Optimizing Antimicrobial Therapy of Sepsis and Septic Shock: Focus on Antibiotic Combination Therapy

 

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Abstract

There has been little improvement in septic shock mortality in the past 70 years, despite ever more broad-spectrum and potent antimicrobials. In the past, resuscitative elements have been the primary area of clinical septic shock management and research. The question of the optimal use of antimicrobial therapy was relatively ignored in recent decades. This review explores the pathophysiology of sepsis in an attempt to produce a better understanding and define key determinants of antimicrobial therapy response in septic shock. Optimizing existing antimicrobials delivery can drive significant improvements in the outcome of sepsis and septic shock. Inappropriate antimicrobial selection and dosing or delays in the administration substantially increase mortality and morbidity in life-threatening infections. Definitive combination therapy (where a pathogen known to be susceptible to a given agent is additionally covered by another agent) remains controversial. Although some in vitro studies, animal models, and clinical studies of infection including endocarditis, gram-negative bacteremia, and neutropenic infections have supported combination therapy, the potential clinical benefit in other severe infections has been questioned. Several meta-analyses have failed to demonstrate improvement of outcome with combination therapy in immunocompetent patients with sepsis and/or gram-negative bacteremia. These meta-analyses did not undertake subgroup analyses of the septic shock population. This article reviews the existing evidence supporting combination therapy for severe infections, sepsis, and septic shock.

• References

• 1 Sands KE, Bates DW, Lanken PN , et al; Academic Medical Center Consortium Sepsis Project Working Group. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 1997; 278 (3) 234-240
  CrossrefPubMedGoogle Scholar
• 2 Brun-Buisson C, Doyon F, Carlet J , et al; French ICU Group for Severe Sepsis. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. JAMA 1995; 274 (12) 968-974
  CrossrefPubMedGoogle Scholar
• 3 Annane D, Aegerter P, Jars-Guincestre MC, Guidet B ; CUB-Réa Network. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med 2003; 168 (2) 165-172
  CrossrefPubMedGoogle Scholar
• 4 Finland M, Jones Jr WF, Barnes MW. Occurrence of serious bacterial infections since introduction of antibacterial agents. J Am Med Assoc 1959; 170 (18) 2188-2197
  CrossrefPubMedGoogle Scholar
• 5 Hemminki E, Paakkulainen A. The effect of antibiotics on mortality from infectious diseases in Sweden and Finland. Am J Public Health 1976; 66 (12) 1180-1184
  CrossrefPubMedGoogle Scholar
• 6 Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 1980; 68 (3) 344-355
  CrossrefPubMedGoogle Scholar
• 7 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348 (16) 1546-1554
  CrossrefPubMedGoogle Scholar
• 8 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29 (7) 1303-1310
  CrossrefPubMedGoogle Scholar
• 9 Eichacker PQ, Natanson C. Increasing evidence that the risks of rhAPC may outweigh its benefits. Intensive Care Med 2007; 33 (3) 396-399
  CrossrefPubMedGoogle Scholar
• 10 Gårdlund B. Activated protein C (Xigris) treatment in sepsis: a drug in trouble. Acta Anaesthesiol Scand 2006; 50 (8) 907-910 A
  CrossrefPubMedGoogle Scholar
• 11 Kumar A. An alternate pathophysiologic paradigm of sepsis and septic shock: implications for optimizing antimicrobial therapy. Virulence 2014; 5 (1) 80-97
  CrossrefPubMedGoogle Scholar
• 12 Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992; 101 (6) 1481-1483
  CrossrefPubMedGoogle Scholar
• 13 Levy MM, Fink MP, Marshall JC , et al; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31 (4) 1250-1256
  CrossrefPubMedGoogle Scholar
• 14 van der Poll T, van Deventer SJH. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13 (2) 413-426 , ix
  CrossrefPubMedGoogle Scholar
• 15 van der Poll T. Coagulation and inflammation. J Endotoxin Res 2001; 7 (4) 301-304
  PubMedGoogle Scholar
• 16 Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348 (2) 138-150
  CrossrefPubMedGoogle Scholar
• 17 Remick DG. Pathophysiology of sepsis. Am J Pathol 2007; 170 (5) 1435-1444
  CrossrefPubMedGoogle Scholar
• 18 Freeman BD, Natanson C. Anti-inflammatory therapies in sepsis and septic shock. Expert Opin Investig Drugs 2000; 9 (7) 1651-1663
  CrossrefPubMedGoogle Scholar
• 19 Khatib R, Johnson LB, Fakih MG , et al. Persistence in Staphylococcus aureus bacteremia: incidence, characteristics of patients and outcome. Scand J Infect Dis 2006; 38 (1) 7-14
  CrossrefPubMedGoogle Scholar
• 20 Chowers MY, Gottesman B, Paul M, Weinberger M, Pitlik S, Leibovici L. Persistent bacteremia in the absence of defined intravascular foci: clinical significance and risk factors. Eur J Clin Microbiol Infect Dis 2003; 22 (10) 592-596
  CrossrefPubMedGoogle Scholar
• 21 Kullberg BJ, Sobel JD, Ruhnke M , et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 2005; 366 (9495) 1435-1442
  CrossrefPubMedGoogle Scholar
• 22 Reboli AC, Rotstein C, Pappas PG , et al; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356 (24) 2472-2482
  CrossrefPubMedGoogle Scholar
• 23 Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115 (9) 674-680
  CrossrefPubMedGoogle Scholar
• 24 Wiggers CJ. Experimental haemorrhage shock. In: Physiology of shock: The Commonwealth Fund. New York, NY: Harvard University Press; 1950: 121-143
  Google Scholar
• 25 De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004; 109 (10) 1223-1225
  CrossrefPubMedGoogle Scholar
• 26 Simoons ML, Serruys PW, vd Brand M , et al. Improved survival after early thrombolysis in acute myocardial infarction. A randomised trial by the Interuniversity Cardiology Institute in The Netherlands. Lancet 1985; 2 (8455) 578-582
  PubMedGoogle Scholar
• 27 Sampalis JS, Lavoie A, Williams JI, Mulder DS, Kalina M. Impact of on-site care, prehospital time, and level of in-hospital care on survival in severely injured patients. J Trauma 1993; 34 (2) 252-261
  CrossrefPubMedGoogle Scholar
• 28 Vallés J, Rello J, Ochagavía A, Garnacho J, Alcalá MA. Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003; 123 (5) 1615-1624
  CrossrefPubMedGoogle Scholar
• 29 Ulloa L, Tracey KJ. The “cytokine profile”: a code for sepsis. Trends Mol Med 2005; 11 (2) 56-63
  CrossrefPubMedGoogle Scholar
• 30 Wang H, Czura CJ, Tracey KJ. Lipid unites disparate syndromes of sepsis. Nat Med 2004; 10 (2) 124-125
  CrossrefPubMedGoogle Scholar
• 31 Simon PM, Delude RL, Lee M , et al; GenIMS Investigators. Duration and magnitude of hypotension and monocyte deactivation in patients with community-acquired pneumonia. Shock 2011; 36 (6) 553-559
  CrossrefPubMedGoogle Scholar
• 32 Kumar A, Haery C, Paladugu B , et al. The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. J Infect Dis 2006; 193 (2) 251-258 A
  CrossrefPubMedGoogle Scholar
• 33 Ovstebo R, Brandtzaeg P, Brusletto B , et al. Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease. J Clin Microbiol 2004; 42 (7) 2980-2987
  CrossrefPubMedGoogle Scholar
• 34 Lala HM, Mills GD, Barratt K, Bonning J, Manikkam NE, Martin D. Meningococcal disease deaths and the frequency of antibiotic administration delays. J Infect 2007; 54 (6) 551-557
  CrossrefPubMedGoogle Scholar
• 35 Rello J, Lisboa T, Lujan M , et al; DNA-Neumococo Study Group. Severity of pneumococcal pneumonia associated with genomic bacterial load. Chest 2009; 136 (3) 832-840
  CrossrefPubMedGoogle Scholar
• 36 DuPont HL, Spink WW. Infections due to gram-negative organisms: an analysis of 860 patients with bacteremia at the University of Minnesota Medical Center, 1958-1966. Medicine (Baltimore) 1969; 48 (4) 307-332 A
  CrossrefPubMedGoogle Scholar
• 37 Marra AR, Edmond MB, Forbes BA, Wenzel RP, Bearman GML. Time to blood culture positivity as a predictor of clinical outcome of Staphylococcus aureus bloodstream infection. J Clin Microbiol 2006; 44 (4) 1342-1346
  CrossrefPubMedGoogle Scholar
• 38 Khatib R, Riederer K, Saeed S , et al. Time to positivity in Staphylococcus aureus bacteremia: possible correlation with the source and outcome of infection. Clin Infect Dis 2005; 41 (5) 594-598
  CrossrefPubMedGoogle Scholar
• 39 Liao C-H, Lai C-C, Hsu M-S , et al. Correlation between time to positivity of blood cultures with clinical presentation and outcomes in patients with Klebsiella pneumoniae bacteraemia: prospective cohort study. Clin Microbiol Infect 2009; 15 (12) 1119-1125
  CrossrefPubMedGoogle Scholar
• 40 Peralta G, Roiz MP, Sánchez MB , et al. Time-to-positivity in patients with Escherichia coli bacteraemia. Clin Microbiol Infect 2007; 13 (11) 1077-1082
  CrossrefPubMedGoogle Scholar
• 41 Martínez JA, Soto S, Fabrega A , et al. Relationship of phylogenetic background, biofilm production, and time to detection of growth in blood culture vials with clinical variables and prognosis associated with Escherichia coli bacteremia. J Clin Microbiol 2006; 44 (4) 1468-1474
  CrossrefPubMedGoogle Scholar
• 42 Chuang Y-C, Chang S-C, Wang W-K. Using the rate of bacterial clearance determined by real-time polymerase chain reaction as a timely surrogate marker to evaluate the appropriateness of antibiotic usage in critical patients with Acinetobacter baumannii bacteremia. Crit Care Med 2012; 40 (8) 2273-2280
  CrossrefPubMedGoogle Scholar
• 43 Ehrlich P. Address in pathology on chemiotherapy. : delivered before the Seventeenth International Congress of Medicine. BMJ 1913; 2 (2746) 353-359
  CrossrefPubMedGoogle Scholar
• 44 Ammerlaan H, Seifert H, Harbarth S , et al; European Practices of Infections with Staphylococcus aureus (SEPIA) Study Group. Adequacy of antimicrobial treatment and outcome of Staphylococcus aureus bacteremia in 9 Western European countries. Clin Infect Dis 2009; 49 (7) 997-1005 A
  CrossrefPubMedGoogle Scholar
• 45 Elhanan G, Sarhat M, Raz R. Empiric antibiotic treatment and the misuse of culture results and antibiotic sensitivities in patients with community-acquired bacteraemia due to urinary tract infection. J Infect 1997; 35 (3) 283-288
  CrossrefPubMedGoogle Scholar
• 46 Blot S, Vandewoude K, De Bacquer D, Colardyn F. Nosocomial bacteremia caused by antibiotic-resistant gram-negative bacteria in critically ill patients: clinical outcome and length of hospitalization. Clin Infect Dis 2002; 34 (12) 1600-1606
  CrossrefPubMedGoogle Scholar
• 47 Blot S, Depuydt P, Vogelaers D , et al. Colonization status and appropriate antibiotic therapy for nosocomial bacteremia caused by antibiotic-resistant gram-negative bacteria in an intensive care unit. Infect Control Hosp Epidemiol 2005; 26 (6) 575-579
  CrossrefPubMedGoogle Scholar
• 48 Haddy RI, Nadkarni DD, Mann BL , et al. Clostridial bacteremia in the community hospital. Scand J Infect Dis 2000; 32 (1) 27-30
  CrossrefPubMedGoogle Scholar
• 49 Kumar A, Ellis P, Arabi Y , et al; Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136 (5) 1237-1248
  CrossrefPubMedGoogle Scholar
• 50 Romero-Vivas J, Rubio M, Fernandez C, Picazo JJ. Mortality associated with nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 1995; 21 (6) 1417-1423
  CrossrefPubMedGoogle Scholar
• 51 Nguyen MH, Peacock Jr JE, Tanner DC , et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med 1995; 155 (22) 2429-2435
  CrossrefPubMedGoogle Scholar
• 52 Garnacho-Montero J, García-Cabrera E, Diaz-Martín A , et al. Determinants of outcome in patients with bacteraemic pneumococcal pneumonia: importance of early adequate treatment. Scand J Infect Dis 2010; 42 (3) 185-192
  CrossrefPubMedGoogle Scholar
• 53 Kumar A, Zarychanski R, Light B , et al; Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 2010; 38 (9) 1773-1785
  CrossrefPubMedGoogle Scholar
• 54 Kollef MH. Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting it right up front. Clin Infect Dis 2008; 47 (1) (Suppl. 01) S3-S13
  CrossrefPubMedGoogle Scholar
• 55 Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother 2010; 54 (11) 4851-4863
  CrossrefPubMedGoogle Scholar
• 56 Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115 (2) 462-474
  CrossrefPubMedGoogle Scholar
• 57 Kollef MH, Morrow LE, Niederman MS , et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest 2006; 129 (5) 1210-1218
  CrossrefPubMedGoogle Scholar
• 58 Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162 (2, Pt 1) 505-511
  CrossrefPubMedGoogle Scholar
• 59 Aarts M-A, Brun-Buisson C, Cook DJ , et al. Antibiotic management of suspected nosocomial ICU-acquired infection: does prolonged empiric therapy improve outcome?. Intensive Care Med 2007; 33 (8) 1369-1378
  CrossrefPubMedGoogle Scholar
• 60 Joung MK, Lee JA, Moon S-Y , et al. Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care 2011; 15 (2) R79
  CrossrefPubMedGoogle Scholar
• 61 Anderson DJ, Engemann JJ, Harrell LJ, Carmeli Y, Reller LB, Kaye KS. Predictors of mortality in patients with bloodstream infection due to ceftazidime-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother 2006; 50 (5) 1715-1720
  CrossrefPubMedGoogle Scholar
• 62 Lodise Jr TP, Patel N, Kwa A , et al. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother 2007; 51 (10) 3510-3515
  CrossrefPubMedGoogle Scholar
• 63 Mathevon T, Souweine B, Traoré O, Aublet B, Caillaud D. ICU-acquired nosocomial infection: impact of delay of adequate antibiotic treatment. Scand J Infect Dis 2002; 34 (11) 831-835
  CrossrefPubMedGoogle Scholar
• 64 Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49 (9) 3640-3645
  CrossrefPubMedGoogle Scholar
• 65 Zahar J-R, Azoulay E, Klement E , et al. Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med 2001; 27 (3) 513-520
  CrossrefPubMedGoogle Scholar
• 66 Gaieski DF, Mikkelsen ME, Band RA , et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38 (4) 1045-1053
  CrossrefPubMedGoogle Scholar
• 67 Lueangarun S, Leelarasamee A. Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study. Interdiscip Perspect Infect Dis 2012; 2012 (2012) 765205
  PubMedGoogle Scholar
• 68 Lin MY, Weinstein RA, Hota B. Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia. Antimicrob Agents Chemother 2008; 52 (9) 3188-3194
  CrossrefPubMedGoogle Scholar
• 69 Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the Bacteraemia Study in Intensive Care (BASIC). J Antimicrob Chemother 2010; 65 (6) 1276-1285
  CrossrefPubMedGoogle Scholar
• 70 Silber SH, Garrett C, Singh R , et al. Early administration of antibiotics does not shorten time to clinical stability in patients with moderate-to-severe community-acquired pneumonia. Chest 2003; 124 (5) 1798-1804
  CrossrefPubMedGoogle Scholar
• 71 Kaasch AJ, Rieg S, Kuetscher J , et al; preSABATO Study Group. Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study. Infection 2013; 41 (5) 979-985
  CrossrefPubMedGoogle Scholar
• 72 Kumar A, Roberts D, Wood KE , et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34 (6) 1589-1596
  CrossrefPubMedGoogle Scholar
• 73 Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003; 36 (11) 1418-1423
  CrossrefPubMedGoogle Scholar
• 74 Menéndez R, Torres A, Reyes S , et al. Initial management of pneumonia and sepsis: factors associated with improved outcome. Eur Respir J 2012; 39 (1) 156-162
  CrossrefPubMedGoogle Scholar
• 75 Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002; 122 (1) 262-268
  CrossrefPubMedGoogle Scholar
• 76 Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998; 129 (11) 862-869
  CrossrefPubMedGoogle Scholar
• 77 Ferrer R, Artigas A, Suarez D , et al; Edusepsis Study Group. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 2009; 180 (9) 861-866
  CrossrefPubMedGoogle Scholar
• 78 Dellinger RP, Levy MM, Carlet JM , et al; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36 (1) 296-327
  CrossrefPubMedGoogle Scholar
• 79 Taccone FS, Laterre P-F, Dugernier T , et al. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 2010; 14 (4) R126
  CrossrefPubMedGoogle Scholar
• 80 Chelluri L, Jastremski MS. Inadequacy of standard aminoglycoside loading doses in acutely ill patients. Crit Care Med 1987; 15 (12) 1143-1145
  CrossrefPubMedGoogle Scholar
• 81 Ocampos-Martinez E, Penaccini L, Scolletta S , et al. Determinants of early inadequate vancomycin concentrations during continuous infusion in septic patients. Int J Antimicrob Agents 2012; 39 (4) 332-337
  CrossrefPubMedGoogle Scholar
• 82 Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin 2011; 27 (1) 19-34
  CrossrefPubMedGoogle Scholar
• 83 Pea F, Viale P. Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock—does the dose matter?. Crit Care 2009; 13 (3) 214
  CrossrefPubMedGoogle Scholar
• 84 Calandra T, Glauser MP. Immunocompromised animal models for the study of antibiotic combinations. Am J Med 1986; 80 (5C): 45-52
  CrossrefPubMedGoogle Scholar
• 85 Finberg RW, Moellering RC, Tally FP , et al. The importance of bactericidal drugs: future directions in infectious disease. Clin Infect Dis 2004; 39 (9) 1314-1320
  CrossrefPubMedGoogle Scholar
• 86 Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Infect Dis 2004; 38 (6) 864-870
  CrossrefPubMedGoogle Scholar
• 87 Lepper MH, Dowling HF ; MH L. Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin; studies including observations on an apparent antagonism between penicillin and aureomycin. AMA Arch Intern Med 1951; 88 (4) 489-494
  CrossrefPubMedGoogle Scholar
• 88 Weinstein MP, Stratton CW, Ackley A , et al. Multicenter collaborative evaluation of a standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985; 78 (2) 262-269
  CrossrefPubMedGoogle Scholar
• 89 Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001; 345 (18) 1318-1330
  CrossrefPubMedGoogle Scholar
• 90 Weinstein MP, Stratton CW, Hawley HB, Ackley A, Reller LB. Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of therapeutic efficacy in acute and chronic osteomyelitis. Am J Med 1987; 83 (2) 218-222
  CrossrefPubMedGoogle Scholar
• 91 Sculier JP, Klastersky J. Significance of serum bactericidal activity in gram-negative bacillary bacteremia in patients with and without granulocytopenia. Am J Med 1984; 76 (3) 429-435
  CrossrefPubMedGoogle Scholar
• 92 Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34 (6) 1227-1231
  CrossrefPubMedGoogle Scholar
• 93 Khatib R, Saeed S, Sharma M, Riederer K, Fakih MG, Johnson LB. Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2006; 25 (3) 181-185
  CrossrefPubMedGoogle Scholar
• 94 Kim S-H, Kim K-H, Kim H-B , et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008; 52 (1) 192-197
  CrossrefPubMedGoogle Scholar
• 95 Rubinstein E, Cammarata S, Oliphant T, Wunderink R ; Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32 (3) 402-412
  CrossrefPubMedGoogle Scholar
• 96 Fagon J, Patrick H, Haas DW , et al; Nosocomial Pneumonia Group. Treatment of gram-positive nosocomial pneumonia. Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Am J Respir Crit Care Med 2000; 161 (3, Pt 1) 753-762
  CrossrefPubMedGoogle Scholar
• 97 Fowler Jr VG, Boucher HW, Corey GR , et al; S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355 (7) 653-665
  CrossrefPubMedGoogle Scholar
• 98 McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 2008; 31 (4) 345-351
  CrossrefPubMedGoogle Scholar
• 99 Crandon JL, Bulik CC, Kuti JL, Nicolau DP. Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa. Antimicrob Agents Chemother 2010; 54 (3) 1111-1116
  CrossrefPubMedGoogle Scholar
• 100 Chytra I, Stepan M, Benes J , et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care 2012; 16 (3) R113
  CrossrefPubMedGoogle Scholar
• 101 Lorente L, Jiménez A, Martín MM, Iribarren JL, Jiménez JJ, Mora ML. Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Int J Antimicrob Agents 2009; 33 (5) 464-468
  CrossrefPubMedGoogle Scholar
• 102 Lorente L, Jiménez A, Palmero S , et al. Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther 2007; 29 (11) 2433-2439
  CrossrefPubMedGoogle Scholar
• 103 Lorente L, Lorenzo L, Martín MM, Jiménez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother 2006; 40 (2) 219-223
  CrossrefPubMedGoogle Scholar
• 104 Lodise Jr TP, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44 (3) 357-363
  CrossrefPubMedGoogle Scholar
• 105 Kasiakou SK, Sermaides GJ, Michalopoulos A, Soteriades ES, Falagas ME. Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials. Lancet Infect Dis 2005; 5 (9) 581-589
  CrossrefPubMedGoogle Scholar
• 106 Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med 2009; 37 (6) 2071-2078
  CrossrefPubMedGoogle Scholar
• 107 Scaglione F, Mouton JW, Mattina R, Fraschini F. Pharmacodynamics of levofloxacin and ciprofloxacin in a murine pneumonia model: peak concentration/MIC versus area under the curve/MIC ratios. Antimicrob Agents Chemother 2003; 47 (9) 2749-2755
  CrossrefPubMedGoogle Scholar
• 108 Winterboer TM, Lecci KA, Olsen KM. Continuing education: alternative approaches to optimizing antimicrobial pharmacodynamics in critically ill patients. J Pharm Pract 2010; 23 (1) 6-18
  CrossrefPubMedGoogle Scholar
• 109 Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37 (5) 1073-1081
  CrossrefPubMedGoogle Scholar
• 110 Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984; 77 (4) 657-662
  CrossrefPubMedGoogle Scholar
• 111 Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis 1984; 149 (3) 443-448
  CrossrefPubMedGoogle Scholar
• 112 Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155 (1) 93-99
  CrossrefPubMedGoogle Scholar
• 113 Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis 2011; 52 (8) 975-981
  CrossrefPubMedGoogle Scholar
• 114 Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004; 43 (13) 925-942
  CrossrefPubMedGoogle Scholar
• 115 Zelenitsky S, Rubinstein E, Ariano R , et al; Cooperative Antimicrobial Therapy of Septic Shock-CATSS Database Research Group. Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents 2013; 41 (3) 255-260
  CrossrefPubMedGoogle Scholar
• 116 Chow JW, Yu VL. Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: a commentary. Int J Antimicrob Agents 1999; 11 (1) 7-12 A
  CrossrefPubMedGoogle Scholar
• 117 Micek ST, Welch EC, Khan J , et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother 2010; 54 (5) 1742-1748
  CrossrefPubMedGoogle Scholar
• 118 Giamarellou H, Zissis NP, Tagari G, Bouzos J. In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1984; 25 (4) 534-536
  CrossrefPubMedGoogle Scholar
• 119 Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections. Rev Infect Dis 1982; 4 (2) 294-301
  CrossrefPubMedGoogle Scholar
• 120 Mouton JW. Combination therapy as a tool to prevent emergence of bacterial resistance. Infection 1999; 27 (Suppl. 02) S24-S28
  PubMedGoogle Scholar
• 121 Anderson ET, Young LS, Hewitt WL. Antimicrobial synergism in the therapy of gram-negative rod bacteremia. Chemotherapy 1978; 24 (1) 45-54
  CrossrefPubMedGoogle Scholar
• 122 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
  PubMedGoogle Scholar
• 123 Kluge RM, Standiford HC, Tatem B , et al. Comparative activity of tobramycin, amikacin, and gentamicin alone and with carbenicillin against Pseudomonas aeruginosa. Antimicrob Agents Chemother 1974; 6 (4) 442-446 A
  CrossrefPubMedGoogle Scholar
• 124 Neu HC. Synergy and antagonism of fluoroquinolones with other classes of antimicrobial agents. Drugs 1993; 45 (Suppl. 03) 54-58
  CrossrefPubMedGoogle Scholar
• 125 Pohlman JK, Knapp CC, Ludwig MD, Washington JA. Timed killing kinetic studies of the interaction between ciprofloxacin and β-lactams against gram-negative bacilli. Diagn Microbiol Infect Dis 1996; 26 (1) 29-33
  CrossrefPubMedGoogle Scholar
• 126 MacGowan AR, Bowker K, Bedford KA, Holt HA, Reeves DS. Synergy testing of macrolide combinations using the chequerboard technique. J Antimicrob Chemother 1993; 32 (6) 913-915
  CrossrefPubMedGoogle Scholar
• 127 Manian FA, Meyer L, Jenne J, Owen A, Taff T. Loss of antimicrobial susceptibility in aerobic gram-negative bacilli repeatedly isolated from patients in intensive-care units. Infect Control Hosp Epidemiol 1996; 17 (4) 222-226
  CrossrefPubMedGoogle Scholar
• 128 Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4 (8) 519-527
  CrossrefPubMedGoogle Scholar
• 129 Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of β-lactam-aminoglycoside synergism: systematic review of randomised trials. Int J Antimicrob Agents 2011; 37 (6) 491-503
  CrossrefPubMedGoogle Scholar
• 130 Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004; 328 (7441) 668
  CrossrefPubMedGoogle Scholar
• 131 Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2006; (1) CD003344
  PubMedGoogle Scholar
• 132 Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2014; 1: CD003344
  PubMedGoogle Scholar
• 133 Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003; 326 (7399) 1111
  CrossrefPubMedGoogle Scholar
• 134 Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001; 161 (15) 1837-1842
  CrossrefPubMedGoogle Scholar
• 135 Baddour LM, Yu VL, Klugman KP , et al; International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170 (4) 440-444
  CrossrefPubMedGoogle Scholar
• 136 Rodríguez A, Mendia A, Sirvent J-M , et al; CAPUCI Study Group. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit Care Med 2007; 35 (6) 1493-1498
  CrossrefPubMedGoogle Scholar
• 137 Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med 1989; 87 (5) 540-546
  CrossrefPubMedGoogle Scholar
• 138 Korvick JA, Bryan CS, Farber B , et al. Prospective observational study of Klebsiella bacteremia in 230 patients: outcome for antibiotic combinations versus monotherapy. Antimicrob Agents Chemother 1992; 36 (12) 2639-2644 A
  CrossrefPubMedGoogle Scholar
• 139 Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med 2010; 38 (8) 1651-1664
  CrossrefPubMedGoogle Scholar
• 140 Abad CL, Kumar A, Safdar N. Antimicrobial therapy of sepsis and septic shock—when are two drugs better than one?. Crit Care Clin 2011; 27 (2) e1-e27
  CrossrefPubMedGoogle Scholar
• 141 Brunkhorst FM, Oppert M, Marx G , et al; German Study Group Competence Network Sepsis (SepNet). Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 2012; 307 (22) 2390-2399
  CrossrefPubMedGoogle Scholar
• 142 Delannoy P-Y, Boussekey N, Devos P , et al. Impact of combination therapy with aminoglycosides on the outcome of ICU-acquired bacteraemias. Eur J Clin Microbiol Infect Dis 2012; 31 (9) 2293-2299
  CrossrefPubMedGoogle Scholar