In vitro evaluation of antibiotics' combinations for empirical therapy of suspected methicillin resistant Staphylococcus aureus severe respiratory infections.
BACKGROUND
Methicillin resistant Staphylococcus aureus (MRSA) is an increasingly common cause of nosocomial infections, causing severe morbidity and mortality worldwide, and accounting in some hospitals for more than 50% of all S. aureus diseases. Treatment of infections caused by resistant bacterial pathogens mainly relies on two therapeutic modalities: development of new antimicrobials and use of combinations of available antibiotics. Combinations of antibiotics used in the empiric treatment of infections with suspected methicillin resistant Staphylococcus aureus etiology were investigated.


METHODS
Double (vancomycin or teicoplanin with either levofloxacin or cefotaxime) and triple (vancomycin or teicoplanin + levofloxacin + one among amikacin, ceftazidime, cefepime, imipenem, piperacillin/tazobactam) combinations were evaluated by means of checkerboard assay and time kill curves. Mutational rates of single and combined drugs at antimicrobial concentrations equal to the resistance breakpoints were also calculated.


RESULTS
Vancomycin or teicoplanin + levofloxacin showed synergy in 16/50 and in 9/50 strains respectively, while vancomycin or teicoplanin + cefotaxime resulted synergic for 43/50 and 23/50 strains, respectively. Triple combinations, involving teicoplanin, levofloxacin and ceftazidime or piperacillin/tazobactam gave synergy in 20/25 strains. Teicoplanin + levofloxacin gave synergy in triple combinations more frequently than vancomycin + levofloxacin. For single antibiotics, mutational frequencies ranged between 10(-5) and <10(-9) for levofloxacin, cefotaxime, amikacin and imipenem, and <10(-9) for vancomycin and teicoplanin. When tested in combinations, mutational frequencies fell below 10(-9) for all the combinations.


CONCLUSIONS
In vitro evidence of synergy between glycopeptides, fluoroquinolones (levofloxacin) and beta-lactams and of reduction of mutational frequencies by combinations are suggestive for a potential role in empirical therapy of severe pneumonia with suspected MRSA etiology.
Drago
Lorenzo
L
Laboratory of Clinical Microbiology, Department of Preclinical Sciences LITA Vialba, University of Milan, Via GB Grassi 74, 20157 Milan, Italy. lorenzo.drago@unimi.it
De Vecchi
Elena
E
Nicola
Lucia
L
Gismondo
Maria Rita
MR
D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D064704:Levofloxacin; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation; D015242:Ofloxacin / Q000494:pharmacology; D011014:Pneumonia / Q000188:drug therapy / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D017334:Teicoplanin / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology; D047090:beta-Lactams / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D017334:Teicoplanin; D064704:Levofloxacin; D014640:Vancomycin; D000583:Amikacin; D015242:Ofloxacin