Pharmacodynamics of Cefepime Alone and in Combination with Various Antimicrobials against Methicillin-Resistant
            <i>Staphylococcus aureus</i>
            in an In Vitro Pharmacodynamic Infection Model

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Reduced susceptibility to daptomycin has been reported in patients with infections due to methicillinresistant Staphylococcus aureus (MRSA). Although infections with daptomycin-nonsusceptible (DNS) MRSA are infrequent, optimal therapy of these strains has not been determined. We investigated the killing effects of novel antibiotic combinations with daptomycin (DAP) against two clinical DNS MRSA isolates (SA-684 and R6003) in a 72-h in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (SEV). Simulated regimens included DAP at 6 mg/kg every 24 h (q24h) alone or in combination with trimethoprim-sulfamethoxazole (TMP/SMX) at 160/800 mg q12h, linezolid (LIN) at 600 mg q12h, cefepime (CEF) at 2 g q12h, and nafcillin (NAF) at 4 g q4h. Bactericidal activity was defined as a >3-log 10 CFU/g kill. Differences in CFU/g were evaluated between 4 and 72 h by analysis of variance with the Bonferroni post hoc test. DAP MICs were 4 and 2 mg/liter for SA-684 and R6003, respectively. In the PK/PD model, DAP alone was slowly bactericidal, achieving a 3-log 10 kill at 24 and 50 h for SA-684 and R6003, respectively. Against SA-684, DAP plus TMP/SMX, CEF, LIN, or NAF was bactericidal at 4, 4, 8, and 8 h, respectively, and maintained this activity for the 72-h study duration. DAP plus TMP/SMX or CEF exhibited superior killing than DAP alone against SA-684 between 4 and 72 h, and overall this was significant (P < 0.05). Against R6003, DAP plus TMP/SMX was bactericidal (8 h) and superior to DAP alone between 8 and 72 h (P < 0.001). The unique combination of DAP plus TMP/SMX was the most effective and rapidly bactericidal regimen against the two isolates tested and may provide a clinical option to treat DNS S. aureus infections.

Section: Discussionmentioning

confidence: 67%

Novel Daptomycin Combinations against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

Steed

Vidaillac

Rybak

2010

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“…Thus, when linezolid must be prescribed, hypermutable strains should be detected by the disk diffusion method (14), and the antibiotic should be administered in combination (22,55), particularly for prolonged treatment. Finally, mutators should be included in the preliminary tests of any new antibiotic.…”

Section: Vol 54 2010 Linezolid Against Hypermutator Cocci In a Pk-pmentioning

confidence: 99%

“…Previous investigations using in vitro pharmacokinetic-pharmacodynamic (PK-PD) models have evaluated the efficiency of linezolid (1,6,22,24,28,49). However, most of these studies used a one-compartment model, which does not avoid dilution of the bacterial population, and none has investigated the impact of the mutator phenotype on the selection of resistant mutants.…”

mentioning

confidence: 99%

Activity of Linezolid in anIn VitroPharmacokinetic-Pharmacodynamic Model Using Different Dosages andStaphylococcus aureusandEnterococcus faecalisStrains with and without a Hypermutator Phenotype

Arpin

Nso

et al. 2010

-, 600-, or 800-mg dose for 48 h was simulated against four strains (MIC, 2 g/ml): Staphylococcus aureus RN4220 and its mutator derivative MutS2, Enterococcus faecalis ATCC 29212, and a mutator clinical strain of E. faecalis, Ef1497. The peak concentrations (4.38 to 4.79, 13.4 to 14.6, and 19.2 to 19.5 g/ml) and half-lives at ␤-phase (5.01 to 6.72 h) fit human plasma linezolid pharmacokinetics. Due to its bacteriostatic property, the cumulative percentages of the dosing interval during which the drug concentration exceeded the MIC (T > MIC), 66.6 and 69.1% of the dosing interval, were not significant, except for Ef1497, with an 800-mg dose and a T > MIC of 80.9%. At the standard 600-mg dosage, resistant mutants (2-to 8-fold MIC increases) were selected only with Ef1497. A lower, 200-mg dosage did not select resistant mutants of E. faecalis ATCC 29212, but a higher, 800-mg dosage against Ef1497 did not prevent their emergence. For the most resistant mutant (MIC, 16 g/ml), characterization of 23S rRNA genes revealed the substitution A2453G in two of the four operons, which was previously described only in in vitro mutants of archaebacteria. Nevertheless, this mutant did not yield further mutants under 600-or 200-mg treatment. In conclusion, linezolid was consistently efficient against S. aureus strains. The emergence of resistant E. faecalis mutants was probably favored by the rapid decline of linezolid concentrations against a strong mutator, a phenotype less exceptional in E. faecalis than in S. aureus.

“…5a). The correlation has been shown to be reproducible and holds for at least 4-log-fold drops in viable counts, well above the sensitivity deemed sufficient to monitor bactericidal agents (14). When this correlation between photons and viable counts in a killing environment is compared to a series of log-fold dilution standards, prepared to give different cell densities per disc in the absence of an antimicrobial agent, there was a significant difference (P Ͻ 0.0001) (Fig.…”

mentioning

confidence: 99%

Use of a Bioluminescent Pseudomonas aeruginosa Strain within an In Vitro Microbiological System, as a Model of Wound Infection, To Assess the Antimicrobial Efficacy of Wound Dressings by Monitoring Light Production

Thorn

Nelson

Greenman

2007

A bioluminescent Pseudomonas aeruginosa was incorporated into an in vitro static diffusion method to determine whether light output could be used as a measure of wound dressing efficacy. A significant linear correlation was observed between viable counts and bioluminescence during exponential growth in planktonic culture (r 2 ‫؍‬ 0.969). Exponential-phase cells were used to inoculate cellulose discs for integration into an in vitro wound model that incorporated a reservoir of serum. A significant linear correlation was found between bioluminescence (photon counts monitored by a low-light camera) and viable counts in this growth environment (r 2 ‫؍‬ 0.982). Three antimicrobial wound dressings were applied to the surface of freshly prepared sample discs within the wound model, and the kill kinetics were codetermined by photon and viable counts. Quantifiable kill rates gave the same order of efficacy for the three wound dressings using both types of measurement, and a significant linear correlation was shown between photon and viable counts (r 2 ‫؍‬ 0.873) within this killing environment. Under all defined conditions, a significant linear correlation between bioluminescence and viable counts was shown but the actual slope of the correlation was different, depending on the physicochemical environment of the cells. Hence, significantly more light per cell (P < 0.0001) was produced when cells in discs were exposed to a killing environment compared to a growing environment. As long as defined conditions are employed, the resulting linear correlation enables the state of the system to be continually monitored without disturbance, allowing more immediate and accurate calculations of kill rates without the need for viable counting.