versión On-line ISSN 1851-7617
Rev. argent. microbiol. vol.42 no.3 Ciudad Autónoma de Buenos Aires jul./set. 2010
Impact of inappropriate antimicrobial therapy on patients with bacteremia in intensive care units and resistance patterns in Latin America
1Medicine Department, School of Medicine, and
2Infectious Diseases Research Group, Universidad Nacional de Colombia. Of. 510, Facultad de Medicina, Ciudad Universitaria, Bogotá, Colombia.
*Correspondence. E-mail: firstname.lastname@example.org
Patient care in an intensive care unit (ICU) is associated with an increased risk of developing nosocomial infections. Bacteremia is responsible for a great number of cases, 23% of which have attributable mortality in developed countries and can affect up to 52% of ICU patients. The main cause of mortality is inadequate and inappropriate antimicrobial empirical therapy. The incorrect use of antimicrobials is a major risk for identifying multidrug resistant microorganisms, thereby involving increased morbidity, mortality and costs. Implementing several surveillance systems and becoming acquainted with resistance patterns represent a valuable tool for identifying, preventing and treating this infectious complication. There is paucity of data regarding antimicrobial resistance in bacteremic patients in Latin America, and the available data reveals a worrying scenario.
Key words: Bacteremia; Nosocomial infection; Latin America; Intensive care units; Antimicrobial drug resistance
Impacto de la terapia antimicrobiana inapropiada en pacientes con bacteriemia en unidades de cuidado intensivo y patrones de resistencia en América Latina. El manejo médico en la unidad de cuidado intensivo (UCI) se asocia con un mayor riesgo de infecciones intrahospitalarias. Las bacteriemias tienen una alta frecuencia en dichas unidades, se presentan hasta en el 52% de los pacientes allí asistidos y en los países desarrollados se les atribuye una mortalidad del 23%, que se debe fundamentalmente al uso de tratamiento empírico inadecuado o inapropiado. El uso incorrecto de los antimicrobianos es uno de los principales factores de riesgo para el desarrollo de la resistencia bacteriana, que conlleva la selección de microorganismos multirresistentes, el aumento de la morbilidad y la mortalidad y el incremento en los días de estancia hospitalaria y del costo por hospitalización. La implementación de diferentes sistemas de vigilancia y el conocimiento de la variabilidad en la resistencia a los antimicrobianos constituyen valiosas herramientas para identificar y prevenir la resistencia a los antibióticos y para orientar la terapéutica. En América Latina disponemos de pocos datos sobre las tasas de resistencia y aquellos disponibles muestran un panorama preocupante.
Palabras clave: Bacteriemia; Infección hospitalaria; América Latina; Unidades de cuidados intensivos; Resistencia a los antimicrobianos
A growing number of patients in Latin American countries require management in an intensive care unit (ICU), which is associated with a greater risk of contracting cross infections (32). Among these, bacteremia frequently occurs and has been reported in about 52% of patients requiring management in the ICU, accounting for 23% attributable mortality in developed countries (6).
Additionally, the excessive, inadequate and inappropriate use of antimicrobial agents represents one of the main risk factors for bacterial resistance, which in turn produces a vicious circle due to the increasing use of (frequently inappropriate) broad-spectrum treatments and greater identification of multi-resistant microorganisms. This also implies an increase in derived costs due to management (newer and more expensive drugs having a broader spectrum), longer stays in ICUs and mortality (19).
The following text reviews the definitions for the incorrect use of antimicrobial drugs, the outcomes associated with this treatment in ICU patients, and the resistance rates reported for bacteremia in ICUs from Latin America.
The American Thoracic Society and the Infectious Disease Society of America define appropriate therapy as the choice of an antimicrobial agent having in vitro activity against the pathogen involved (1); an adequate antimicrobial treatment does not just define the administration of the active antibiotic (appropriate) but also the different factors determining a correct response to treatment (dose, interval dose, administration route, penetration at the infection site and combination of antibiotics when indicated).
CLINICAL IMPACT OF INAPPROPRIATE THERAPY
One of the fundamental roles of antibiotics is a reduction in mortality. This is taken for granted today; however, historical studies dating back to the beginning of antimicrobial therapy reported that in 1938, the use of an antibiotic reduced mortality from 27% to 8% amongst patients suffering from pneumonia (11).
A meta-analysis conducted by Kuti et al. identified 22 studies in which differences in mortality were evaluated in patients with bacteremia (18). The general result showed that mortality was greater in patients receiving inappropriate antibiotic therapy at the start of treatment, with an odds ratio (OR) of 2.33 (1.96-2.76, 95% confidence interval). These studies were carried out on hospital- acquired infections caused by different microorganisms (gram-positive and gram-negative ones, see Table 1).
Table 1. Mortality rates attributable to inappropriate antimicrobial therapy in bacteremia caused by different microorganisms in third level hospitals.
* Additional mortality is the difference between mortality among control and case groups.
In a cohort of patients having nosocomial bacteremia, Garrouste-Orgeas et al., demonstrated the favourable impact of an early and adequate establishment of antimicrobial treatment on patients with ICU-acquired bacteremia. Mortality in the control group (paired by previous stay in ICU and comorbidities) that was not in the ICU at the moment of bacteremia was between 34.9% and 39.9%, while the mortality rate for patients in the ICU was 57.3% and 69.7% for those receiving appropriate and inappropriate antibiotic treatment, respectively (9).
A retrospective study of bacteremia at Rush Hospital in Chicago (20) revealed differences in mortality amongst patients with bacteremia and neutropenia in an ICU, compared to those who had not been admitted to ICU. Even though inappropriate therapy was correlated with mortality in both groups, OR was 17 in the group in the ICU and 5 in the group which had been in ICU.
ECONOMIC IMPACT OF INAPPROPRIATE THERAPY
Increasing bacterial resistance has become a public health problem involving patients, healthcare institutions and health-service administrators. In addition to the increase in morbidity and mortality, the costs inherent to the disease or to different interventions have increased (prolonged hospitalisation, increased stay in ICU, antibiotic treatment, administrative process and equipment for isolating patients, and microbiological studies) (22, 27).
Many studies have sought to quantify the cost attributable to diagnosing and treating ICU-acquired bacteremia, in order to demonstrate the impact on the economy, by evaluating the available data, and proposing preventive strategies for reducing nosocomial infections and increased costs (10).
The sum of the evidence available to date has supported the concept of increased costs and prolonged hospital stay associated with the use of inappropriate antibiotic therapy. However, evaluating costs associated with hospital-acquired infection is complex and depends on a number of variables including pre-established objectives in the studies, yielding variability in the results according to the chosen population, the number of patients and their individual condition (4), the standardization of local or international currency, hospitalisation costs according to the complexity level of different institutions, the treatment time in the different countries where the studies were carried out and quantification of direct and indirect costs (19, 27).
Dimick et al. published a prospective study in 2001 comparing costs for patients with or without bacteremia (7). Average cost in dollars for the latter were less than half the costs for patients with bacteremia (US$ 40,313 vs. US$ 102,965, a statistically significant difference). Multivariate analysis revealed that bacteremia was associated with a 120% increase in the total hospitalisation cost (mean $ 56,167; $ 11,523 to $ 165,735 95% confidence interval; p = 0.001).
Vandijck et al. have recently made a direct evaluation of the costs arising from antimicrobial therapy aimed at quantifying the daily cost of antibiotic treatment in patients with bacteremia in ICU, without considering associated costs (attention by specialised personnel, days being managed in an ICU, laboratory tests) (30). This study included 310 patients presenting 446 episodes of bacteremia (1.4 episodes/patient), and found that the daily antimicrobial therapy cost was € 114.3, which was higher in patients with bacteremia without a documented infectious focus (€ 137.7), followed by catheter-related bacteremia (€ 122.7), pulmonary focus (€ 112.8), abdominal focus (€ 98.0), surgical wound infection (€ 89.2), and urinary tract infection (€ 87.9) (30).
Coagulase-negative staphylococci were the microorganisms isolated with greatest frequency in this work (€ 129.04), followed by Escherichia coli. Daily antibiotic treatment cost for a patient having multi-resistant organisms was 50% higher than that for susceptible ones (€165.09 vs. € 82.67; p < 0.001). Gram-positive bacteremia was more costly compared to that caused by gram-negative bacteria (€ 117.1 vs. € 86.8; p = 0.152) (30).
IMPACT ON HOSPITAL STAY
The previously mentioned article by Dimick et al. analyzed the impact on the length of stay. In patients with bacteremia an extra length of stay of 22 days was observed (range between 7 and 70). Patients with bloodstream infection had an increased ICU stay of 20 days (range, 0.1 - 58) (7).
RESISTANCE RATES IN PATIENTS WITH BACTEREMIA IN LATIN AMERICA
The importance of growing resistance to antibiotics in both nosocomial and community-acquired infections is widely known and has thus generated worldwide alarm. An important factor contributing to resistance in Latin America is the high frequency of self-medication and the use of leftover antibiotics (15, 25). Several publications have advised against this widespread practice, which might be responsible for the high level of antimicrobial resistance found in primary care and the impact on those patients requiring in-hospital assistance (33). This has led to the design of different surveillance systems, which provide important information about variability in antimicrobial resistance in different countries and hospitals; and also serve as therapeutic guidelines providing valuable information for prevention, control and detection of resistance (24).
The SENTRY surveillance program, a longitudinal, multicenter study (more than 80 medical institutions around the world, 10 of which are in Latin America) was begun in 1997, and represents the most complete surveillance program in the world. It is characterised by rapidity in communication and socialisation of data regarding the emergence of antimicrobial resistance (28). Table 2 presents the results of this program and other studies in Latin America for different microorganisms. The information about resistance in bloodstream infections for the region is scarce and our group has provided some data on the problem in Colombia.
Table 2. Resistance rates reported in Latin America among microorganisms causing bloodstream infection (2, 5, 26).
Bacteremia represents a frequent complication arising from hospital stay, especially in critically ill patients. Its occurrence is associated with increased mortality and longer hospital stays with increased costs in those who survive. Inappropriate therapy means the antimicrobial therapy to which a particular microorganism is resistant in vitro. Inadequate therapy also includes other aspects such as dosage and administration intervals. Antimicrobial resistance in Latin America is far-reaching amongst the microorganisms identified so far in bacteremia. It constitutes a worrying issue, bearing in mind that it is associated with a greater probability of inappropriate empirical therapy and is greatly responsible for bacteremia-related mortality and complications.
This project was financed by a subsidy from the Universidad Nacional de Colombia School of Medicine and its Research Division (División de Investigaciones Sede Bogotá código 202010011363).
All authors declare no conflicts of interests.
1. American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388-416. [ Links ]
2. Biedenbach DJ, Moet GJ, Jones RN. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (1997-2002). Diagn Microbiol Infect Dis 2004; 50: 59-69. [ Links ]
3. Cheong HS, Kang CI, Wi YM, Kim ES, Lee JS, Ko KS, et al. Clinical significance and predictors of community-onset Pseudomonas aeruginosa bacteremia. Am J Med 2008; 121: 709-14. [ Links ]
4. Chrischilles EA, Scholz DA. Dollars and sense: a practical guide to cost analysis for hospital epidemiology and infection control. Clin Perform Qual Health Care 1999; 7: 107-11. [ Links ]
5. Cortés JA, Buitrago G, Leal AL, Junca A, Garzón D, Contreras K, et al. Etiología de las bacteriemias en pacientes críticos en Colombia, 2001-2007. Acta Med Colomb 2008; 33: 122. [ Links ]
6. Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol 2003; 41: 3655-60. [ Links ]
7. Dimick JB, Pelz RK, Consunji R, Swoboda SM, Hendrix CW, Lipsett PA. Increased resource use associated with catheter-related bloodstream infection in the surgical intensive care unit. Arch Surg 2001;136: 229-34. [ Links ]
8. Falagas ME, Kasiakou SK, Rafailidis PI, Zouglakis G, Morfou P. Comparison of mortality of patients with Acinetobacter baumannii bacteremia receiving appropriate and inappropriate empirical therapy. J Antimicrob Chemother 2006; 57: 1251-4. [ Links ]
9. Garrouste-Orgeas M, Timsit JF, Tafflet M, Misset B, Zahar JR, Soufir L, et al. Excess risk of death from intensive care unit-acquired nosocomial bloodstream infections: a reappraisal. Clin Infect Dis 2006; 42: 1118-26. [ Links ]
10. González-Salvatierra R, Guzmán-Blanco M. Conferencia Panamericana de Resistencia Antimicrobiana en la Américas. Rev Panam Infectol 1999; 3: S1-5. [ Links ]
11. Harbarth S, Nobre V, Pittet D. Does antibiotic selection impact patient outcome? Clin Infect Dis 2007; 44: 87-93. [ Links ]
12. Kang CI, Kim SH, Kim HB, Park SW, Choe YJ, Oh MD, et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis 2003; 37: 745-51. [ Links ]
13. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother 2005; 49: 760-6. [ Links ]
14. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, et al. Bloodstream infections due to extended-spectrum betalactamase- producing Escherichia coli and Klebsiella pneumoniae: risk factors for mortality and treatment outcome, with special emphasis on antimicrobial therapy. Antimicrob Agents Chemother 2004; 48: 4574-81. [ Links ]
15. Kardas P, Pechere JC, Hughes DA, Cornaglia G. A global survey of antibiotic leftovers in the outpatient setting. Int J Antimicrob Agents 2007; 30: 530-6. [ Links ]
16. 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: 181-5. [ Links ]
17. Kim SH, Park WB, Lee CS, Kang CI, Bang JW, Kim HB, et al. Outcome of inappropriate empirical antibiotic therapy in patients with Staphylococcus aureus bacteraemia: analytical strategy using propensity scores. Clin Microbiol Infect 2006;12: 13-21. [ Links ]
18. Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and bloodstream infection: a meta-analysis. J Crit Care 2008; 23: 91-100. [ Links ]
19. Laupland KB, Lee H, Gregson DB, Manns BJ. Cost of intensive care unit-acquired bloodstream infections. J Hosp Infect 2006; 63: 124-32. [ Links ]
20. 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: 3188-94. [ Links ]
21. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcome analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003; 36: 1418-23. [ Links ]
22. McGowan JE, Jr. Economic impact of antimicrobial resistance. Emerg Infect Dis 2001; 7: 286-92. [ Links ]
23. Micek ST, Lloyd AE, Ritchie DJ, Reichley RM, Fraser VJ, Kollef MH. Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 2005; 49: 1306-11. [ Links ]
24. Miranda MC, Perez F, Zuluaga T, Olivera M del R, Correa A, Reyes SL, et al. Antimicrobial resistance in gram-negative bacteria isolated from intensive care units of Colombian hospitals, WHONET 2003, 2004 and 2005. Biomedica 2006; 26: 424-33. [ Links ]
25. Multicenter study on self-medication and self-prescription in six Latin American countries. Drug Utilization Research Group, Latin America. Clin Pharmacol Ther 1997; 61: 488- 93. [ Links ]
26. Ocaña Carrizo AV, Rocchi M, Gasparotto A, Conrero I, Navarro M, Factorovich S, et al. Bacteremia by enterobacteria in adults from a university hospital: a five year analysis. Rev Argent Microbiol 2007; 39: 38-43. [ Links ]
28. Sader HS, Jones RN, Gales AC, Silva JB, Pignatari AC. SENTRY antimicrobial surveillance program report: Latin American and Brazilian results for 1997 through 2001. Braz J Infect Dis 2004; 8: 25-79. [ Links ]
29. Thom KA, Schweizer ML, Osih RB, McGregor JC, Furuno JP, Perencevich EN, et al. Impact of empiric antimicrobial therapy on outcomes in patients with Escherichia coli and Klebsiella pneumoniae bacteremia: a cohort study. BMC Infect Dis 2008; 8: 116. [ Links ]
30. Vandijck DM, Depaemelaere M, Labeau SO, Depuydt PO, Annemans L, Buyle FM, et al. Daily cost of antimicrobial therapy in patients with intensive care unit-acquired, laboratory-confirmed bloodstream infection. Int J Antimicrob Agents 2008; 31: 161-5. [ Links ]
31. Wang FD, Chen YY, Chen TL, Liu CY. Risk factors and mortality in patients with nosocomial Staphylococcus aureus bacteremia. Am J Infect Control 2008; 36: 118-22. [ Links ]
32. Wenzel RP, Thompson RL, Landry SM, Russell BS, Miller PJ, Ponce de Leon S, et al. Hospital-acquired infections in intensive care unit patients: an overview with emphasis on epidemics. Infect Control 1983; 4: 371-5. [ Links ]
33. Wolff MJ. Use and misuse of antibiotics in Latin America. Clin Infect Dis 1993; 17 Suppl 2: S346-51. [ Links ]