scholarly journals Activities of Garenoxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

2004 ◽  
Vol 48 (3) ◽  
pp. 765-773 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. P. Bédos ◽  
J. Mohler ◽  
G. Peytavin ◽  
R. Isturiz ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Wild Type Strain ◽  
Survival Rates ◽  
Pharmacokinetic Parameters ◽  
Gram Negative Bacteria ◽  
Single Mutation ◽  
Wild Type ◽  
Time Curve ◽  
Concentration Time

ABSTRACT Garenoxacin is a novel des-F(6) quinolone with enhanced in vitro activities against both gram-positive and gram-negative bacteria. We compared the activity of garenoxacin with that of trovafloxacin (TVA) against Streptococcus pneumoniae, together with their efficacies and their capacities to select for resistant mutants, in a mouse model of acute pneumonia. In vitro, garenoxacin was more potent than TVA against wild-type S. pneumoniae and against a mutant with a single mutation (parC), a mutant with double mutations (gyrA and parC), and a mutant with triple mutations (gyrA, parC, and parE). Swiss mice were infected with 105 CFU of virulent, encapsulated S. pneumoniae strain P-4241 or its derived isogenic parC, gyrA, gyrA parC, and efflux mutants and 107 CFU of poorly virulent clinical strains carrying a parE mutation or gyrA, parC, and parE mutations. The drugs were administered six times, every 12 h, beginning at either 3 or 18 h postinfection. The pulmonary pharmacokinetic parameters in mice infected with strain P-4241 and treated with garenoxacin or TVA (25 mg/kg of body weight) were as follows: maximum concentration of drug in serum (C max; 17.3 and 21.2 μg/ml, respectively), C max/MIC ratio (288 and 170, respectively), area under the concentration-time curve (AUC; 48.5 and 250 μg · h/ml, respectively), and AUC/MIC ratio (808 and 2,000, respectively). Garenoxacin at 25 and 50 mg/kg was highly effective (survival rates, 85 to 100%) against the wild-type strain and mutants harboring a single mutation. TVA was as effective as garenoxacin against these strains. TVA at 200 mg/kg and garenoxacin at 50 mg/kg were ineffective against the mutant with the parC and gyrA double mutations and the mutant with the gyrA, parC, and parE triple mutations. The efficacy of garenoxacin was reduced only when strains bore several mutations for quinolone resistance.

scholarly journals Fluoroquinolone Resistance in Streptococcus pneumoniae: Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin

2007 ◽  
Vol 51 (4) ◽  
pp. 1315-1320 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Michael J. Rybak ◽  
Brian Tsuji ◽  
Thomas P. Lodise ◽  
Glenn W. Kaatz
Keyword(s):  
Streptococcus Pneumoniae ◽  
Sequence Analysis ◽  
Fluoroquinolone Resistance ◽  
Second Step ◽  
Wild Type ◽  
Time Curve ◽  
Resistance Development ◽  
Concentration Time ◽  
Structural Differences

ABSTRACT The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (108.5 to 109 log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and ≤60, 34 and 37, ≤82 and ≤86, and ≤24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P < 0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P < 0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin > gatifloxacin > moxifloxacin = gemifloxacin, which may be related to structural differences within the class.

scholarly journals Activity of Gemifloxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

2005 ◽  
Vol 49 (3) ◽  
pp. 1046-1054 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. P. Bédos ◽  
J. Mohler ◽  
P. Moine ◽  
C. Cherbuliez ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Wild Type Strain ◽  
Acquired Resistance ◽  
Survival Rates ◽  
High Dose ◽  
Single Mutation ◽  
Double Mutation ◽  
Poor Efficacy

ABSTRACT Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin and trovafloxacin, their abilities to select for resistance in vitro and in vivo, and their efficacies in a mouse model of acute pneumonia. Immunocompetent Swiss mice were infected with 105 CFU of a virulent, encapsulated S. pneumoniae strain, P-4241, or its isogenic parC, gyrA, parC gyrA, and efflux mutant derivatives (serotype 3); and leukopenic mice were infected with 107 CFU of two poorly virulent clinical strains (serotype 11A) carrying either a parE mutation or a parC, gyrA, and parE triple mutation. The drugs were administered six times every 12 h, starting at either 3 or 18 h postinfection. In vitro, gemifloxacin was the most potent agent against strains with and without acquired resistance to fluoroquinolones. While control mice died within 6 days, gemifloxacin at doses of 25 and 50 mg/kg of body weight was highly effective (survival rates, 90 to 100%) against the wild-type strain and against mutants harboring a single mutation, corresponding to area under the time-versus-serum concentration curve at 24 h (AUC24)/MIC ratios of 56.5 to 113, and provided a 40% survival rate against a mutant with a double mutation (parC and gyrA). A total AUC24/MIC ratio of 28.5 was associated with poor efficacy and the emergence of resistant mutants. Trovafloxacin was as effective as gemifloxacin against mutants with single mutations but did not provide any protection against the mutant with double mutations, despite treatment with a high dose of 200 mg/kg. Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo.

scholarly journals Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

2012 ◽  
Vol 116 (5) ◽  
pp. 1124-1133 ◽  
Author(s):  
Bruce Hullett ◽  
Sam Salman ◽  
Sean J. O'Halloran ◽  
Deborah Peirce ◽  
Kylie Davies ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Pharmacokinetic Model ◽  
Inhibitory Concentration ◽  
Prediction Interval ◽  
Cyclooxygenase 2 ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

scholarly journals Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

scholarly journals Contributions of the 8-Methoxy Group of Gatifloxacin to Resistance Selectivity, Target Preference, and Antibacterial Activity against Streptococcus pneumoniae

2001 ◽  
Vol 45 (6) ◽  
pp. 1649-1653 ◽  
Author(s):  
Hideyuki Fukuda ◽  
Ryuta Kishii ◽  
Masaya Takei ◽  
Masaki Hosaka
Keyword(s):  
Antibacterial Activity ◽  
Streptococcus Pneumoniae ◽  
Type Strain ◽  
Methoxy Group ◽  
Wild Type Strain ◽  
Dna Gyrase ◽  
Wild Type ◽  
Topoisomerase Iv ◽  
Mutant Strains

ABSTRACT Gatifloxacin (8-methoxy, 7-piperazinyl-3′-methyl) at the MIC selected mutant strains that possessed gyrA mutations at a low frequency (3.7 × 10−9) from wild-type strainStreptococcus pneumoniae IID553. AM-1147 (8-methoxy, 7-piperazinyl-3′-H) at the MIC or higher concentrations selected no mutant strains. On the other hand, the respective 8-H counterparts of these two compounds, AM-1121 (8-H, 7-piperazinyl-3′-methyl) and ciprofloxacin (8-H, 7-piperazinyl-3′-H), at one and two times the MIC selected mutant strains that possessed parC mutations at a high frequency (>2.4 × 10−6). The MIC of AM-1147 increased for the gyrA mutant strains but not for theparC mutant strains compared with that for the wild-type strain. These results suggest that fluoroquinolones that harbor 8-methoxy groups select mutant strains less frequently and prefer DNA gyrase, as distinct from their 8-H counterparts. The in vitro activities of gatifloxacin and AM-1147 are twofold higher against the wild-type strain, eight- and twofold higher against the first-stepparC and gyrA mutant strains, respectively, and two- to eightfold higher against the second-step gyrA andparC double mutant strains than those of their 8-H counterparts. These results indicate that the 8-methoxy group contributes to enhancement of antibacterial activity against target-altered mutant strains as well as the wild-type strain. It is hypothesized that the 8-methoxy group of gatifloxacin increases the level of target inhibition, especially against DNA gyrase, so that it is nearly the same as that for topoisomerase IV inhibition in the bacterial cell, leading to potent antibacterial activity and a low level of resistance selectivity.

scholarly journals Efficacy of Trovafloxacin against Penicillin-Susceptible and Multiresistant Strains of Streptococcus pneumoniae in a Mouse Pneumonia Model

1998 ◽  
Vol 42 (4) ◽  
pp. 862-867 ◽  
Author(s):  
Jean-Pierre Bédos ◽  
Véronique Rieux ◽  
Jacqueline Bauchet ◽  
Martine Muffat-Joly ◽  
Claude Carbon ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Resistant Strain ◽  
Survival Rates ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Beta Lactam ◽  
Time Curve ◽  
Swiss Mice ◽  
Resistant Strains

ABSTRACT The increasing emergence of penicillin-resistant and multidrug-resistant strains of Streptococcus pneumoniaewill create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 μg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 μg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 μg/ml) and a ciprofloxacin-resistant strain (MIC, 32 μg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant S. pneumoniae but appears to be ineffective against a ciprofloxacin-resistant strain.

scholarly journals Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

2003 ◽  
Vol 47 (8) ◽  
pp. 2606-2614 ◽  
Author(s):  
George P. Allen ◽  
Glenn W. Kaatz ◽  
Michael J. Rybak
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pharmacodynamic Model ◽  
The Other ◽  
Time Curve ◽  
Development Of Resistance ◽  
Concentration Time ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT The differential effects of moxifloxacin and levofloxacin on the development of resistance in four Streptococcus pneumoniae isolates were examined by using an in vitro pharmacodynamic model. Therapeutic regimens (moxifloxacin: peak, 4.5 μg/ml; half-life [t 1/2], 12 h; and levofloxacin: peak, 6 μg/ml; t 1/2, 6 h) were tested against two fluoroquinolone-susceptible isolates (strains 79 and ATCC 49619) and KD2138 and KD2139 (parC and gyrA mutants, respectively, of ATCC 49619). Mutant prevention concentration (MPC)-targeted regimens with modified pharmacokinetics of each drug were simulated to match the area under the concentration-time curve (AUC) above the MPC for the two fluoroquinolones. Moxifloxacin MICs and MPCs (MIC/MPC) for isolates 79, ATCC 49619, KD2138, and KD2139, respectively, were 0.125 and 0.5, 0.125 and 0.5, 0.25 and 8, and 0.25 and 4 μg/ml. Levofloxacin MICs and MPCs for the same isolates were 1 and 4, 0.5 and 2, 1 and 64, and 0.5 and 32 μg/ml, respectively. Therapeutic levofloxacin concentrations led to isolation of mutants of ATCC 49619 (S79Y in ParC), KD2138 (S81Y in GyrA), and KD2139 (S79Y in ParC). Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates. MPC-targeted moxifloxacin (lower-than-normal peak = 0.75 to 1.5 μg/ml, administered at levofloxacin's t 1/2) caused growth of a GyrA variant (S81Y) of KD2138 and a ParC variant (S79Y) of KD2139, while no mutants of ATCC 49619 were recovered. MPC-targeted levofloxacin (higher-than-normal peak = 14.5 to 29.5 μg/ml, administered at moxifloxacin's t 1/2) against KD2138 and KD2139 did not prevent the development of the mutations observed in therapeutic regimens, but resistance in the fluoroquinolone-susceptible ATCC 49619 was no longer noted. Normalization of the respective AUC/MPC ratios of moxifloxacin and levofloxacin did not eliminate differences in resistance selectivity of the two agents in all cases. We conclude that the reduced recovery of resistant mutants of S. pneumoniae following moxifloxacin exposure compared to levofloxacin may be due to intrinsic differences between the drugs. Increasing the concentration and exposure (t 1/2) to exceed the MPC may prevent mutations from occurring in fluoroquinolone-susceptible strains. However, this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations. Further study of the MPC concept to evaluate these relationships is warranted.

scholarly journals Pharmacodynamics of Moxifloxacin against Anaerobes Studied in an In Vitro Pharmacokinetic Model

2005 ◽  
Vol 49 (10) ◽  
pp. 4234-4239 ◽  
Author(s):  
Alan R. Noel ◽  
Karen E. Bowker ◽  
Alasdair P. MacGowan
Keyword(s):  
Pharmacokinetic Model ◽  
Antibacterial Effect ◽  
Maximum Effect ◽  
Wild Type ◽  
Time Curve ◽  
Concentration Time ◽  
Effect Measure ◽  
Dose Ranging ◽  
Emergence Of Resistance

ABSTRACT The antibacterial effects of moxifloxacin against Bacteroides fragilis, Clostridium perfringens, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with Escherichia coli. The AUC/MIC ratios for 50% and 90% effects, using a log CFU drop at 24 h as the antibacterial effect measure, were 34 and 59, respectively, aerobic and 54 and 96, respectively, anaerobic. These values are not significantly different. Dose ranging at AUC/MIC ratios of 9 to 216 against the anaerobes indicated a differing AUC/MIC ABE pattern, and the AUC/MICs for 50% and 90% effects were lower: for B. fragilis, they were 10.5 and 25.7, respectively; for C. perfringens, they were 8.6 and 16.2; and for GPAC, they were 7.3 and 17.4. The maximum-effect log drops were as follows: for B. fragilis, −3.2 ± 0.2 logs; for C. perfringens, −3.7 ± 0.1 logs; and for GPAC, −2.5 ± 0.1 logs. Although the anaerobes were not eradicated, there was no emergence of resistance. Comparison of the ABE of moxifloxacin to that of ertapenem against B. fragilis indicated that moxifloxacin was superior at 24 h and 48 h. In contrast, ertapenem was superior to moxifloxacin against GPAC at 24 h and 48 h and against C. perfringens at 48 h. Both drugs performed equivalently against C. perfringens at 24 h. Monte Carlo simulations using human serum AUC data and an AUC/MIC anaerobe target of 7.5 suggests a >90% target achievement at MICs of <2 mg/liter. This divides the B. fragilis wild-type MIC distribution. The pharmacodynamic properties of moxifloxacin against anaerobes are different than those against aerobic species. The clinical implications of these differences need further exploration.

scholarly journals Pharmacodynamic Assessment Based on Mutant Prevention Concentrations of Fluoroquinolones To Prevent the Emergence of Resistant Mutants of Streptococcus pneumoniae

2007 ◽  
Vol 51 (11) ◽  
pp. 3810-3815 ◽  
Author(s):  
Tomoyuki Homma ◽  
Toshihiko Hori ◽  
Giichi Sugimori ◽  
Yoshinori Yamano
Keyword(s):  
Streptococcus Pneumoniae ◽  
Population Analysis ◽  
Pharmacodynamic Model ◽  
Time Curve ◽  
Concentration Time ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
The Relationship ◽  
Concentration Curves

ABSTRACT The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC0-24)/MPC and peak concentration (C max)/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC0-24/MPC and C max/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC0-24/MPC and C max/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.

scholarly journals Impact of recA on Levofloxacin Exposure-Related Resistance Development

2010 ◽  
Vol 54 (10) ◽  
pp. 4262-4268 ◽  
Author(s):  
Renu Singh ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Vincent H. Tam
Keyword(s):  
Potential Role ◽  
Wild Type Strain ◽  
Sos Response ◽  
Infection Model ◽  
Wild Type ◽  
Time Curve ◽  
Resistance Development ◽  
E Coli ◽  
Serial Samples

ABSTRACT Genetic mutations are one of the major mechanisms by which bacteria acquire drug resistance. One of the known mechanisms for inducing mutations is the SOS response system. We investigated the effect of disrupting recA, an inducer of the SOS response, on resistance development using an in vitro hollow-fiber infection model. A clinical Staphylococcus aureus isolate and a laboratory wild-type strain of Escherichia coli were compared to their respective recA-deleted isogenic daughter isolates. Approximately 2 × 105 CFU/ml of bacteria were subjected to escalating levofloxacin exposures for up to 120 h. Serial samples were obtained to ascertain simulated drug exposures and total and resistant bacterial burdens. Quinolone resistance determining regions of gyrA and grlA (parC for E. coli) in levofloxacin-resistant isolates were sequenced to confirm the mechanism of resistance. The preexposure MICs of the recA-deleted isolates were 4-fold lower than those of their respective parents. In S. aureus, a lower area under the concentration-time curve over 24 h at steady state divided by the MIC (AUC/MIC) was required to suppress resistance development in the recA-deleted mutant (an AUC/MIC of >23 versus an AUC/MIC of >32 was necessary in the mutant versus the parent isolate, respectively), and a prominent difference in the total bacterial burden was observed at 72 h. Using an AUC/MIC of approximately 30, E. coli resistance emergence was delayed by 24 h in the recA-deleted mutant. Diverse mutations in gyrA were found in levofloxacin-resistant isolates recovered. Disruption of recA provided additional benefits apart from MIC reduction, attesting to its potential role for pharmacologic intervention. The clinical relevance of our findings warrants further investigations.

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