Department of Epidemiology MC-45, Albany Medical Center Hospital, 43 New Scotland Avenue, Albany, NY 12208, USA
Received 9 May 2001; returned 31 October 2001; revised 10 December 2001; accepted 25 January 2002.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The reasons for the emergence of MRSA are multifactorial and can be attributed to host factors, infection control practices and antimicrobial pressures.1214 The appearance of bacterial resistance phenotypes has been linked to the clinical use of antimicrobial agents to which the bacteria express resistance.15 One study demonstrated that a patients normal colonizing flora changes within 2448 h under selective antibiotic pressures.16 A recent review of more than 20 studies by Monnet & Frimodt-Moller17 identified consistent associations and doseeffect relationships that support a causal relationship between MRSA and antimicrobial drug use. One of these studies demonstrated that ciprofloxacin and cephalosporins promoted the colonization and ultimately the spread of MRSA in one hospital.18 In studies where antimicrobial classes are analysed separately both cephalosporins and fluoroquinolones are often identified as risk factors for MRSA.19 A multi-centre study of 50 Belgian hospitals associated an increasing incidence of MRSA with increasing use of ceftazidime and cefsulodin, co-amoxiclav and fluoroquinolones.19 Dziekan et al.20 also showed that fluoroquinolone use was an independent risk factor for MRSA as well as nasogastric tubes and central venous catheters. In separate studies, both Crossley et al.21 and Hershow et al.22 noted that patients with MRSA infection had a significantly longer length of stay (LOS) before infection and were likely to have received antimicrobial therapy. A recent publication identified levofloxacin therapy, ICU setting and LOS as being independently associated with MRSA.23
Over the past 3 years, there has been a significant increase in the incidence of nosocomial MRSA at our institution. During this time, there was no significant difference in the number of admissions or patient days. Concurrent with this increase in MRSA incidence was an increase in the usage of fluoroquinolone and ß-lactam/ß-lactamase inhibitor antimicrobials. The purpose of this study was to identify characteristics that were associated with nosocomial MRSA infection.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Statistical methods
Statistical analysis was carried out using SPSS Version 8 (SPSS, Chicago, IL, USA). Continuous variables were compared with a t-test for independent samples (two-tailed). Dichotomous variables were compared with a two-tailed Fishers exact test for 2 x 2 comparisons or a Pearsons 2 test for greater than two variables. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed. A logistic regression model was carried out by a forward selection using the likelihood ratio statistic.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
Although patients infected with MRSA tended to have a higher crude mortality rate, 28.9% compared with 19.5% (P = 0.10), most of these deaths were not related to infection. In a separate analysis, independent risk factors for attributed mortality were bacteraemia with an OR of 4.2 (95% CIs 1.3, 13.5), diabetes OR 3.9 (95% CIs 1.2, 12.0), kidney failure OR 4.9 (95% CIs 1.4, 16.5), steroids OR 3.5 (95% CIs 1.0, 12.1) and haemodynamic instability OR 5.7 (95% CIs 1.8, 18.7). The attributed mortality rate for MRSA-infected patients, 8.3%, was not significantly different from that of the MSSA-infected patients, 5.7% (P = 0.46).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients who received levofloxacin had the highest risk for MRSA infection with an OR of 8.01. More MRSA-infected patients received macrolides but macrolides did not retain statistical significance based on the total amount of drug administered. In our adult population from 1997 to 1999, 33.9% of the S. aureus isolates were resistant to levofloxacin and 44.8% were resistant to macrolides. Antimicrobial use has historically been associated with MRSA and a number of different classes of antibiotics.1223,27,28,3541 Mechanisms of fluoroquinolone resistance in S. aureus, DNA gyrase, IV topoisomerase and NorA-mediated efflux and macrolide resistance ermA and ermC genes are well documented.40,42,43 In addition to the molecular studies, several clinical studies have shown an association with fluoroquinolone use and S. aureus resistance.44,45 Isaacs et al.44 postulated that the factors which predispose S. aureus to develop methicillin resistance may also predispose them to ciprofloxacin resistance. In their study, they identified an increase in ciprofloxacin resistance in isolates after using ciprofloxacin to treat MRSA infections. Although there are no known biological mechanisms for fluoroquinolones to select resistance to b-lactam antibiotics in staphylococci, evidence is mounting that fluoroquinolones exhibit some type of influence on MRSA. Ciprofloxacin resistance in MRSA developed rapidly whereas the rate of ciprofloxacin resistance in MSSA nationwide is c. 2.4%. These data indicate that there are intrinsic factors which lead to greater acquisition of fluoroquinolone resistance in MRSA.46 Hetero-resistant S. aureus populations include sub-populations that contain the mecA gene and these resistant sub-populations can be selected for by exposure to increasing concentrations of antibiotics below MIC levels.16 It was demonstrated that mecA-positive S. aureus strains which exhibit this hetero-resistance showed an increase in the proportion of oxacillin-resistant cells following exposure to fluoroquinolones.47
In summary, patients infected with MRSA were more likely to have had surgery, a previous hospitalization and a longer LOS before infections. All of these factors are known to increase the probability of a patient developing an MRSA infection. The two risk factors that contributed the greatest risk for developing an MRSA infection were enteral feedings and levofloxacin as shown by their ORs and highly significant P values. Whether these two risk factors have an associated effect is unknown and beyond the scope of this analysis. Further investigation is warranted because this could lead to a modifiable practice change. The relationships between antimicrobial use and MRSA are complex and more studies that address these issues are needed. However, most studies agree that, in addition to good infection control practices, the prudent use of antimicrobial agents is one of the major steps to reducing the growing problem of antibiotic resistance.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2
.
Witte, W. (1999). Antibiotic resistance in Gram positive bacteria: epidemiological aspects. Journal of Antimicrobial Chemotherapy 44, 19.
3 . Cunha, B. A. (1998). Antibiotic resistance. Control strategies. Critical Care Clinics 14, 30927.[ISI][Medline]
4 . Panlilio, A. L., Culver, D. H., Gaynes, R. P., Banerjee, S., Henderson, T., Tolson, J. et al. (1992). Methicillin-resistant Staphylococcus aureus in U. S. hospitals, 19751991. Infection Control and Hospital Epidemiology 13, 5826.[ISI][Medline]
5 . Archibald, L., Phillips, L., Monnet, D., McGowan, J. E., Tenover, F. & Gaynes, R. (1997). Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit. Clinical Infectious Diseases 24, 2115.[ISI][Medline]
6 . Bartlett, M., McIntyre, L., Moseley, R., OConnor, J., Shaw, J. & Whitehead, C. (2000). Methicillin-resistant S. aureus rates increase 260% in hospitals participating in HIPs international monitoring systems. Centers for Disease Control and National Center for Infectious Diseases Focus 9, 4.
7 . Akram, J. & Glatt, A. E. (1998). True community-acquired methicillin-resistant Staphylococcus aureus bacteremia. Infection Control and Hospital Epidemiology 19, 1067.[ISI][Medline]
8 . Centers For Disease Control. (1999). Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureusMinnesota and North Dakota, 19971999. Morbidity and Mortality Weekly Report 48, 70710.
9 . Goetz, A., Posey, K., Fleming, J., Jacobs, S., Boody, L., Wagener, M. et al. (1999). Methicillin-resistant Staphylococcus aureus in the community: a hospital-based study. Infection Control and Hospital Epidemiology 20, 68991.[ISI][Medline]
10 . Kallen, A., Driscoll, T., Thorton, S., Olson, P. & Wallace, M. (2000). Increase in community-acquired methicillin-resistant staphylococcus at a naval medical center. Infection Control and Hospital Epidemiology 21, 2236.[ISI][Medline]
11 . Kak, V. & Levine, D. P. (1999). Editorial response: community-acquired methicillin Staphylococcus aureus infectionswhere do we go from here? Clinical Infectious Diseases 29, 8012.[ISI][Medline]
12 . Ayliffe, G. A. J. (1996). Recommendations for the Control of Methicillin-Resistant Staphylococcus aureus (MRSA). Division of Emerging and other Communicable Diseases Surveillance and Control, World Health Organisation, Geneva, Switzerland.
13 . Herwaldt, L. A. (1999). Control of methicillin-resistant Staphylococcus aureus in the hospital setting. American Journal of Medicine 106, 11s8s.
14 . Monnet, D. (1998). Methicillin-resistant Staphylococcus aureus and its relationship to antimicrobial use: possible implications for control. Infection Control and Hospital Epidemiology 19, 5529.[ISI][Medline]
15 . Rice, L. (1999). Editorial response: a silver bullet for colonization and infection with methicillin-resistant Staphylococcus aureus still eludes us. Clinical Infectious Diseases 28, 106770.[ISI][Medline]
16 . Schentag, J. J., Hyatt, J. M., Carr, J. R., Paladino, J. A., Birmingham, M. C., Zimmer, G. S. et al. (1998). Genesis of methicillin-resistant Staphylococcus aureus (MRSA). How treatment of MRSA infections has selected for vancomycin resistant Enterococcus faecium and the importance of antibiotic management and infection control. Clinical Infectious Diseases 26, 120414.[ISI][Medline]
17 . Monnet, D. & Frimodt-Moller, N. (2001). Antimicrobial-drug use and methicillin-resistant Staphylococcus aureus. Emerging Infectious Diseases 7, 13.[ISI][Medline]
18
.
Hill, D. A., Herford, T. & Parratt, D. (1998). Antibiotic usage and methicillin-resistant Staphylococcus aureus and analysis of causality. Journal of Antimicrobial Chemotherapy 42, 6767.
19 . Crowcroft, N. S., Ronveaux, O, Monnet, D. L. & Mertens, R. (1999). Methicillin-resistant Staphylococcus aureus and antimicrobial use in Belgian hospitals. Infection Control and Hospital Epidemiology 20, 316.[ISI][Medline]
20 . Dziekan, G., Hahn, A., Thune, K., Schwarzer, G., Schafer, K., Daschner, F. D. et al. (2000). Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study. Journal of Hospital Infection 46, 26370.[ISI][Medline]
21 . Crossley, K., Loesch, D., Landesman, B., Mead, K., Chern, M. & Strate, R. (1979). An outbreak of infections caused by strains of Staphylococcus aureus resistant to methicillin and aminoglycosides I: clinical studies. Journal of Infectious Diseases 139, 2739.[ISI][Medline]
22 . Hershow, R. C., Khayr, W. F. & Smith, N. L. (1992). A comparison of clinical virulence of nosocomially acquired methicillin resistant and methicillin-sensitive Staphylococcus aureus infections in a university hospital. Infection Control and Hospital Epidemiology 13, 58793.[ISI][Medline]
23 . Fu-Yu, C., Muddoloro, M. & Alcid, D. (2000). Levofloxacin associated increase in methicillin-resistant Staphylococcus aureus infections. In Program and Abstracts of the Thirty-eighth Annual Meeting of the Infectious Diseases Society of America, New Orleans, LA, 2000. Abstract 163, p. 241. Infectious Diseases Society of America, New Orleans, LA.
24 . Garner, J. S., Jarvis, W. R., Emori, T. G., Horan, T. C. & Hughes, J. M. (1988). CDC definitions for nosocomial infections. American Journal of Infection Control 16, 12840.[ISI][Medline]
25 . National Committee for Clinical Laboratory Standards. (1988). Performance Standards for Antimicrobial Susceptibility Testing; Ninth Informational Supplement: Document M100-S9. NCCLS, Wayne, PA.
26 . Asensio, A., Guerrero, A., Quereda, C., Lizan, M. & Martinez-Ferrer, M. (1996). Colonization and infection with methicillin-resistant Staphylococcus aureus: associated factors and eradication. Infection Control and Hospital Epidemiology 17, 208.[ISI][Medline]
27 . Boyce, J. M., Landry, M., Deetz, T. R. & Dupont, H. L. (1981). Epidemiologic studies of an outbreak of nosocomial methicillin-resistant Staphylococcus aureus infections. Infection Control 2, 1106.[ISI][Medline]
28 . Ayliffe, G. A. J. (1997). The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus. Clinical Infectious Diseases 24, S749.[ISI][Medline]
29 . Barie, P. S. (1998). Antibiotic resistant gram positive cocci: implications for surgical practice. World Journal of Surgery 22, 11826.[ISI][Medline]
30 . Mueller, B. A., Brierton, D. G., Abel, S. R. & Bowman, L. (1994). Effect of enteral feeding with ensure on oral bioavailabilities of ofloxacin and ciprofloxacin. Antimicrobial Agents and Chemotherapy 38, 21015.[Abstract]
31 . Wright, D. H., Pietz, S. L., Konstantinides, F. N. & Rotschafer, J. C. (2000). Decreased in vitro fluoroquinolone concentrations after admixture with an enteral feeding formulation. Journal of Parenteral and Enteral Nutrition 24, 428.[ISI][Medline]
32 . Healy, D. P., Brodbeck, M. C. & Clendening, C. E. (1996). Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gastrostomy and jejunostomy tubes. Antimicrobial Agents and Chemotherapy 40, 610.[Abstract]
33 . Mimoz, O., Binter, V., Jacolot, A., Edouard, A., Tod, M., Petitjean, O. et al. (1998). Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients. Intensive Care Medicine 24, 104751.[ISI][Medline]
34 . Vincent, J., Teng, R., Pelletier, S. M., Willavize, S. A. & Friedman, H. L. (1998). The bioavailability of nasogastric versus tablet form oral trovofloxacin in healthy subjects. American Journal of Surgery 176, 23S6S.[ISI][Medline]
35 . Fagon, J. Y., Maillet, J. M. & Novara, A. (1998). Hospital acquired pneumonia: methicillin resistance and intensive care unit admission. American Journal of Medicine 104, 17S23S.
36 . Pujol, M., Pena, C., Pallares, R., Ayats, J., Ariza, J. & Gudio, F. (1994). Risk factors for nosocomial bacteremia due to methicillin resistant Staphylococcus aureus. European Journal of Clinical Microbiology and Infectious Diseases 13, 96102.[ISI][Medline]
37 . Witte, W., Braulke, C., Heuck, D. & Cuny, C. (1994). Analysis of nosocomial outbreaks with multiply and methicillin-resistant Staphylococcus aureus (MRSA) in Germany: implications for hospital hygiene. Infection 22, S12834.[ISI][Medline]
38 . Rosdahl, V. T. & Knudsen, A. M. (1991). The decline of methicillin resistance among Danish Staphylococcus aureus strains. Infection Control and Hospital Epidemiology 12, 838.[ISI][Medline]
39 . Law, M. R. & Gill, O. N. (1988). Hospital-acquired infection with methicillin-resistant and methicillin-sensitive staphylococci. Epidemiology and Infection 101, 6239.[ISI][Medline]
40 . Acar, J. F. & Goldstein, F. W. (1997). Trends in bacterial resistance to fluoroquinolones. Clinical Infectious Diseases 24, S6773.[ISI][Medline]
41 . Landman, D., Chockalingam, M. & Quale, J. (1999). Reduction in the incidence of methicillin-resistant Staphylococcus aureus and ceftazidime-resistant Klebsiella pneumoniae following changes in a hospital antibiotic formulary. Clinical Infectious Diseases 28, 10626.[ISI][Medline]
42 . Kaatz, G. W. & Seo, S. M. (1997). Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 41, 27337.[Abstract]
43 . Ng, E. Y., Trucksis, M. & Hooper, D. C. (1994). Quinolone resistance mediated by nor A: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrobial Agents and Chemotherapy 38, 134555.[Abstract]
44 . Isaacs, R. D., Kunke, P. J., Cohen, R. L. & Smith, J. W. (1988). Ciprofloxacin resistance in epidemic methicillin-resistant Staphylococcus aureus. Lancet ii, 843.
45 . Manhold, C., von Rolbicki, U., Brase, R., Timm, J., von Pritzbuer, E., Heimesaat, M. et al. (1998). Outbreaks of Staphylococcus aureus infections during treatment of late onset pneumonia with ciprofloxacin in a prospective, randomized study. Intensive Care Medicine 24, 132730.[ISI][Medline]
46 . Gottlieb, T. & Mitchell, D. (1998). The independent evolution of resistance to ciprofloxacin, rifampin, and fusidic acid in methicillin-resistant Staphylococcus aureus in Australian teaching hospitals (19901995). Journal of Antimicrobial Chemotherapy 42, 6773.[Abstract]
47
.
Venezia, R. A., Damaracki, B. E., Evans, A. M., Preston, K. E. & Graffunder, E. M. (2001). Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure. Journal of Antimicrobial Chemotherapy 48, 37581.