Hyperoxia prolongs the aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa

Park, M. K.; Muhvich, K. H.; Myers, Roy A.M.; Marzella, Louis

doi:10.1128/aac.35.4.691

Cited by 73 publications

(27 citation statements)

References 31 publications

(28 reference statements)

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“…Whatever the precise mechanism, the time for recovery from tobramycin exposure to control values for crude protein synthesis, 13-galactosidase activity, cell morphology, and DNA complexity are correlated with one another and with the standard definition of the PAE (9). The PAE associated with aminoglycoside therapy has been incorporated into theories regarding optimal dosing regimens (10,19,20,28,29,33,35). The results presented in this study suggest that the PAE provides a reasonable basis for allowing aminoglycoside concentrations to fall below detectable limits for a portion of the dosing interval.…”

Section: Methodsmentioning

confidence: 99%

“…that DNA synthesis was inhibited in E. coli transiently exposed to gentamicin at low multiples of the MIC in Mueller-Hinton broth during the PAE (13). Another study using pulse-chase [35S]methionine labelling suggested that protein synthesis inhibition immediately after tobramycin exposure might be correlated with the duration of PAE (28). We examined the effects of transient in vitro exposure to tobramycin on macromolecular synthesis in a clinical isolate of E. coli in order to correlate the molecular mechanism of action of tobramycin with the observed PAE.…”

Section: Methodsmentioning

confidence: 99%

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Correlation of tobramycin-induced inhibition of protein synthesis with postantibiotic effect in Escherichia coli

Barmada

Kohlhepp

Leggett

et al. 1993

Antimicrob Agents Chemother

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Scant data exist on intracellular events during aminoglycoside-induced postantibiotic effect (PAE). We examined DNA, RNA, and protein syntheses after tobramycin exposure using [3H1thymidine, [14C]uracil, and [14CJalanine incorporation in a clinical Escherichia coli strain. Late-log-phase bacteria in oxygenated minimal salts medium at 37°C were exposed to tobramycin (7.5 ,ug/ml) The persistent suppression of bacterial growth observed after brief exposure to an antimicrobial agent has been termed the postantibiotic effect (PAE) (9, 24). Aminoglycosides, quinolones, tetracyclines, and rifampin induce a PAE against gram-negative bacilli (2,8,9,18,25,30). The mechanisms by which antibiotics induce a PAE have not been defined. Inhibition of DNA synthesis has been shown to correlate with the time required for quinolone-treated Escherichia coli to resume growth (14). ,B-Lactam exposure suppresses thymidine uptake with decreased DNA synthesis in gram-positive cocci during PAE (13, 26). The saturable linear dose-response curve of the PAE for macrolides, tetracyclines, and rifampin suggests a drug-receptor interaction, such as with subunits of susceptible bacterial ribosomes (9).Aminoglycoside antibiotics exhibit pleiotropic effects on bacteria, including inhibition of ribosomal and plasma membrane functions (12, 15). The precise mechanism of aminoglycoside action has not been elucidated for either bactericidal effects (11,16,22,31) or PAEs (13). Moreover, to our knowledge, no studies comparing DNA, RNA, and protein syntheses before, during, and after aminoglycoside-induced PAE have been reported. The aim of this study was to correlate these synthetic functions with PAE in E. coli exposed to tobramycin in vitro. MATERIALS AND METHODSBacterial strain, media, and MIC determination. A clinical isolate of E. coli capable of growth in a minimal salts medium was stored in 15% glycerol at -70°C. Bacteria were grown and all studies were performed with bubbling in a carbon * Corresponding author. minimal medium consisting of the following (per liter): NH4Cl, 2 g; Na2HPO4, 6 g; KH2PO4, 3 g; NaCl, 3 g; MgCl2-6H20, 0.062 g; Na2SO4, 0.08 g; and glucose, 6 g (31). A few preliminary experiments were also performed in Mueller-Hinton broth (Difco, Madison, Wis.).PAE determination. The PAE was measured in the standard fashion (9) by comparing regrowth curves determined by serial viable counts of exposed and unexposed control organisms. Bacteria from an overnight culture were inoculated into fresh minimal medium and allowed to grow to log phase and an optical density at 540 nm of 0.2. An aliquot was diluted 100-fold (to approximately 106 CFU/ml) and designated the control. Tobramycin (7.5 ,1g/ml) was added to the remaining cells (twice the MIC determined for this E. coli strain in this medium). After a 30-min exposure to tobramycin, bacteria were filtered with a 0.45-,um-pore-size filter (Gelman Sciences, Ann Arbor, Mich.) and resuspended in fresh minimal medium for further study. In all PAE experiments, zero hour designated the start of...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Correlation of tobramycin-induced inhibition of protein synthesis with postantibiotic effect in Escherichia coli

Barmada

Kohlhepp

Leggett

et al. 1993

Antimicrob Agents Chemother

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“…However, there is no evidence that hyperoxia acts synergistically with protein synthesis inhibitors through free radical mechanisms to inhibit bacterial growth after a short antibiotic exposure. It appears more likely that the synergistic effects of hyperoxia with antimicrobial agents that are protein synthesis inhibitors (18) are mediated by an inhibitory effect of hyperoxia on protein synthesis.…”

mentioning

confidence: 99%

“…We exposed bacteria to hyperoxia (for 1 or 18 h) before examining the PAE to determine whether increased antiox- (18). e Significantly different from data for bacteria under normoxic conditions (P < 0.01).…”

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confidence: 99%

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Hyperoxia and prolongation of aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa: role of reactive oxygen species

Park

Myers

Marzella

1993

Antimicrob Agents Chemother

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Hyperoxia prolongs the postantibiotic effect (PAE) of the aminoglycoside tobramycin in Pseudomonas aeruginosa. We tested the hypothesis that the PAE is prolonged because hyperoxia increases free radical flux while tobramycin inhibits the induction of antioxidant defenses. Exposure ofP. aeruginosa to hyperoxia (100%O 02) for 1 h increased superoxide dismutase, catalase, and glutathione levels. In the presence of tobramycin (1 x the MIC), the induction of antioxidant defenses by hyperoxia was nearly abrogated. Neither preexposure ofP. aeruginosa to hyperoxia nor supplementation with the antioxidants copper(II) (diisopropylsalicylate)2 (superoxide dismutase-like), catalase, or dimethyl sulfoxide abolished prolongation of the PAE of tobramycin induced by hyperoxia.We recently showed that hyperoxia acts in synergy with an aminoglycoside antibiotic to prolong the postantibiotic effect (PAE) of tobramycin against Pseudomonas aeruginosa (18). The PAE describes the period of bacterial growth suppression that results from a brief exposure to an antimicrobial agent (14). For aminoglycosides, the PAE represents the time required for synthesis of new ribosomes (4).Hyperoxia increases the intracellular flux of 02 and other reactive oxygen species (8). In the study described here, we tested the hypothesis that hyperoxia enhances the PAE of tobramycin against P. aeruginosa by increasing the intracel- MIC of tobramycin for P. aeruginosa ATCC 27853 was 0.5 p,g/ml.The antioxidant enzymes and free radical scavengers were used at the highest concentration which did not inhibit bacterial growth, namely, CuDIPS at 1 x 10-4 M, CAT at 4 x 10' M, and DMSO at 0.4 M. The antioxidants were added before exposure to hyperoxia. The PAE was measured as described previously (18).For enymatic and thiol assays, bacteria (final concentration, -10' CFU/ml) were grown for 2 h in a shaking water bath under ambient conditions (21% 02, 37°C, 100 rpm) before a 1-h exposure to hyperoxia and/or tobramycin (lx the MIC). Bacteria were then filtered onto 0.2-,m-pore-size filters, washed, and resuspended in 50 mM phosphate buffer (pH 7.0); filters were removed after vortexing. Bacteria were centrifuged at 10,000 x g for 15 min at 4°C. After decanting and resuspending with 50 mM phosphate buffer (pH 7.0) with 0.1 mM EDTA, bacterial cells were lysed by sonication (model W185 sonifier; Branson, Plainview, N.Y.) at 60 W (45 s, eight times). Membranes were sedimented by centrifugation at 27,500 x g for 30 min.

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Influence of Hyperbaric Oxygen on the Pharmacokinetics of Single‐Dose Gentamicin in Healthy Volunteers

Merritt,

Slade

1993

Pharmacotherapy

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Study Objective. To determine the single‐dose pharmacokinetics of gentamicin in healthy humans undergoing hyperbaric oxygen (HBO) exposure.Design. Randomized, crossover trial.Setting. Specialized hyperbaric research facility within a United States Air Force medical center.Subjects. Five healthy men between 28 and 43 years of age.Interventions. Each subject received a total of two doses of intravenous gentamicin 1.5 mg/kg lean body weight spaced at least 2 weeks apart. One dose was infused under normobaric oxygen (NBO) conditions and the other under HBO conditions.Measurements and Main Results. Gentamicin pharmacokinetic values were determined on 11 serum samples per subject collected sequentially out to 300 minutes after infusion. Using PCNONLIN, the following results demonstrated no difference between the pharmacokinetic values under HBO and NBO conditions, respectively: β half‐life (112, 115 min); volume of distribution (0.201, 0.184 L/kg); peak concentration (6.52, 7.23 mg/L); clearance (0.0754, 0.0676 L/kg/hr).Conclusions. Hyperbaric oxygen produced no changes in the measured pharmacokinetic values of gentamicin under the conditions specified in this study. It is possible that numerous HBO exposures could produce a cumulative effect on gentamicin pharmacokinetics that would not be discernible in a single‐dose study. Because of the profound physiologic effects of HBO, drugs with narrow therapeutic indexes should be evaluated under HBO conditions if they are to be given to patients receiving HBO treatments.

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Hyperoxia prolongs the aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa

Cited by 73 publications

References 31 publications

Correlation of tobramycin-induced inhibition of protein synthesis with postantibiotic effect in Escherichia coli

Correlation of tobramycin-induced inhibition of protein synthesis with postantibiotic effect in Escherichia coli

Hyperoxia and prolongation of aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa: role of reactive oxygen species

Influence of Hyperbaric Oxygen on the Pharmacokinetics of Single‐Dose Gentamicin in Healthy Volunteers

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