less than 0.5, the combinatio...