Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

Firsov, Alexander A.; Lubenko, Irene Yu; Vostrov, Sergey N.; Portnoy, Yury A.; Zinner, Stephen H.

doi:10.1128/aac.49.7.2642-2647.2005

Cited by 24 publications

(23 citation statements)

References 42 publications

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“…In our in vitro studies, we found that levofloxacin was bactericidal against S. aureus in both the log and the stationary phases, in agreement with the findings presented in previous reports (19,28,31,34). In contrast, the efficacy of rifampin alone was greatly influenced by the inoculum size, as well as by the emergence of resistant strains.…”

Section: Discussionsupporting

confidence: 81%

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Murillo¹,

Pachón²,

Euba³

et al. 2008

Antimicrob Agents Chemother

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Since levofloxacin at high doses was more active than levofloxacin at conventional doses and was the best therapy alone in a rat model of staphylococcal foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model, rifampin at 25 mg/kg of body weight/12 h, levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, levofloxacin at 50 mg/kg/day, levofloxacin at 50 mg/kg/day plus rifampin, or a control treatment was administered for 7 days; and therapy with for levofloxacin at 100 mg/kg/day alone and rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with levofloxacin at concentrations >2؋ MIC and rifampin and tended to occur in the stationary phase. At the end of 7 days of therapy, levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from tissue cage fluid (P < 0.05 compared with the results for groups except those receiving rifampin alone). At the end of 14 days of therapy with levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (P < 0.05 compared with the results with the combined therapy), 3.36, and 5.4 log CFU/ml, respectively. No rifampin or levofloxacin resistance was detected in any group except that receiving rifampin alone. In conclusion, high-dose levofloxacin was the best treatment and no resistant strains appeared; the addition of rifampin showed an antagonistic effect. The efficacy of the rifampin-levofloxacin combination is not significantly improved by the dosage of levofloxacin.Orthopedic prosthetic infections are difficult to treat because of the presence of bacterial biofilms. The definitive therapy for such infections requires a combination of surgical and medical approaches and the use of selected antibiotics active against the microorganisms involved (11, 40, 48).On the basis of previous experimental and clinical studies, rifampin plays a main role in the treatment of staphylococcal foreign-body infections (4,45,47,49), while fluoroquinolones are considered the best drugs for use in combination with rifampin (14,15,46). Recent work recommended the use of a combination of high doses of levofloxacin (750 to 1,000 mg/ day) plus rifampin for the treatment of staphylococcal prosthetic infections (48), even though the information available from this setting is limited (3, 34, 39).The rat model of staphylococcal tissue cage infection is a well-standardized model of chronic foreign-body infection that has provided relevant information in this regard (8,9,32,44). Using this model, we previously reported that high-dose levofloxacin (equivalent to 750 to 1,000 mg/day) was more active than the conventional levofloxacin dose (500 mg/day) and that it was the best therapy for u...

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Section: Discussionsupporting

confidence: 81%

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Murillo¹,

Pachón²,

Euba³

et al. 2008

Antimicrob Agents Chemother

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“…In the case of levofloxacin, the great majority of PK-PD human studies have been performed with a dose of 500 mg/day (19,32,40); our experimental group for levofloxacin 50 showed TCF levels consistent with this human dose. However, high doses of levofloxacin (750 to 1,000 mg/day) have been approved for treatment of nosocomial pneumonia and complicated skin structure infections and have recently been recommended for orthopedic prosthetic infections (47), given the inherent difficulties in curing them.…”

Section: Discussionmentioning

confidence: 95%

“…It is well established that the efficacy of fluoroquinolones is concentration dependent and that a peak/MIC ratio of Ն10 and an AUC/MIC ratio of Ͼ125 are required to ensure clinical efficacy and to avoid the possible development of resistant strains; moreover, an AUC/MIC ratio of close to 250 is recommended to achieve high efficacy in fluoroquinolones (12,16,37). However, these pharmacodynamic parameters were defined using ciprofloxacin against gram-negative bacilli (21), and recent studies have questioned their application when newer fluoroquinolones are used against different bacteria (19).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the use of high doses has recently been recommended based on its pharmacodynamic (PD) properties and on information obtained from in vitro models (19,20,47). The present research used this foreign-body infection model to evaluate the efficacy of usual and high doses of levofloxacin compared to other antistaphylococcal antimicrobials, such as rifampin, cloxacillin, and vancomycin; linezolid, a promising new drug in the therapy of these infections, was also included.…”

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confidence: 99%

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Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Murillo¹,

Domènech²,

García

et al. 2006

Antimicrob Agents Chemother

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Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic-and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: ؊1.24, ؊2.26, ؊2.1, ؊1.56, ؊1.47, ؊1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P ‫؍‬ 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r ‫؍‬ 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.Patients suffering from orthopedic device infections will have usually undergone surgical interventions and received antibiotic therapies over a long period of time, these being major clinical issues. It is very difficult to eradicate such infections using antibiotics because of the formation of biofilm, a protein matrix including bacteria with reduced metabolism and with tolerance to antimicrobials (2,9,11,38).These infections are frequently caused by Staphylococcus aureus, and rifampin has been shown to be the most effective antimicrobial agent in such cases, in in vitro and experimental studies (26, 48) and in clinical practice (14,15,46). Since this drug should not be given alone due to the development of early bacterial resistance, antibiotic combinations are required. The combination of rifampin and fluoroquinolones has been found to be particularly efficacious and is thus usually recommended (10,14,44).In recent years, the experimental foreign-body infection model developed by Lucet et al. (26) has provided relevant data regarding the antimicrobial efficacy of several antibiotics ...

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“…As a result, only a few studies really provide accurate predictions of AUC/MIC and C max /MIC breakpoints. In a series of in vitro studies from our laboratory, different organisms were exposed to a wide range of AUC/MICs of novel fluoroquinolones and ciprofloxacin as a reference drug [2]. A specific pathogen-independent relationship between the log AUC/MIC and the intensity of the antimicrobial effect (I E -area between the control growth and time-kill curves [1]) was inherent in each antibiotic.…”

Section: Prediction Of the Antimicrobial Effect Using In Vitro Dynamimentioning

confidence: 99%

Antibiotic pharmacodynamics and bacterial resistance: Usefulness of in vitro models

Zinner

Firsov²

2007

Curr Infect Dis Rep

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Antistaphylococcal Effect Related to the Area under the Curve/MIC Ratio in an In Vitro Dynamic Model: Predicted Breakpoints versus Clinically Achievable Values for Seven Fluoroquinolones

Cited by 24 publications

References 42 publications

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Antibiotic pharmacodynamics and bacterial resistance: Usefulness of in vitro models

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