scholarly journals Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

2008 ◽  
Vol 52 (4) ◽  
pp. 1401-1406 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Karen E. Bowker ◽  
Alan R. Noel
Keyword(s):  
Staphylococcus Aureus ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Population Analysis ◽  
Viable Count ◽  
Superior Effect ◽  
Dose Ranging ◽  
Kill Curve ◽  
Emergence Of Resistance

ABSTRACT The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillin-sensitive S. aureus [MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using S. aureus at a standard inoculum of 106 CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 108 CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 108 CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (P < 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ± 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ± 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC24 as ABE was 24.9% ± 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2× and 4× the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.

scholarly journals Pharmacodynamics of Ceftaroline against Staphylococcus aureus Studied in anIn VitroPharmacokinetic Model of Infection

2013 ◽  
Vol 57 (6) ◽  
pp. 2451-2456 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Alan R. Noel ◽  
Sharon Tomaselli ◽  
Karen E. Bowker
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Exposure ◽  
Population Analysis ◽  
Intermediate Phenotype ◽  
Ceftaroline Fosamil ◽  
Content Type ◽  
Dose Ranging ◽  
Mrsa Strains ◽  
Emergence Of Resistance

ABSTRACTAnin vitrosingle-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline againstStaphylococcus aureus(both methicillin-susceptibleS. aureus[MSSA] and methicillin-resistantS. aureus[MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12S. aureusstrains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fTMIC) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a −1-log-unit drop, and one of 32.1% ± 8.1% was associated with a −2-log-unit drop. The MSSA and MRSA strains had similarfTMICvalues.fTMICvalues increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related tofTMIC.fTMICs of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treatS. aureusstrains with MICs of ≤2 μg/ml. AnfTMICof 25 to 30% would make a suitable pharmacodynamic index target, butfTMICvalues of ≥50% are needed to suppress the emergence of resistance and require clinical evaluation.

scholarly journals Pharmacodynamics of Telavancin Studied in anIn VitroPharmacokinetic Model of Infection

2010 ◽  
Vol 55 (2) ◽  
pp. 867-873 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Alan R. Noel ◽  
Sharon Tomaselli ◽  
Heather C. Elliott ◽  
Karen E. Bowker
Keyword(s):  
Population Analysis ◽  
Clinical Effectiveness ◽  
Bactericidal Effect ◽  
Viable Count ◽  
Time Curve ◽  
Dose Ranging ◽  
Mrsa Strains ◽  
Kill Curve ◽  
Emergence Of Resistance

ABSTRACTThe antibacterial effects of telavancin, vancomycin, and teicoplanin against sixStaphylococcus aureusstrains (1 methicillin-susceptibleS. aureus[MSSA] strain, 4 methicillin-resistantS. aureus[MRSA] strains, and 1 vancomycin-intermediateS. aureus[VISA] strain) and threeEnterococcussp. strains (1Enterococcus faecalisstrain, 1Enterococcus faeciumstrain, and 1 vancomycin-resistantE. faecium[VREF] strain) were compared using anin vitropharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptibleS. aureus(VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (AUBKC48) in comparison to vancomycin or teicoplanin (P< 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P< 0.05). Against the threeEnterococcusspp. tested, telavancin was superior to vancomycin in terms of its AUBKC24, AUBKC48, and greater early bactericidal effect (P< 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3Enterococcusstrains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for theEnterococcusspp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than withS. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity againstEnterococcusspp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for bothS. aureusandEnterococcusspp.

scholarly journals Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

2003 ◽  
Vol 47 (3) ◽  
pp. 1096-1100 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Karen E. Bowker
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Antibacterial Effect ◽  
Population Analysis ◽  
Antimicrobial Effect ◽  
Fluoroquinolone Resistance ◽  
Mechanism Of Resistance ◽  
Emergence Of Resistance

ABSTRACT Antibacterial effect and emergence of resistance to gemifloxacin and levofloxacin were studied in an in vitro pharmacokinetic model of infection. A panel of Streptococcus pneumoniae strains with known mechanisms of resistance were used; two strains had no known resistance mechanism, two had efflux pumps, three had gyrA plus parC mutations, and one had only a parC mutation. Gemifloxacin MICs were in the range of 0.016 to 0.25 mg/liter, and levofloxacin MICs ranged from 1 to 16 mg/liter. Antimicrobial effect was measured by area under the bacterial-kill curve up to 72 h, and emergence of resistance was determined by population analysis profile before and during drug exposure. The area under the curve (AUC)/MIC ratios for gemifloxacin and levofloxacin were 35 to 544 and 3 to 48, respectively. As expected on the basis of these AUC/MIC ratio differences, antibacterial effect was much greater for gemifloxacin than levofloxacin. In the gemifloxacin simulations, mechanism of resistance as well as MIC determined the antibacterial effect, as indicated by gemifloxacin’s greater effect against efflux strains compared to those with gyrA or parC mutations despite similar MICs. This was not true of levofloxacin. Emergence of resistance was not easily demonstrated with either agent, and mechanism of resistance did not have any impact on it.

scholarly journals Pharmacodynamics of Minocycline against Staphylococcus aureus in an In Vitro Pharmacokinetic Model

2008 ◽  
Vol 52 (12) ◽  
pp. 4370-4373 ◽  
Author(s):  
Karen E. Bowker ◽  
Alan R. Noel ◽  
Alasdair P. MacGowan
Keyword(s):  
Staphylococcus Aureus ◽  
Pharmacokinetic Model ◽  
Viable Count ◽  
Maximal Effect ◽  
Time Curve ◽  
Emax Model ◽  
Before And After ◽  
Kill Curve ◽  
Unit Reduction

ABSTRACT Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log10-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P < 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r 2 of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and −1-log-unit, −2-log-unit, and −3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.

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 Activity of Colistin against Heteroresistant Acinetobacter baumannii and Emergence of Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2007 ◽  
Vol 51 (9) ◽  
pp. 3413-3415 ◽  
Author(s):  
Chun-Hong Tan ◽  
Jian Li ◽  
Roger L. Nation
Keyword(s):  
Continuous Infusion ◽  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Growth Control ◽  
Pharmacodynamic Model ◽  
Bacterial Density ◽  
Control Population ◽  
Emergence Of Resistance

ABSTRACT Three clinically relevant intermittent regimens, and a continuous infusion, of colistin were simulated in an in vitro pharmacokinetic/pharmacodynamic model against two colistin-heteroresistant strains of Acinetobacter baumannii. Extensive initial killing was followed by regrowth as early as 6 h later; bacterial density in the 24- to 72-h period was within 1 log10 CFU/ml of growth control. Population analysis profiles revealed extensive emergence of resistant subpopulations regardless of the colistin regimen.

scholarly journals Pharmacodynamics of Razupenem (PZ601) Studied in anIn VitroPharmacokinetic Model of Infection

2011 ◽  
Vol 55 (4) ◽  
pp. 1436-1442 ◽  
Author(s):  
Alasdair P. MacGowan ◽  
Alan Noel ◽  
Sharon Tomaselli ◽  
Heather Elliott ◽  
Karen Bowker
Keyword(s):  
Antibacterial Effect ◽  
Population Analysis ◽  
Viable Count ◽  
Bacteriostatic Effect ◽  
Series Of Experiments ◽  
Initial Clearance ◽  
Mrsa Strains ◽  
Unit Reduction ◽  
Recovery Medium

ABSTRACTSimulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in anin vitropharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains ofStaphylococcus aureus(one methicillin-sensitiveS. aureus[MSSA] strain [MIC, 0.015 μg/ml] and five methicillin-resistantS. aureus[MRSA] strains [MIC range, 0.09 to 3 μg/ml]) and five strains ofEnterobacteriaceae(threeEscherichia colistrains [two containing extended-spectrum β-lactamases {ESBLs}] and twoEnterobactersp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 μg/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2× MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 μg/ml) and at 120 h with strain 27706 (MIC, 1.5 μg/ml). AgainstE. coliandEnterobacterspp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 μg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except forEnterobacterstrain 34425 (MIC, 6.0 μg/ml), where colonies were recovered from media containing 2×, 4×, and 8× MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% ± 1.4%, and that for a 1-log-unit reduction in count was 12.5% ± 5.8%. Population profiles indicated growth on 2× MIC recovery medium atfT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments withEnterobacteriaceae, thefT>MIC for a 24-h bacteriostatic effect was 34.2% ± 7.6% and that for a 1-log-unit reduction in count was 42.5% ± 7.8%. Population analysis profiles indicated growth on recovery media with 2×, 4×, and 8× MIC atfT>MICs in the range of 1 to 69% but rarely at values of ≥70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of ≤3.0 μg/ml andEnterobacteriaceaewith MICs of ≤0.4 μg/ml.fT>MIC targets of ≥35% for MRSA and ≥70% forEnterobacteriaceaeshould provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.

scholarly journals 569. Evaluation of a Povidone-Iodine Preparation for Nasal Decolonization of Methicillin-Resistant Staphylococcus aureus

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S269-S269
Author(s):  
Hussein Abou Ghaddara ◽  
Jennifer Cadnum ◽  
Y Karen Ng Wong ◽  
Curtis Donskey
Keyword(s):  
Staphylococcus Aureus ◽  
Povidone Iodine ◽  
Perioperative Period ◽  
Control Group ◽  
Single Application ◽  
Methicillin Resistant ◽  
Dosing Intervals ◽  
And Control ◽  
Emergence Of Resistance

Abstract Background Mupirocin is commonly used for nasal decolonization of Staphylococcus aureus, but it has limitations including frequent emergence of resistance and non-adherence due to the need for repeated applications. Povidone-iodine is increasingly used as an alternative for nasal decolonization because it has a low propensity for emergence of resistance and rapid in vitro antibacterial activity. However, limited data are available on the microbiological efficacy of povidone-iodine for suppression of nasal S. aureus. Methods We compared the effectiveness of a single application or 5 days of twice daily application of a commercial 10% povidone-iodine preparation vs. phosphate-buffered saline for a reduction in nasal MRSA in methicillin-resistant S. aureus (MRSA)-colonized patients (9–11 per treatment group). Nasal swabs were collected for quantitative culture of MRSA before and at 1, 6, 12 and 24 hours after the single application or before each dose for the 5-day regimen. Analysis of variance was used to compare MRSA colony counts in povidone iodine vs. control patients. Results The concentrations of MRSA in the nares were similar for povidone-iodine and control group patients prior to treatment. As shown in the figure, the single application of povidone-iodine resulted in a statically significant reduction in nasal MRSA in comparison to controls at 2 and 6 hours after treatment (P10 colonies per swab). Conclusion Our findings suggest that single preoperative applications povidone-iodine could be useful for short-term suppression of S. aureus during the perioperative period. Additional studies are needed to evaluate the efficacy of the povidone-iodine preparation for MRSA decolonization when used at more frequent dosing intervals or in combination with chlorhexidine bathing. Disclosures All authors: No reported disclosures.

scholarly journals Prospective Comparison of the Clinical Impacts of Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Susceptible MRSA

2009 ◽  
Vol 53 (8) ◽  
pp. 3447-3452 ◽  
Author(s):  
K. C. Horne ◽  
B. P. Howden ◽  
E. A. Grabsch ◽  
M. Graham ◽  
P. B. Ward ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Population Analysis ◽  
Clinical Status ◽  
Area Under The Curve ◽  
Prospective Comparison ◽  
In Vitro Investigation ◽  
Mrsa Strains ◽  
Cure Rates ◽  
Post Hoc

ABSTRACT Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [≥0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 μg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.

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