Should Antibiotic Combinations Be Used to Treat Ventilator-Associated Pneumonia?

ABSTRACT

This review summarizes the rationale for using or not using combinations of antibiotics to treat ventilator-associated pneumonia (VAP). Patients suffering from VAP require empirical antibiotic treatment before the identification of an etiologic agent. Most treatment failures are related to inappropriate initial antibiotic treatment with insufficient coverage of multidrug-resistant (MDR) pathogens. Guidelines require initial (empirical) treatment of VAP with a combination of antibiotics. However, this contributes to overexposure to antibiotics and further emergence of MDR microorganisms. We review the rationale for using combinations of antibiotics to cover MDR gram-negatives. However, clinical data supporting this strategy are limited. In fact, systematic combination therapy may have contributed to the overuse of antibiotics and to the emergence of MDR microorganisms. Nevertheless, combination therapy is our best strategy to treat severe infections due to suspected MDR microorganisms. Optimally, therapeutic strategies should be sufficiently broad to cover relevant pathogens while minimizing the risk for emergence of antimicrobial resistance.

KEYWORDS

Ventilator-associated pneumonia - monotherapy - combined therapy - guidelines - synergy - multidrug resistance

REFERENCES

• 1 Mandell L A, Campbell Jr G D. Nosocomial pneumonia guidelines: an international perspective.  Chest. 1998;  113(Suppl 3) 188S-193S
• 2 Chastre J, Fagon J Y. Ventilator-associated pneumonia.  Am J Respir Crit Care Med. 2002;  165 867-903
• 3 Anonymous American Thoracic Society and Infectious Diseases Society of America . Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.  Am J Respir Crit Care Med. 2005;  171 338-416
• 4 Alvarez-Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group.  Intensive Care Med. 1996;  22 387-394
• 5 Luna C M, Vujacich P, Niederman M S et al.. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia.  Chest. 1997;  111 676-685
• 6 Sanchez-Nieto J M, Torres A, Garcia-Cordoba F et al.. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: a pilot study.  Am J Respir Crit Care Med. 1998;  157 371-376
• 7 Trouillet J L, Chastre J, Vuagnat A et al.. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.  Am J Respir Crit Care Med. 1998;  157 531-539
• 8 Rello J, Sa-Borges M, Correra H, Leal S R, Baraibar J. Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicrobial prescribing practices.  Am J Respir Crit Care Med. 1999;  160 608-613
• 9 Kollef M H, Ward S, Sherman G et al.. Inadequate treatment of nosocomial infections is associated with certain empiric antibiotic choices.  Crit Care Med. 2000;  28 3456-3464
• 10 Bercault N, Boulain T. Mortality rate attributable to ventilator-associated nosocomial pneumonia in an adult intensive care unit: a prospective case-control study.  Crit Care Med. 2001;  29 2303-2309
• 11 Dupont H, Mentec H, Sollet J P, Bleichner G. Impact of appropriateness of initial antibiotic therapy on the outcome of ventilator-associated pneumonia.  Intensive Care Med. 2001;  27 355-362
• 12 Dupont H, Montravers P, Gauzit R, Veber B, Pouriat J L, Martin C. Outcome of postoperative pneumonia in the Eole study.  Intensive Care Med. 2003;  29 179-188
• 13 Leroy O, Meybeck A, d’Escrivan T, Devos P, Kipnis E, Georges H. Impact of adequacy of initial antimicrobial therapy on the prognosis of patients with ventilator-associated pneumonia.  Intensive Care Med. 2003;  29 2170-2173
• 14 Garrouste-Orgegas M, Clec’h C, Timsit J F et al.. Efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity.  Intensive Care Med. 2004;  30 1327-1333
• 15 Mueller E W, Hanes S D, Croce M A, Wood G C, Boucher B A, Fabian T C. Effect from multiple episodes of inadequate empiric antibiotic therapy for ventilator-associated pneumonia on morbidity and mortality among critically ill trauma patients.  J Trauma. 2005;  58 94-101
• 16 Hanes S D, Demirkan K, Tolley E et al.. Risk factors for late-onset nosocomial pneumonia caused by Stenotrophomonas maltophilia in critically ill trauma patients.  Clin Infect Dis. 2002;  35 228-235
• 17 Richards M J, Edwards J R, Culver D H, Gaynes R P. Nosocomial infections in combined medical-surgical intensive care units in the United States.  Infect Control Hosp Epidemiol. 2000;  21 510-515
• 18 Anonymous . Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus statement, American Thoracic Society, November 1995.  Am J Respir Crit Care Med. 1996;  153 1711-1725
• 19 Williams R J, Heymann D L. Containment of antibiotic resistance.  Science. 1998;  279 1153-1154
• 20 Wenzel R P, Edmond M B. Managing antibiotic resistance.  N Engl J Med. 2000;  343 1961-1963
• 21 Kollef M H, Fraser V J. Antibiotic resistance in the intensive care unit.  Ann Intern Med. 2001;  134 298-314
• 22 Niederman M S. Appropriate use of antimicrobial agents: challenges and strategies for improvement.  Crit Care Med. 2003;  31 608-616
• 23 Fagon J Y, Chastre J, Vuagnat A, Trouillet J L, Novara A, Gibert C. Nosocomial pneumonia and mortality among patients in intensive care units.  JAMA. 1996;  275 866-869
• 24 Papazian L, Bregeon F, Thirion X et al.. Effect of ventilator-associated pneumonia on mortality and morbidity.  Am J Respir Crit Care Med. 1996;  154 91-97
• 25 Heyland D K, Cook D J, Griffith L, Keenan S P, Brun-Buisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group.  Am J Respir Crit Care Med. 1999;  159(4 Pt 1) 1249-1256
• 26 Kollef M H. Ventilator-associated pneumonia. a multivariate analysis.  JAMA. 1993;  270 1965-1970
• 27 Ibrahim E H, Tracy L, Hill C, Fraser V J, Kollef M H. The occurrence of ventilator-associated pneumonia in a community hospital: risk factors and clinical outcomes.  Chest. 2001;  120 555-561
• 28 Vincent J L, Bihari D J, Suter P M et al.. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) study.  JAMA. 1995;  274 639-644
• 29 Cook D J, Walter S D, Cook R J et al.. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients.  Ann Intern Med. 1998;  129 433-440
• 30 Anonymous . Monitoring hospital-acquired infections to promote patient safety-United States, 1990-1999.  MMWR Morb Mortal Wkly Rep. 2000;  49 149-153
• 31 Fagon J Y, Chastre J, Domart Y et al.. Nosocomial pneumonia in patients receiving continuous mechanical ventilation: prospective analysis of 52 episodes with use of a protected specimen brush and quantitative culture techniques.  Am Rev Respir Dis. 1989;  139 877-884
• 32 Kollef M H. Epidemiology and risk factors for nosocomial pneumonia: emphasis on prevention.  Clin Chest Med. 1999;  20 653-670
• 33 Eggimann P, Hugonnet S, Sax H et al.. Ventilator-associated pneumonia: caveat for benchmarking.  Intensive Care Med. 2003;  29 2086-2089
• 34 Anonymous . National Nosocomial Infections Surveillance (NNIS) System Report. Data summary from January 1992-June 2003.  Am J Infect Control. 2003;  31 481-498
• 35 Anonymous . Data summary from January 1992 through June 2004, issued October 2004.  Am J Infect Control. 2004;  32 470-485
• 36 Hugonnet S, Eggimann P, Borst F, Maricot P, Cherrolet J C, Pittet D. Impact ventilator-associated pneumonia on resource utilization and patient’ outcomes.  Infect Control Hosp Epidemiol. 2004;  25 1090-1096
• 37 Fagon J Y, Chastre J, Hance A J, Montravers P, Novara A, Gibert C. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay.  Am J Med. 1993;  94 281-288
• 38 Devos N, Pinsard M, Rigaud J P, Berthelot G, Cannone M. Morbidité et mortalité des pneumopathies acquises sous ventilation mécanique (PAVM).  Reanimation. 2001;  10(Suppl 1) S158-S162
• 39 Rello J, Jubert P, Valles J, Artigas A, Rue M, Niederman M S. Evaluation of outcome for intubated patients with pneumonia due to Pseudomonas aeruginosa .  Clin Infect Dis. 1996;  23 973-978
• 40 Rello J, Ollendorf D A, Oster G et al.. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.  Chest. 2002;  122 2115-2121
• 41 Baker A M, Meredith J W, Haponik E F. Pneumonia in intubated trauma patients: microbiology and outcomes.  Am J Respir Crit Care Med. 1996;  153 343-349
• 42 Kollef M H. Prevention of hospital-associated pneumonia and ventilator-associated pneumonia.  Crit Care Med. 2004;  32 1396-1405
• 43 Richards M J, Edwards J R, Culver D H, Gaynes R P. Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System.  Crit Care Med. 1999;  27 887-892
• 44 Craven D E, Steger K A. Epidemiology of nosocomial pneumonia. new perspectives on an old disease.  Chest. 1995;  108(Suppl 2) 1S-16S
• 45 Valles J, Artigas A, Rello J et al.. Continuous aspiration of subglottic secretions in preventing ventilator-associated pneumonia.  Ann Intern Med. 1995;  122 179-186
• 46 Cook D, De Jonghe B, Brochard L, Brun-Buisson C. Influence of airway management on ventilator-associated pneumonia: evidence from randomized trials.  JAMA. 1998;  279 781-787
• 47 Bonten M J, Gaillard C A, de Leeuw P W, Stobberingh E E. Role of colonization of the upper intestinal tract in the pathogenesis of ventilator-associated pneumonia.  Clin Infect Dis. 1997;  24 309-319
• 48 Prod’hom G, Leuenberger P, Koerfer J et al.. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. a randomized controlled trial.  Ann Intern Med. 1994;  120 653-662
• 49 Livermore D M. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare?.  Clin Infect Dis. 2002;  34 634-640
• 50 Epp S, Kohler T, Plesiat P, Michea-hamzehpour M, Pechère J C. C-terminal region of Pseudomonas aeruginosa outer membrane porin OprD modulates susceptibility to meropenem.  Antimicrob Agents Chemother. 2001;  45 1780-1787
• 51 Nordmann P, Poirel L. Emerging carbapenemases in gram-negative aerobes.  Clin Microbiol Infect. 2002;  8 321-331
• 52 Bradford P A. Extended-spectrum beta-lactamases in the 21th century: characterization, epidemiology, and detection of this important resistance threat.  Clin Microbiol Rev. 2001;  14 933-951
• 53 Rahal J J, Urban C, Horn D et al.. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella .  JAMA. 1998;  280 1233-1237
• 54 Meyer K S, Urban C, Eagan J A, Berger B J, Rahal J J. Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins.  Ann Intern Med. 1993;  119 353-358
• 55 Gales A C, Jones R N, Forward K R, Linares J, Sader H S, Verhoef J. Emerging importance of multi-drug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY Antimicrobial Surveillance Program (1997-1999).  Clin Infect Dis. 2001;  32 S104-S113
• 56 Celis R, Torres A, Gatell J M, Almela M, Rodriguez-Roisin R, Agusti-Vidal A. Nosocomial pneumonia: a multivariate analysis of risk and prognosis.  Chest. 1988;  93 318-324
• 57 Kollef M H, Sherman G, Ward S, Fraser V J. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients.  Chest. 1999;  115 462-474
• 58 Iregui M, Ward S, Sherman G, Fraser V J, Kollef M H. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia.  Chest. 2002;  122 262-268
• 59 Luna C M, Blanzaco D, Niederman M S et al.. Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome.  Crit Care Med. 2003;  31 676-682
• 60 Craig W A. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid.  Infect Dis Clin North Am. 2003;  17 479-501
• 61 Mouton J W. Impact of pharmacodynamics on breakpoint selection for susceptibility testing.  Infect Dis Clin North Am. 2003;  17 579-598
• 62 Buijk S L, Gyssens I C, Mouton J W, Van Vliet A, Verbrugh H A, Bruining H A. Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections.  J Antimicrob Chemother. 2002;  49 121-128
• 63 Elphick H E, Tan A. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis.  Cochrane Database Syst Rev. 2005;  2 CD002007
• 64 MacKenzie F M, Gould I M. The post-antibiotic effect.  J Antimicrob Chemother. 1993;  32 519-537
• 65 Craig W A. Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man.  J Antimicrob Chemother. 1993;  31(Suppl D) 149-158
• 66 Nestaas E, Bangstad H J, Sandvik L, Wathne K O. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis.  Arch Dis Child Fetal Neonatal Ed. 2005;  90 F294-F300
• 67 Hatala R, Dinh T, Cook D J. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis.  Ann Intern Med. 1996;  124 717-725
• 68 Barza M, Ioannidis J P, Cappelleri J C, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis.  BMJ. 1996;  312 338-345
• 69 Bartal C, Danon A, Schlaeffer F et al.. Pharmacokinetic dosing of aminoglycosides: a controlled trial.  Am J Med. 2003;  114 194-198
• 70 Heineman H S, Lofton W M. Unpredictable response of Pseudomonas aeruginosa to synergistic antibiotic combinations in vitro.  Antimicrob Agents Chemother. 1978;  13 827-831
• 71 Neu H C. Synergy and antagonism of fluoroquinolones with other classes of antimicrobial agents.  Drugs. 1993;  45(Suppl 3) 54-58
• 72 Pohlman J K, Knapp C C, Ludwig M D, Washington J A. Timed killing kinetic studies of the interaction between ciprofloxacin and beta-lactams against gram-negative bacilli.  Diagn Microbiol Infect Dis. 1996;  26 29-33
• 73 Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik S D. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection.  J Intern Med. 1998;  244 379-386
• 74 Dellinger R P, Carlet J M, Masur H et al.. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.  Crit Care Med. 2004;  32 858-873
• 75 Neuhauser M M, Weinstein R A, Rydman R, Danziger L H, Karam G, Quinn J P. Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use.  JAMA. 2003;  289 885-888
• 76 Paramythiotou E, Lucet J C, Timsit J F et al.. Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: role of antibiotics with antipseudomonal activity.  Clin Infect Dis. 2004;  38 670-677
• 77 Villers D, Espaze E, Coste-Burel M et al.. Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology.  Ann Intern Med. 1998;  129 182-189
• 78 Harbarth S, Liassine N, Dharan S, Herrault P, Auckenthaler R, Pittet D. Risk factors for persistent carriage of methicillin-resistant Staphylococcus aureus .  Clin Infect Dis. 2000;  31 1380-1385
• 79 Jones R N, Pfaller M A. Ciprofloxacin as broad-spectrum empiric therapy: are fluoroquinolones still viable monotherapeutic agents compared with beta-lactams: data from the MYSTIC Program (US)?.  Diagn Microbiol Infect Dis. 2002;  42 213-215
• 80 Nseir S, Di Pompeo C, Soubrier S et al.. First-generation fluoroquinolone use and subsequent emergence of multiple drug-resistant bacteria in the intensive care unit.  Crit Care Med. 2005;  33 283-289
• 81 Niederman M S. Reexamining quinolone use in the intensive care unit: use them right or lose the fight against resistant bacteria.  Crit Care Med. 2005;  33 443-444
• 82 O’Grady N P, Barie P S, Bartlett J G et al.. Practice guidelines for evaluating new fever in critically ill adult patients. Task Force of the Society of Critical Care Medicine and the Infectious Diseases Society of America.  Clin Infect Dis. 1998;  26 1042-1059
• 83 Hughes W T, Armstrong D, Bodey G P et al.. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.  Clin Infect Dis. 2002;  34 730-751
• 84 Bochud P Y, Calandra T, Glauser M P. Antibiotics in sepsis.  Intensive Care Med. 2001;  27(Suppl 14) S33-S48
• 85 Bochud P Y, Bonten M J, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review.  Crit Care Med. 2004;  32(Suppl) S495-S512
• 86 Mangi R J, Greco T, Ryan J, Thornton G, Andriole V T. Cefoperazone versus combination antibiotic therapy of hospital-acquired pneumonia.  Am J Med. 1988;  84 68-74
• 87 Fernandez-Guerrero M, Gudiol F, Rodriguez-Torres A, Arnau C, Valdes L, Vallve C. Nosocomial pneumonia: comparative multicentre trial between monotherapy with cefotaxime and treatment with antibiotic combinations.  Infection. 1991;  19(Suppl 6) S320-S325
• 88 Croce M A, Fabian T C, Stewart R M et al.. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients.  J Trauma. 1993;  35 303-309
• 89 Cometta A, Baumgartner J D, Lew D et al.. Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients.  Antimicrob Agents Chemother. 1994;  38 1309-1313
• 90 Sieger B, Berman S J, Geckler R W, Farkas S A. Empiric treatment of hospital-acquired lower respiratory tract infections with meropenem or ceftazidime with tobramycin: a randomized study. Meropenem Lower Respiratory Infection Group.  Crit Care Med. 1997;  25 1663-1670
• 91 Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia.  Eur J Clin Microbiol Infect Dis. 1998;  17 313-317
• 92 Alvarez-Lerma F. Efficacy of meropenem as monotherapy in the treatment of ventilator-associated pneumonia.  J Chemother. 2001;  13 70-81
• 93 Reeves J H, Russell G M, Cade J F, McDonald M. Comparison of ceftriaxone with cefotaxime in serious chest infections.  Chest. 1989;  96 1292-1297
• 94 Mangi R J, Peccerillo K M, Ryan J et al.. Cefoperazone versus ceftriaxone monotherapy of nosocomial pneumonia.  Diagn Microbiol Infect Dis. 1992;  15 441-447
• 95 Thomas P, Daly S, Misan G, Steele T. Comparison of the efficacy and adverse effect profile of cefotaxime and ceftriaxone in ICU patients with susceptible infections.  Diagn Microbiol Infect Dis. 1992;  15 89-97
• 96 Barckow D, Schwigon C D. Cefepime versus cefotaxime in the treatment of lower respiratory tract infections.  J Antimicrob Chemother. 1993;  32(Suppl B) 187-193
• 97 Fink M P, Snydman D R, Niederman M S et al.. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.  Antimicrob Agents Chemother. 1994;  38 547-557
• 98 Siami G A, Wilkins W T, Bess D T, Christman J W. Comparison of ciprofloxacin with imipenem in the treatment of severe pneumonia in hospitalised geriatric patients.  Drugs. 1995;  49(Suppl 2) 436-438
• 99 Torres A, Bauer T T, Leon-Gil C et al.. Treatment of severe nosocomial pneumonia: a prospective randomised comparison of intravenous ciprofloxacin with imipenem/cilastatin.  Thorax. 2000;  55 1033-1039
• 100 Jaccard C, Troillet N, Harbarth S et al.. Prospective randomized comparison of imipenem-cilastatin and piperacillin-tazobactam in nosocomial pneumonia or peritonitis.  Antimicrob Agents Chemother. 1998;  42 2966-2972
• 101 West M, Boulanger B R, Fogarty C et al.. Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study.  Clin Ther. 2003;  25 485-506
• 102 Paul M, Benuri-Silbiger I, Soares-Weiser K, Liebovici L. Beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomized trials.  BMJ. 2004; 
• 103 Holloway W J. Treatment of infections in hospitalized patients with ticarcillin plus clavulanic acid: a comparative study.  Am J Med. 1985;  79 168-171
• 104 Cone L A, Woodard D R, Stoltzman D S, Byrd R G. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia.  Antimicrob Agents Chemother. 1985;  28 33-36
• 105 Mandell L A, Nicolle L E, Ronald A R et al.. A prospective randomized trial of ceftazidime versus cefazolin/tobramycin in the treatment of hospitalized patients with pneumonia.  J Antimicrob Chemother. 1987;  20 95-107
• 106 Mouton Y, Deboscker Y, Bazin C et al.. Prospective, randomized, controlled study of imipenem-cilastatin versus cefotaxime-amikacin in the treatment of lower respiratory tract infection and septicemia at intensive care units [in French].  Presse Med. 1990;  19 607-612
• 107 Koehler C O, Arnold H. Controlled clinical study of ceftazidime (3 × 1 g daily) versus piperacillin + tobramycin in patients with nosocomial pneumonia.  Int J Exp Clin Chemother. 2005;  328 688
• 108 Sukoh M, Inoue T, Morita Y et al.. Clinical evaluation of combination therapy of sulbactam/cefoperazone and aminoglycoside in respiratory tract infections.  Jpn J Antibiot. 1994;  47 170-180
• 109 Takamoto M, Ishibashi T, Toyoshima H et al.. Imipenem/cilastatin sodium alone or combined with amikacin sulfate in respiratory infections.  Jpn J Antibiot. 1994;  47 1131-1144
• 110 Rubinstein E, Lode H, Grassi C. Ceftazidime monotherapy vs. ceftriaxone/tobramycin for serious hospital-acquired gram-negative infections. Antibiotic Study Group.  Clin Infect Dis. 1995;  20 1217-1228
• 111 Safdar N, Handelsman J, Maki D G. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia? A meta-analysis.  Lancet Infect Dis. 2004;  4 519-527
• 112 Kollef M H. The importance of appropriate initial antibiotic therapy for hospital-acquired infections.  Am J Med. 2003;  115 582-584
• 113 Diaz E, Rello J, Valles J. Antibiotic use and the risk of pneumonia: 20 years of studies, but where are we now?.  Clin Infect Dis. 2004;  38 1409-1411
• 114 Niederman M S. Therapy of ventilator-associated pneumonia: what more can we do to use less antibiotics?.  Crit Care Med. 2004;  32 2344-2345
• 115 Calandra T, Glauser M P. Immunocompromised animal models for the study of antibiotic combinations.  Am J Med. 1986;  80(Suppl 5C) 45-52
• 116 Klastersky J, Zinner S H. Synergistic combinations of antibiotics in gram-negative bacillary infections.  Rev Infect Dis. 1982;  4 294-301
• 117 Giamarellou H. Aminoglycosides plus beta-lactams against gram-negative organisms: evaluation of in vitro synergy and chemical interactions.  Am J Med. 1986;  80(6B) 126-137
• 118 Acar J F. Antibiotic synergy and antagonism.  Med Clin North Am. 2000;  84 1391-1406
• 119 Rahal Jr J J. Rationale for use of antimicrobial combinations in treatment of gram-negative infections: a review of recent reviews.  Am J Med. 1983;  75 68-71
• 120 Klastersky J, Cappel R, Daneau D et al.. Clinical significance of in vitro synergism between antibiotics in gram-negative infections.  Antimicrob Agents Chemother. 1972;  2 470-475
• 121 Bernabeu-Wittel M, Pichardo C, Garcia-Curiel A et al.. Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia.  Clin Microbiol Infect. 2005;  11 319-325
• 122 Navas D, Caillon J, Gras-Le Guen C et al.. Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics.  J Antimicrob Chemother. 2004;  54 767-771
• 123 Klastersky J, Henri A, Hensgens C, Daneau D. Gram-negative infections in cancer: study of empiric therapy comparing carbenicillin-cephalothin with and without gentamicin.  JAMA. 1974;  227 45-48
• 124 Gribble M J, Chow A W, Naiman S C et al.. Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections.  Antimicrob Agents Chemother. 1983;  24 388-393
• 125 De Jongh C, Joshi J H, Thompson B W et al.. A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.  Am J Med. 1986;  80(Suppl 5C) 101-111
• 126 Baddour L M, Wilson W R, Bayer A S et al.. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association-executive summary: endorsed by the Infectious Diseases Society of America.  Circulation. 2005;  111 3167-3184
• 127 Gruneberg R N, Antunes F, Chambers H F et al.. The role of glycopeptide antibiotics in the treatment of infective endocarditis.  Int J Antimicrob Agents. 1999;  12 191-198
• 128 Francioli P, Etienne J, Hoigne R, Thys J P, Gerber A. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for 4 weeks: efficacy and outpatient treatment feasibility.  JAMA. 1992;  267 264-267
• 129 EORTC International Antimicrobial Therapy Cooperative Group . Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia.  N Engl J Med. 1987;  317 1692-1698
• 130 The EORTC International Antimicrobial Therapy Cooperative Group . The efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia.  Ann Intern Med. 1993;  119 584-593
• 131 Cometta A, Zinner S H, De Bock R et al.. Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer.  Antimicrob Agents Chemother. 1995;  39 445-452
• 132 Eggimann P, Glauser M P, Aoun M, Meunier F, Calandra T. Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients.  J Antimicrob Chemother. 1993;  32(Suppl B) 151-163
• 133 Sanders J W, Powe N R, Moore R D et al.. Ceftazidime monotherapy for empiric treatment of febrile neutropenic patients: a meta-analysis.  J Infect Dis. 1991;  164 907-916
• 134 Rolston K VI, Berkey P, Bodey G P et al.. A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients.  Arch Intern Med. 1992;  152 283-291
• 135 Cometta A, Calandra T, Gaya H et al.. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer.  Antimicrob Agents Chemother. 1996;  40 1108-1115
• 136 Paul M, Liebovici L. Systematic reviews and meta-analysis of febrile neutropenia.  Mayo Clin Proc. 2005;  80 1122-1125
• 137 Paul M, Liebovici L. Combination antibiotic therapy for Pseudomonas aeruginosa bacteraemia.  Lancet Infect Dis. 2005;  5 192-193
• 138 Chastre J, Wolff M, Fagon J Y et al.. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.  JAMA. 2003;  290 2588-2598
• 139 El Amari E B, Chamot E, Auckenthaler R, Pechere J C, Van Delden C. Influence of previous exposure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic isolates.  Clin Infect Dis. 2001;  33 1859-1864
• 140 Chamot E, Boffi E A, Rohner P, Van Delden C. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia.  Antimicrob Agents Chemother. 2003;  47 2756-2764