The Slow Recovery of Bacteria From the Toxic Effects of Penicillin

Eagle, Harry; Musselman, Arlyne D.

doi:10.1128/jb.58.4.475-490.1949

Cited by 102 publications

(23 citation statements)

References 7 publications

(10 reference statements)

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“…Beta-lactam antibiotics can differ, however, in their bactericidal activity, as demonstrated for such structurally closely-related members of the group as amoxicillin and ampicillin (2,24). Another factor which might influence the in vivo effect of these cephalosporins is the post-antibiotic effect (4,8,12,19). It has been demonstrated for beta-lactam antibiotics and the pneumococcus in vitro that the concentration-dependent nature of the PAE declines when the concentration exceeds 10 times the MIC (4).…”

Section: Discussionmentioning

confidence: 99%

EXPERIMENTAL PNEUMOCOCCUS INFECTION IN MICE: COMPARATIVE IN VITRO AND IN VIVO EFFECT OF CEFUROXIME, CEFOTAXIME AND CEFTRIAXONE

Frimodt‐Møller

Bentzon

Thomsen

1987

Acta Pathologica Microbiologica Scandinavica Series B: Microbio

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In a mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3, the 50% effective dose, ED50, after single doses one hour post‐inoculation was considerably lower for ceftriaxone (CRO) than for cefuroxime (CXM) and cefotaxime (CTX), in spite of the same minimal inhibitory concentration, MIC, of 0.02 mcg/ml against the pneumococcus for all 3 drugs. The bactericidal activity as measured by time‐kill curves was similar for the 3 drugs, as was the post‐antibiotic effect in vitro. Protein binding in mouse serum was considerably higher for CRO (87%) than for both CTX (35%) and CXM (15%), respectively. Of pharmacokinetic parameters investigated on doses equal to the ED50s, the time the serum antibiotic concentration remained above the MIC (ΔT(MIC)) was the factor that varied the least among 3 drugs. Therefore, the superior in vivo effect for CRO is not due to higher intrinsic activity against the pathogen but to the long serum‐elimination half‐life resulting in an extended ΔT(MIC), probably related to the high serum protein binding.

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Section: Discussionmentioning

confidence: 99%

EXPERIMENTAL PNEUMOCOCCUS INFECTION IN MICE: COMPARATIVE IN VITRO AND IN VIVO EFFECT OF CEFUROXIME, CEFOTAXIME AND CEFTRIAXONE

Frimodt‐Møller

Bentzon

Thomsen

1987

Acta Pathologica Microbiologica Scandinavica Series B: Microbio

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“…Even after the antibiotic had been degraded by a penicillinase, the target populations exhibited a significant lag before resuming growth (Bigger, 1944;Parker & Marsh, 1946;Eagle, 1949;. Subsequent studies have observed PAE following treatment with a variety of antibiotics, including aminoglycosides (Zhanel & Craig, 1994), b-lactams (Hanberger et al, 1990;Odenholt-Tornqvist & Löwdin, 1991), fluoroquinolones (Athamna, 2004;Mizunaga, 2005), and others (Zhanel & Hoban, 1991;Odenholt-Tornqvist, 1993), and against both Gram-positive and Gram-negative bacterial species (Eagle & Musselman, 1949;Bundtzen et al, 1981). PAE has also been observed in animal models (Craig, 1993;Gudmundsson & Einarsson, 1993), where, in addition to suppressing growth, transient antibiotic treatment can render the surviving population more susceptible to innate immune responses and result in decreased virulence expression (Eagle, 1949).…”

Section: Introductionmentioning

confidence: 99%

Drug detoxification dynamics explain the postantibiotic effect

Srimani

Huang

Lopatkin³

et al. 2017

Molecular Systems Biology

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The postantibiotic effect (PAE) refers to the temporary suppression of bacterial growth following transient antibiotic treatment. This effect has been observed for decades for a wide variety of antibiotics and microbial species. However, despite empirical observations, a mechanistic understanding of this phenomenon is lacking. Using a combination of modeling and quantitative experiments, we show that the PAE can be explained by the temporal dynamics of drug detoxification in individual cells after an antibiotic is removed from the extracellular environment. These dynamics are dictated by both the export of the antibiotic and the intracellular titration of the antibiotic by its target. This mechanism is generally applicable for antibiotics with different modes of action. We further show that efflux inhibition is effective against certain antibiotic motifs, which may help explain mixed cotreatment success.

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“…The failure to kill slowly or nongrowing bacteria is a characteristic common to most antibiotics and has been named phenotypic tolerance (2,5,(23)(24)(25)(26). Another pharmacodynamic factor described early in the antibiotic era was the persistent suppression of bacterial growth after the active drug had disappeared (1,8,21). This so-called postantibiotic effect (PAE) is today well studied both in vitro and in vivo.…”

mentioning

confidence: 99%

Studies of the killing kinetics of benzylpenicillin, cefuroxime, azithromycin, and sparfloxacin on bacteria in the postantibiotic phase

Odenholt

Löwdin

Cars

1997

Antimicrob Agents Chemother

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Most antibiotics are known to be incapable of killing nongrowing or slowly growing bacteria with few exceptions. Bacterial cell division is inhibited during the postantibiotic phase (PA phase) after short exposure to antibiotics. Only scarce and conflicting data are available concerning the ability of antibiotics to kill bacteria in the PA phase. The aim of the present study was to investigate the killing effect of four different antibiotics on bacteria in the PA phase. A postantibiotic effect (PAE) was induced by exposing Streptococcus pyogenes and Haemophilus influenzae to 10x MICs of benzylpenicillin, cefuroxime, sparfloxacin, and azithromycin. The bacteria were thereafter reexposed to a 10x MIC of the same antibiotic used for the induction of the PAE at the beginning of and after 2 and 4 h in the PA phase. Due to a very long PAE, the bacteria in PA phase induced by azithromycin were also exposed to 10x MICs after 6 and 8 h. A previously unexposed culture exposed to a 10x MIC was used as a control. The results seem to be dependent on both the antibiotic used and the bacterial species. The antibiotics exhibiting a fork bactericidal action gave significantly reduced killing of the bacteria in PA phase (cefuroxime with S. pyogenes, P < 0.01, and sparfloxacin with H. influenzae, P < 0.001), which was restored at 4 h for cefuroxime with S. pyogenes. There was a tendency to restoration of the bactericidal activity also with sparfloxacin and H. influenzae, but there was still a significant difference in killing between the control and the test bacteria in PA phase at 4 h. However, in the combinations with a lesser bactericidal effect (benzylpenicillin with S. pyogenes and sparfloxacin with S. pyogenes), there was no difference in killing between the control and the test bacteria in PA phase. Azithromycin induced long PAEs in both S. pyogenes and H. influenzae and exhibited a slower bactericidal action on both the control and the bacteria in PA phase especially at the end of the PAE, when the killing was almost bacteriostatic. Our findings in this study support the concept that a long interval (> 12 h) between doses of azithromycin, restoring full bactericidal action, may be beneficial to optimize efficacy of this drug but is not necessary for the other antibiotics evaluated, since the bactericidal effect seems to be restored already at 4 h.

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The Slow Recovery of Bacteria From the Toxic Effects of Penicillin

Cited by 102 publications

References 7 publications

EXPERIMENTAL PNEUMOCOCCUS INFECTION IN MICE: COMPARATIVE IN VITRO AND IN VIVO EFFECT OF CEFUROXIME, CEFOTAXIME AND CEFTRIAXONE

EXPERIMENTAL PNEUMOCOCCUS INFECTION IN MICE: COMPARATIVE IN VITRO AND IN VIVO EFFECT OF CEFUROXIME, CEFOTAXIME AND CEFTRIAXONE

Drug detoxification dynamics explain the postantibiotic effect

Studies of the killing kinetics of benzylpenicillin, cefuroxime, azithromycin, and sparfloxacin on bacteria in the postantibiotic phase

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