Effect of Linezolid Alone and in Combination With Other Antibiotics.docx (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2005
Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.
International Journal of Infectious Diseases, 2010
Background: Staphylococcus aureus is a facultatively anaerobic, Gram-positive coccus. It is a major pathogen associated with serious community and hospitalacquired infections. By designation methicillin resistant Staphylococcus aureus (MRSA) is a strain of Staphylococcus aureus that is resistant to all beta-lactams, including penicillins, cephalosporins and carbapenems. Vancomycin has a narrow spectrum of activity, restricted to most Gram-positive bacteria, and is the drug of choice for the treatment of methicillin resistant Staphylococcus aureus. This agent, however, requires intravenous administration, and occasionally patients experience unacceptable side effects. Linezolid, a member of the new oxazolidinone class of antibiotics, has shown very good activity against methicillin resistant Staphylococcus aureus, has excellent oral bioavailability and is inexpensive as compared to vancomycin. Aims and Objectives: Comparison of in vitro activities of vancomycin and linezolid against methicillin resistant Staphylococcus aureus. Materials and Method: The study was conducted over a period of 6 months. Fifty Methicillin resistant Staphylococcus aureus isolated from the clinical isolates of Military hospital Rawalpindi were subjected to the determination of Minimum inhibitory concentrations of linezolid and vancomycin using E-strips. Minimum inhibitory concentrations 50 and minimum inhibitory concentrations 90 were calculated. Results: All the isolated organisms were uniformly susceptible to both the antibiotics. Vancomycin showed higher minimum inhibitory concentrations (MICs) as compared to linezolid MICs. Conclusion: This study suggests that linezolid and vancomycin have similar in vitro efficacy for methicillin resistant Staphylococcus aureus infections. Linezolid's oral dosing option can allow earlier discharge of hospitalized patients and its low cost reduces health care expenses.
Antimicrobial Agents and Chemotherapy, 2003
The in vitro activities of linezolid were determined alone and in combination with vancomycin, ciprofloxacin, gentamicin, fusidic acid, or rifampin against five methicillin-susceptible Staphylococcus aureus (MSSA) and five methicillin-resistant S. aureus (MRSA) strains. Similar responses were obtained against MSSA and MRSA. When combined with fusidic acid, gentamicin, or rifampin, linezolid prevented selection of resistant mutants but showed no synergy. When linezolid was combined with vancomycin and ciprofloxacin, a slight antagonism was observed. While the combination with linezolid may reduce the emergence of mutants resistant to the associated drugs, the absence of synergy, especially in the case of vancomycin and ciprofloxacin, does not argue in favor of such combinations.
Objectives: To evaluate the in-vitro activities of linezolid, vancomycin, ciprofloxacin, gentamicin, amikacin, trimethoprim and fusidic acid, against methicillin resistant isolates. Materials and Methods: Three hundred and twenty two non-duplicate archived Staphylococcal isolates recovered from routine cultures performed in the microbiology laboratory from wounds, and abscesses swabs, urine, blood, pus, derived from both in-and out patients were tested. Results: A total of 274 S. aureus and 76 CNS clinical isolates were included in the study, 46.7% were MRSA and 21% methicillin resistant CNS (MRCNS). None of the strains was found to be resistant to linezolid and vancomycin. The resistance rates of MRSA isolates to antibiotics were as follows: 86% to gentamicin, 84.3% to fusidic acid, 80% to trimethoprim, 78.2% to ciprofloxacin and 76.5% to amikacin. Similar trend were also obtained for MRCNS isolates. The majority (70%) of MRSA isolates were resistant to all used classes of antibiotics in the study, while only 4.3% were sensitive to such antimicrobial agents. Conclusion: Due to the high prevalence of multi-drug resistant MRSA, this study has provided valuable baseline information to clinicians regarding the benefit of linezolid, suggesting that it can be used as an alternative drug in such severe life threatening infections caused by MRSA, especially if the side effect of vancomycin was observed.
JPMA. The Journal of the Pakistan Medical Association, 2011
To compare the in vitro activities of vancomycin and linezolid against methicillin resistant Staphyloccus aureus in our set up to help in formulating a better empirical treatment and reduce the emergence of vancomycin resistant Staphylococcus aureus. The study was conducted over a period of 6 months (1st July 2009-31st Dec 2009). Fifty Methicillin resistant Staphylococcus aureus isolated from the clinical isolates of Military Hospital Rawalpindi were subjected to the determination of Minimum inhibitory concentrations of linezolid and vancomycin using E-strips. All the isolated organisms were uniformly susceptible to both the antibiotics. Vancomycin showed higher minimum inhibitory concentrations (MICs) as compared to linezolid MICs. This study suggests that linezolid and vancomycin have similar in vitro efficacy for methicillin resistant Staphyloccus aureus infections.
Core Evidence, 2012
Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated and hospital-associated strains, is a major cause of human morbidity and mortality. Treatment options have become limited due to the emergence of MRSA strains with decreased sensitivity to vancomycin, which has long been the first-line therapy for serious infections. This has prompted the search for novel antibiotics that are efficacious against MRSA. Linezolid, an oxazolidinone class of antibiotic, was approved by the Food and Drug Administration in 2000 for treatment of MRSA infections. Since then, there have been a multitude of clinical trials and research studies evaluating the effectiveness of linezolid against serious infections, including pneumonia (both community-and hospital-acquired), skin and soft-tissue infections such as diabetic foot ulcers, endocarditis, osteomyelitis, prosthetic devices, and others. The primary aim of this review is to provide an up-to-date evaluation of the clinical evidence for using linezolid to treat MRSA infections, with a focus on recently published studies, including those on nosocomial pneumonia. Other objectives are to analyze the cost-effectiveness of linezolid compared to other agents, and to review the pharmokinetics and pharmacodynamics of linezolid, emphasizing the most current concepts.
International Journal of Infectious Diseases, 2010
Background: Staphylococcus aureus is a facultatively anaerobic, Gram-positive coccus. It is a major pathogen associated with serious community and hospitalacquired infections. By designation methicillin resistant Staphylococcus aureus (MRSA) is a strain of Staphylococcus aureus that is resistant to all beta-lactams, including penicillins, cephalosporins and carbapenems. Vancomycin has a narrow spectrum of activity, restricted to most Gram-positive bacteria, and is the drug of choice for the treatment of methicillin resistant Staphylococcus aureus. This agent, however, requires intravenous administration, and occasionally patients experience unacceptable side effects. Linezolid, a member of the new oxazolidinone class of antibiotics, has shown very good activity against methicillin resistant Staphylococcus aureus, has excellent oral bioavailability and is inexpensive as compared to vancomycin. Aims and Objectives: Comparison of in vitro activities of vancomycin and linezolid against methicillin resistant Staphylococcus aureus. Materials and Method: The study was conducted over a period of 6 months. Fifty Methicillin resistant Staphylococcus aureus isolated from the clinical isolates of Military hospital Rawalpindi were subjected to the determination of Minimum inhibitory concentrations of linezolid and vancomycin using E-strips. Minimum inhibitory concentrations 50 and minimum inhibitory concentrations 90 were calculated. Results: All the isolated organisms were uniformly susceptible to both the antibiotics. Vancomycin showed higher minimum inhibitory concentrations (MICs) as compared to linezolid MICs. Conclusion: This study suggests that linezolid and vancomycin have similar in vitro efficacy for methicillin resistant Staphylococcus aureus infections. Linezolid's oral dosing option can allow earlier discharge of hospitalized patients and its low cost reduces health care expenses.
R E S U M E N El objetivo de este estudio fue investigar los efectos in vitro de linezolid en combinación con cinco antimicrobianos antiestafilocócicos (doxiciclina, fosfomicina, levofloxacino, rifampicina y vancomicina) en cepas de Staphylococcus aureus sensibles a meticilina (SASM). Se utilizaron cinco cepas de SASM (hf008, hf095, hf295, hf602 y hf946) aisladas de muestras procedentes de infecciones humanas. Se utilizó el método del damero para evaluar la sinergia entre linezolid y los cinco antimicrobianos, y se trazaron curvas de tiempo-muerte con las combinaciones más activas. El resultado más habitual para las combinaciones de linezolid con rifampicina, vancomicina y doxiciclina fue indiferencia. La combinación con levofloxacino produjo antagonismo en dos de las cinco cepas. Sin embargo, frente a cuatro cepas se observó sinergia con la combinación de linezolid y fosfomicina, con un índice de concentración inhibitoria fraccionada (ICIF) >0,5. Ni linezolid ni fosfomicina en solitario inhibieron el crecimiento a 1/4x CMI, pero la combinación de ambos fármacos a 1/4 de la CMI respectiva mostró un efecto bacteriostático sinérgico, un descenso de 2-3 log 10 respecto al antimicrobiano más activo en solitario. En resumen, la combinación de linezolid y fosfomicina a concentraciones subinhibitorias se mostró sinérgica, ejerciendo un efecto bacteriostático. P a l a b r a s c c l a v e : Oxazolidinona -Fosfomicina -Sinergia S U M M A R Y The objective of this paper was to investigate the in vitro effects of linezolid combined with five antistaphylococcal antibiotics -doxycycline, fosfomycin, levofloxacin, rifampicin and vancomycin -upon methicillin-susceptible Staphylococcus aureus (MSSA). Five MSSA isolates from clinical specimens of human infections -hf008, hf095, hf295, hf602 and hf946 -were used in this study. The checkerboard method was used to assess synergism between linezolid and the five antibiotics, and time-kill curves were carried out with the most active combinations. Indifference was the most common result achieved by the checkerboard method when linezolid was combined with rifampicin, vancomycin or doxycycline. The combination with levofloxacin yielded antagonism for two of the five isolates. However, four isolates showed synergy for the combination of linezolid plus fosfomycin with a fractional inhibitory concentration index (FICI) >0.5. Neither linezolid nor fosfomycin alone inhibited growth at 1/4x minimum inhibitory concentration (MIC); but the combination of both drugs at 1/4 the respective MIC showed a synergistic bacteriostatic effect, a 2-3 log 10 decrease with respect to the most active antibiotic alone. In summary, the combination of subinhibitory concentrations of linezolid and fosfomycin presented synergism, exerting a bacteriostatic effect. K e y w w o r d s : Oxazolidinone -Fosfomycin -Synergism 2006; Vol. 19 (Nº 3) In vitro activity of linezolid in combination against methicillin-susceptible S. aureus 253
European Journal of Clinical Microbiology & Infectious Diseases, 2010
The objective of this study was to evaluate the in vitro and in vivo efficacies of linezolid (35 mg/kg/5 h), vancomycin (60 mg/kg/5 h), imipenem (30 mg/kg/5 h), linezolid+imipenem, linezolid+vancomycin and vancomycin+ imipenem against two clinical Staphylococcus aureus isolates with reduced susceptibility to glycopeptides using time-kill curves and the murine peritonitis model. Time-kill curves were performed over 24 h. For the murine peritonitis model, peritonitis was induced by the intraperitoneal inoculation of 10 8 CFU/ml of each bacterial strain. Four hours later (0 h), the mice were randomly assigned to a control group or to therapeutic groups receiving subcutaneous treatment for 25 h. Bacterial counts in peritoneal fluid, bacteraemia and mortality rates were determined. The time-kill curves showed that the addition of linezolid to imipenem yielded synergistic results after 24 h. The addition of linezolid decreased vancomycin activity. In the animal model, vancomycin and linezolid monotherapies produced comparable bacterial decreases in mice infected with each strain but linezolid achieved higher rates of blood sterilisation. Linezolid tested either in monotherapy or in combination showed similar efficacy against both strains in terms of bacterial killing, number of negative blood cultures and survival. Linezolid and vancomycin were moderately bactericidal and similar in efficacy against glycopeptide-intermediate or-resistant S. aureus. Linezolid combinations, as effective as linezolid tested alone, could be considered as alternative options for the treatment of glycopeptide-intermediate S. aureus (GISA) infections.