Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study

Marya D Zilberberg, Andrew F Shorr, Scott T Micek, Cristina Vazquez-Guillamet, Marin H Kollef, Marya D Zilberberg, Andrew F Shorr, Scott T Micek, Cristina Vazquez-Guillamet, Marin H Kollef

Abstract

Introduction: The impact of in vitro resistance on initially appropriate antibiotic therapy (IAAT) remains unclear. We elucidated the relationship between non-IAAT and mortality, and between IAAT and multi-drug resistance (MDR) in sepsis due to Gram-negative bacteremia (GNS).

Methods: We conducted a single-center retrospective cohort study of adult intensive care unit patients with bacteremia and severe sepsis/septic shock caused by a gram-negative (GN) organism. We identified the following MDR pathogens: MDR P. aeruginosa, extended spectrum beta-lactamase and carbapenemase-producing organisms. IAAT was defined as exposure within 24 hours of infection onset to antibiotics active against identified pathogens based on in vitro susceptibility testing. We derived logistic regression models to examine a) predictors of hospital mortality and b) impact of MDR on non-IAAT. Proportions are presented for categorical variables, and median values with interquartile ranges (IQR) for continuous.

Results: Out of 1,064 patients with GNS, 351 (29.2%) did not survive hospitalization. Non-survivors were older (66.5 (55, 73.5) versus 63 (53, 72) years, P = 0.036), sicker (Acute Physiology and Chronic Health Evaluation II (19 (15, 25) versus 16 (12, 19), P < 0.001), and more likely to be on pressors (odds ratio (OR) 2.79, 95% confidence interval (CI) 2.12 to 3.68), mechanically ventilated (OR 3.06, 95% CI 2.29 to 4.10) have MDR (10.0% versus 4.0%, P < 0.001) and receive non-IAAT (43.4% versus 14.6%, P < 0.001). In a logistic regression model, non-IAAT was an independent predictor of hospital mortality (adjusted OR 3.87, 95% CI 2.77 to 5.41). In a separate model, MDR was strongly associated with the receipt of non-IAAT (adjusted OR 13.05, 95% CI 7.00 to 24.31).

Conclusions: MDR, an important determinant of non-IAAT, is associated with a three-fold increase in the risk of hospital mortality. Given the paucity of therapies to cover GN MDRs, prevention and development of new agents are critical.

Figures

Figure 1
Figure 1
Sepsis severity, resistance and initial treatment. IAAT, initially appropriate antibiotic therapy; MDR, multidrug resistant. P <0.001 for each comparison.

References

    1. Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008;6:751–763. doi: 10.1586/14787210.6.5.751.
    1. National Nosocomial Infections Surveillance (NNIS) system J Infect Control 2004, 32:470.
    1. Obritsch MD, Fish DN, MacLaren R, Jung R. National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002. Antimicrob Agents Chemother. 2004;48:4606–4610. doi: 10.1128/AAC.48.12.4606-4610.2004.
    1. Zilberberg MD, Shorr AF. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J Hosp Med. 2013;8:559–563.
    1. Zilberberg MD, Shorr AF. Secular trends in Gram-negative resistance among urinary tract infection hospitalizations in the United States, 2000–2009. Infect Control Hosp Epidemiol. 2013;34:940–946. doi: 10.1086/671740.
    1. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S, National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009–2010. Infect Control Hosp Epidemiol. 2013;34:1–14. doi: 10.1086/668770.
    1. Micek ST, Kollef KE, Reichley RM, Roubinian N, Kollef MH. Health care-associated pneumonia and community-acquired pneumonia: a single-center experience. Antimicrob Agents Chemother. 2007;51:3568–3573. doi: 10.1128/AAC.00851-07.
    1. 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;122:262–268. doi: 10.1378/chest.122.1.262.
    1. Alvarez-Lerma F. ICU-acquired pneumonia study group: modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. Intensive Care Med. 1996;22:387–394. doi: 10.1007/BF01712153.
    1. Zilberberg MD, Shorr AF, Micek MT, Mody SH, Kollef MH. Antimicrobial therapy escalation and hospital mortality among patients with HCAP: a single center experience. Chest. 2008;134:963–968. doi: 10.1378/chest.08-0842.
    1. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med. 2011;39:46–51. doi: 10.1097/CCM.0b013e3181fa41a7.
    1. 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;115:462–474. doi: 10.1378/chest.115.2.462.
    1. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med. 2003;31:2742–2751. doi: 10.1097/01.CCM.0000098031.24329.10.
    1. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115:529–535. doi: 10.1016/j.amjmed.2003.07.005.
    1. Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, Pérez XL, Sirvent JM. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009;180:861–866. doi: 10.1164/rccm.200812-1912OC.
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637. doi: 10.1097/CCM.0b013e31827e83af.
    1. 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;29:1303–1310. doi: 10.1097/00003246-200107000-00002.
    1. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004;4:519–527. doi: 10.1016/S1473-3099(04)01108-9.
    1. National Committee for Clinical Laboratory Standards . Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement. M100-S12. Wayne, PA: National Committee for Clinical Laboratory Standards; 2002.
    1. Clinical Laboratory Standards Institute . Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth Informational Supplement. M100-S17. Clinical Laboratory Standards Institute: Wayne, PA; 2007.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–829. doi: 10.1097/00003246-198510000-00009.
    1. Falagas M, Fragoulis K, Kasiakou S, Sermaidis G, Michalopoulos A. Nephrotoxicity of intravenous colistin: a prospective evaluation. Int J Antimicrob Agents. 2005;26:504–507. doi: 10.1016/j.ijantimicag.2005.09.004.
    1. Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, Gregorakos L. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit Care. 2003;7:R78–R83. doi: 10.1186/cc2358.
    1. Falagas E, Kasiakou S. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10:R27. doi: 10.1186/cc3995.
    1. Florescu DF, Qiu F, McCartan MA, Mindru C, Fey PD, Kalil AC. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression. Clin Infect Dis. 2012;54:670–680. doi: 10.1093/cid/cir934.
    1. GAIN: How a New Law is Stimulating the Development of Antibiotics. []
    1. Hospital-Acquired Pneumonia Guideline Committee of the American Thoracic Society and Infectious Diseases Society of America Guidelines for the management of adults with hospital-acquired pneumonia, ventilator-associated pneumonia, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416. doi: 10.1164/rccm.200405-644ST.
    1. O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, Lipsett PA, Masur H, Mermel LA, Pearson ML, Raad II, Randolph AG, Rupp ME, Saint S, Healthcare Infection Control Practices Advisory Committee (HICPAC) (Appendix 1) Guidelines for prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52:1087–1099. doi: 10.1093/cid/cir138.
    1. Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM, Infectious Diseases Society of America; Society for Healthcare Epidemiology of America Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin Infect Dis. 2007;44:159–177. doi: 10.1086/510393.

Source: PubMed

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