Relevance of the inoculum effect of antibiotics in the outcome of experimental infections caused by <i>Escherichia coli</i>

Soriano, Francisco; Ponte, Carmen; Santamaría, M; Jimenez-Arriero, Manuel

doi:10.1093/jac/25.4.621

Cited by 42 publications

(39 citation statements)

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“…One can argue that this was due to an inoculum effect. However, this cannot in itself explain the failure of the drug; there are many reasons why the effect of a drug on a highly complex process of infection might be much more evident at a low than a high inoculum (11,36).…”

Section: Resultsmentioning

confidence: 99%

Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection

Lemaitre

Mazigh

Scavizzi

1991

Antimicrob Agents Chemother

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Section: Resultsmentioning

confidence: 99%

Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection

Lemaitre

Mazigh

Scavizzi

1991

Antimicrob Agents Chemother

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“…25 There have been other in vitro and animal studies that support the inoculum effect. [26][27][28] Likewise, MPC increases with bacterial density because of the inoculum effect. 29 Thus, antibiotic MPCs determined on agar plates are likely to be higher than the standard low-inoculum antibiotic MIC against the least susceptible single-step mutant-that is, MPC should be regarded as the actual MIC rather than the theoretically defined standard low-inoculum MIC against the least susceptible single-step mutants.…”

Section: Discussionmentioning

confidence: 99%

Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

Liu

et al. 2013

J Antibiot

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No mutant-prevention concentration (MPC) with methicillin-resistant Staphylococcus epidermidis (MRSE) has been reported. The study aimed to evaluate the propensity of vancomycin individually and in combination to prevent MRSE from mutation. A total of 10 MRSE clinical isolates were included in the study. Susceptibility testing demonstrated that the susceptibility rates to vancomycin, rifampicin, levofloxacin and fosfomycin were 100, 100, 50 and 90%, respectively. The fractional inhibition concentration indices (FICI) for vancomycin combined with rifampicin, levofloxacin or fosfomycin were X1.5 but p2, X1.5 but p2, and 40.5 but p1.5, respectively, implying indifferent interactivity. The MPC with susceptible strains was determined to be the lowest antibiotic concentration inhibiting visible growth among 10 10 CFU on four agar plates (9 cm in diameter) after a 72-h incubation at 37 1C. The MPCs were 16B32, 464, X64 and 4B16 lg ml À1 for vancomycin, rifampicin, fosfomycin and levofloxacin, respectively. The vancomycin MPCs of combinations with fosfomycin (32 lg ml À1 ), levofloxacin (2 lg ml À1 ) and rifampicin (2 or 4 lg ml À1 ) were 1B4, 16B32 and 16B32 lg ml À1 , respectively. Against mutants selected by vancomycin, rifampicin, levofloxacin and fosfomycin individually, antibiotics had standard MICs of 2B4 lg ml À1 for vancomycin, 464 lg ml À1 for rifampicin, 4B8 lg ml À1 for levofloxacin and X64 lg ml À1 for fosfomycin. Thus single-step mutation can lead to resistance of MRSE to rifampicin, levofloxacin and fosfomycin, rather than non-susceptibility to vancomycin. Vancomycin-fosfomycin combination might be a superior alternative to vancomycin in blocking the growth of MRSE mutants, especially for high-organism-burden infections.

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“…Earlier recommenda- tions (5, 7) indicate that a peak-to-MIC ratio of 4 to 10 is required for the maximal bactericidal effects of beta-lactam antibiotics. By using a rat model of E. coli peritonitis, it was shown that piperacillin, cefotaxime, and aztreonam prevented mortality when peak concentrations in serum exceeded the MIC by a factor of 60 to greater than 1,000 (23). This group of antibiotics was shown to have a pronounced inoculum effect with the organism.…”

Section: Discussionmentioning

confidence: 99%

“…The explanations for the observed inoculum effect have not yet been defined. One explanation is that an organism may be less susceptible when it is present in large numbers because of the combined production of 1-lactamases (2,20), or, alternatively, preferential affinity for some penicillin-binding proteins may be involved (23).…”

Section: Discussionmentioning

confidence: 99%

Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections

Onyeji

Nicolau

Nightingale

et al. 1994

Antimicrob Agents Chemother

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The duration of time that serum drug levels remain above the MIC (time above the MIC) for the pathogen has been shown to be the most significant parameter determining the efficacies of beta-lactam antibiotics. In the described study, we investigated the optimal time above the MIC of ceftibuten and cefaclor using a nonneutropenic mouse model of intra-abdominal infections caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. The abilities of the drugs to protect mice against the organisms were determined in mouse protection tests, and the doses were fractionated to produce various dosing regimens with different times above the MIC. All drug-organism combinations showed a significant correlation (r > 0.9) between drug efficacy and the time above the MIC. Also, with ceftibuten treatment, the different dosing regimens that produced equal times above the MIC resulted in the same efficacy, whereas with cefaclor, an apparent dose-dependent effect was observed. These results showed that for a 100% recovery from K. pneumoniae and E. coli infections, the optimal times above the MIC with ceftibuten treatment were 2.2 and 1.6 h, respectively. Relatively high doses of both antibiotics were required to ensure recovery from S. pneumoniae infections. In vitro time-kill studies demonstrated that cefaclor exhibits a marked inoculum effect against the pathogens, and there was a concentration-dependent killing at a large inoculum size. On the other hand, ceftibuten showed no inoculum effect. It is suggested that optimization of both dose and time above the MIC appears to be necessary for the treatment of S. aureus infections with cefaclor, and this may apply to other beta-lactams that exhibit marked inoculum effects.The therapeutic efficacies of antimicrobial agents are dependent on a variety of factors, including dosage. To optimize the efficacies of cephalosporins, studies in animals and trials in humans have been undertaken to compare the therapeutic outcomes resulting from different antibiotic dosing regimens. The results of such studies have consistently demonstrated that the major parameter correlating drug efficacy is the duration of time that the serum drug concentration exceeds the MIC (6, 8-10, 14, 18, 19, 24). However, there has been no study to determine the optimal time that drug levels should remain above the MIC in any dosing interval.Ceftibuten, an orally active cephalosporin, has been demonstrated to have antibacterial activity in vitro against a wide range of gram-negative and certain gram-positive bacteria (11, 22). Its activity against common respiratory tract pathogens was found to be superior or comparable to those reported for other oral cephalosporins (12). Cefaclor has been shown to be effective in the treatment of respiratory tract, urinary tract, and skin infections and also has a broad range of activity against gram-positive and gram-negative bacteria (4, 13).The study described here was undertaken to investigate, using an experimentally induced infection...

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Relevance of the inoculum effect of antibiotics in the outcome of experimental infections caused by Escherichia coli

Cited by 42 publications

References 0 publications

Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection

Failure of beta-lactam antibiotics and marked efficacy of fluoroquinolones in treatment of murine Yersinia pseudotuberculosis infection

Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections

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