SUPPLEMENT ARTICLE

Collateral Damage from Cephalosporin or Quinolone Antibiotic Therapy

David L. Paterson
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Collateral damage is a term used to refer to ecological adverse effects of antibiotic therapy; namely, the selection of drug-resistant organisms and the unwanted development of colonization or infection with multidrug-resistant organisms. The risk of such damage can be assessed for different antibiotic classes by a variety of epidemiologic studies. Cephalosporin use has been linked to subsequent infection with vancomycin-resistant enterococci, extended-spectrum b-lactamaseproducing Klebsiella pneumoniae, b-lactamresistant Acinetobacter species, and Clostridium difcile. Quinolone use has been linked to infection with methicillin-resistant Staphylococcus aureus and with increasing quinolone resistance in gram-negative bacilli, such as Pseudomonas aeruginosa. Neither third-generation cephalosporins nor quinolones appear suitable for sustained use in hospitals as workhorse antibiotic therapy. Traditionally, studies of antimicrobial therapy have assessed clinical and bacteriological efcacy in the treatment of infection. This is intuitive and is clearly the most appropriate way to study the effectiveness of antibiotics. However, treatment of serious communityacquired and hospital-acquired infections with antibiotics that may be associated with collateral damage that is, the selection of antibiotic-resistant organisms or Clostridium difcile and the unwanted development of colonization or infection with such organismsalso needs to be evaluated. Although such collateral damage has pertinence to the outpatient treatment of community-acquired pneumonia (CAP), here I concentrate on the effects of inpatient treatment with antibiotics commonly used for pneumonia and on the 2 antibiotic classes most commonly linked to collateral damage cephalosporins and quinolones. HOW CAN WE IDENTIFY COLLATERAL DAMAGE FROM ANTIBIOTICS? Three types of epidemiological studies can potentially link antibiotic use with ecological adverse effects. The rst type is case-control studies, which assess antibiotic use in persons infected with an antibiotic-resistant organism (case-patients) and in control subjects. There has been considerable recent discussion about the optimal design of such studies, especially with respect to selection of the control group [14]. The second type of study assesses accumulated data on antibiotic use (often expressed in dened daily doses per 1000 patientdays) in an institution and correlates them with rates of antibiotic resistance in that institution. Such studies may yield divergent results from those of studies with a case-control design that assess antibiotic use in individual patients [5]. The third type of study assesses an intervention aimed at limiting use of antibiotics of various classes to decrease selection pressure leading to antibiotic resistance. Animal colonization studies, such as those described by Donskey et al. [6], have also studied the effects of antibiotics on bacterial ora, but these are not assessed herein. Each study design is subject to considerable degrees of bias. Unfortunately, few scoring systems are available that can assess the adequacy of conclusions derived
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Reprints or correspondence: Dr. David L. Paterson, Antibiotic Management Program, Division of Infectious Disease, University of Pittsburgh Medical Center, Ste. 3A, Falk Medical Bldg., 3601 5th Ave., Pittsburgh, PA 15213 (patersond @msx.dept-med.pitt.edu). Clinical Infectious Diseases 2004; 38(Suppl 4):S3415 2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2004/3810S4-0004$15.00

from individual studies. Each study design has its own limitations. The literature is replete with examples in which the different study designs yield different results when assessing risk factors for certain infection types. Additionally, it must be recognized that the 2 antibiotic types under discussion here (cephalosporins and quinolones) may be used to treat infections other than CAP. With these important caveats, published studies that have assessed antibiotic use and subsequent collateral damage are reviewed here.

CEPHALOSPORINS Gram-positive cocci. The cephalosporins commonly used in the treatment of CAP are cefuroxime, ceftriaxone, and cefotaxime. Cefepime is sometimes also used, especially in the treatment of nursing homeacquired pneumonia. Cephalosporins lack signicant activity against enterococci. Before the emergence of vancomycin-resistant enterococci (VRE), it had been shown that cephalosporin use was associated with signicant infections with enterococci [7]. In the era of VRE, a number of case-control studies have shown that use of third-generation cephalosporins may be a risk factor for infection with VRE. Dahms et al. [8], in a comparison of surgical inpatients with enterococcal infections due to vancomycin-resistant and vancomycin-susceptible strains, found that prior use of a thirdgeneration cephalosporin was a risk factor for infection with VRE. Ostrowsky et al. [9], in a study that compared 35 patients colonized with VRE with 255 patients without VRE colonization at admission to 2 Boston surgical intensive care units (ICUs), found that prior receipt of a second- or third-generation cephalosporin was a risk factor for VRE colonization. Loeb et al. [10], in an assessment of risk factors for VRE colonization during a hospital outbreak, found that prior cephalosporin use was the only potentially modiable risk factor. Finally, a review of 126 adult ICUs from across the United States showed that rates of third-generation cephalosporin use were associated with VRE prevalence [11]. The results of these studies imply that reduction in the use of second- and third-generation cephalosporins might result in a reduction in the occurrence of VRE. Of interest is a recent evaluation of the effects of restriction of third-generation cephalosporin use [12]. Despite an 85.8% decrease in the use of third-generation cephalosporins during the evaluation period, the prevalence of VRE increased steadily. This result might be construed to mean that reduction in third-generation cephalosporin use is completely ineffective in the control of VRE. However, the prevalence of VRE is affected by multiple factors, including concurrent infection-control interventions and concurrent trends in the use of antibiotics with antianaerobic bacterial activity [12, 13]. In the treatment of fever in neutropenic patients, the replacement of ceftazidime by piperacillin/tazoS342 CID 2004:38 (Suppl 4) Paterson

bactam for rst-line empirical therapy was associated with a decrease in the prevalence of VRE [14]. More institutions need to publish their experience with alteration in cephalosporin use and its effect on VRE prevalence in order for a clearer understanding of this relationship to emerge. Third-generation cephalosporin use has also been associated with infection with methicillin-resistant Staphylococcus aureus (MRSA) in some case-control studies [15]. A formulary change that decreased the use of cephalosporins and increased the use of b-lactam/b-lactamase inhibitor antibiotics resulted in a small but statistically signicant reduction in MRSA infections [16]. Gram-negative bacilli. In contrast to the scenario with gram-positive organisms, there does appear to be a clear-cut relationship between the use of third-generation cephalosporin antibiotics and colonization or infection with certain multidrug-resistant gram-negative bacilli. This has been demonstrated in studies correlating total hospital antibiotic consumption with hospital-wide antibiotic resistance rates, in case-control studies, and in studies assessing the effects of limitation of cephalosporins on hospital-wide antibiotic resistance rates. Quale and Landman and their colleagues [1720] have published a number of signicant papers assessing outbreaks of multiresistant gram-negative bacilli in multiple hospitals in Brooklyn, New York. Total hospital consumption of a variety of antibiotic classes was related to the prevalence of extendedspectrum b-lactamase (ESBL)producing Klebsiella pneumoniae and multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in 15 hospitals. Furthermore, total hospital use of cephalosporins plus aztreonam was directly correlated with the prevalence of ESBL-producing K. pneumoniae and multiresistant A. baumannii but not multidrug-resistant P. aeruginosa [1720]. Several case-control studies have also shown a relationship between prior use of third-generation cephalosporins and subsequent colonization or infection with ESBL-producing organisms [2125]. Studies that have not shown this association have generally been underpowered or have examined a focal monoclonal outbreak, associated with poor infection control [26]. Several studies have used education of prescribers as a means of reducing cephalosporin use and have observed reductions in the rates of ESBL production by gram-negative organisms [27, 28]. More forcefully, Rahal et al. [29] used extensive class restriction of cephalosporins as a means of controlling ESBLproducing Klebsiella infections. Following restriction, neither ceftriaxone nor cefuroxime was used for CAP in their institution, and the use of a cephalosporin for any condition other than pediatric infection, meningitis, gonococcal infection, or spontaneous bacterial peritonitis was allowed only after approval from the hospitals infectious disease service. The use of all cephalosporins decreased by 80%. This was accompanied

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by a 44% reduction in the incidence of ESBL-producing Klebsiella infections. Although it has been widely noted that imipenem resistance in P. aeruginosa became more common during the period of cephalosporin restriction, the P. aeruginosa isolates, unlike the Klebsiella infections, were not multidrugresistant. C. difcile. A plethora of case-control studies have associated C. difcile infections with prior use of cephalosporins [3037], with the exception of 1 case-control study [38]. In 1 prospective, crossover study in non-ICU wards, use of cefotaxime, as opposed to piperacillin/tazobactam, was associated with a signicantly increased incidence of C. difcile infection [34]. Restriction of use of injectable third-generation cephalosporins (resulting in a 92% reduction in use of these antibiotics) was associated with a halving of cases of C. difcile associated diarrhea in 1 particular center [39].

QUINOLONES Gram-positive cocci. There is a potential connection between prior quinolone use and colonization or infection with MRSA. Several case-control studies have shown that prior receipt of a quinolone was associated with subsequent MRSA infection [40 43]. In a study of 10 urban teaching hospitals across the United States over a prolonged period, an overall decrease in susceptibility of S. aureus to methicillin was observed [44]. This coincided with an increase in quinolone use in 9 of the 10 institutions. It is noteworthy that the majority of MRSA strains are now also quinolone-resistant, and hence selection of such strains by quinolone use is biologically plausible. It is interesting that exposure of clinical isolates of MRSA to subinhibitory concentrations of quinolones induces the production of bronectin-binding proteins and increases the adhesion of staphylococci to bronectin-coated surfaces [45, 46]. There are few data on the relationship between prior quinolone use and colonization or infection with VRE. However, Lautenbach et al. [12] found a borderline association between VRE prevalence and quinolone use (P p .07). Gram-negative bacilli. There is little doubt that patients who develop an infection with a gram-negative bacillus and who have previously received a quinolone will have an increased risk of infection with a quinolone-resistant strain. This has been demonstrated in patients who have received quinolones as prophylaxis against infections with gram-negative bacilli while neutropenic and while receiving quinolones as prophylaxis against spontaneous bacterial peritonitis [4749]. Additionally, prior quinolone use is a risk factor for subsequent infection with quinolone-resistant, ESBL-producing organisms [50, 51]. The multihospital studies in Brooklyn did not nd a relationship between hospitals rate of use of quinolones and the number of infections with ceftazidime-resistant K. pneumoniae,

ceftazidime-resistant A. baumanii, carbapenem-resistant A. baumanii, or carbapenem-resistant P. aeruginosa [17, 18]. However, case-control studies have identied prior quinolone use as a risk factor for infection with ESBL-producing Klebsiella species and Escherichia coli in nursing homes and nosocomial Acinetobacter infections in an ICU [52, 53]. A major concern worldwide has been the increasing resistance of P. aeruginosa to multiple antibiotics. Quinolones represent an important option for treatment of P. aeruginosa infection [54]. However, increasing quinolone use for indications other than P. aeruginosa infection is likely to reduce the susceptibility of P. aeruginosa to quinolones [55]. Zervos et al. [44], in their multihospital study, have shown that as quinolone use rises in an institution, susceptibility of P. aeruginosa to quinolones deteriorates. Of note, in the single institution in which there was a reduction in quinolone use over time, there was also an improvement in the quinolone susceptibility of isolates. C. difcile. For many years, quinolone use has been regarded as creating little risk of C. difcile infection [56]. However, recent case-control studies have concluded that use of quinolones may indeed be a risk factor for nosocomial C. difcile infection [37, 5759]. It remains to be seen whether quinolones with enhanced antianaerobic bacterial activity increase or decrease the risk of nosocomial C. difcile infection [58, 59].

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CONCLUSIONS No two hospitals are alike in the intensity of antibiotic use or adequacy of and adherence to infection control procedures. Numerous confounding factors may make extrapolation of results from one particular hospital or region to another misleading. Differences in the variety of surgical services offered, the extent of environmental bacterial contamination, baseline prevalence of antibiotic-resistant organisms, the colonization density of drug-resistant organisms, the age of the population served, and even the nurse-to-patient ratio may lead to differ-

Table 1. Summary of potential collateral damage from use of cephalosporins and quinolones.
Class of agent, pathogen(s) selected for Third-generation cephalosporins Vancomycin-resistant enterococci Extended-spectrum b-lactamaseproducing Klebsiella species b-lactamresistant Acinetobacter species Clostridium difcile Quinolones Methicillin-resistant Staphylococcus aureus Quinolone-resistant gram-negative bacilli, including Pseudomonas aeruginosa

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ences in risk factors for infections with multiresistant organisms. With these caveats in mind, of the major antibiotic classes, aminoglycosides, b-lactam/b-lactamase inhibitor combinations, and macrolides appear least frequently to be associated with subsequent infection with multiresistant organisms. In contrast, cephalosporin and quinolone use has been linked more frequently to collateral damage (in the form of antibioticresistant superinfections) (table 1). Such infections include those with multiresistant gram-positive and gram-negative bacteria as well as C. difcile. Intervention studies in an individual hospital showing that sustained reduction in rates of infection with multiresistant organisms coincides with reduction in the use of certain antibiotic classes (assuming that other variables, such as infection-control interventions, are kept constant) may be the closest thing to proof of the concept that certain antibiotic classes are less suitable than others as workhorse antibiotic therapy.

References
1. Harris AD. Control group selection is an important but neglected issue in studies of antibiotic resistance [letter]. Ann Intern Med 2000; 132: 925. 2. Harris AD, Karchmer TB, Carmeli Y, Samore MH. Methodological principles of case-control studies that analyzed risk factors for antibiotic resistance: a systematic review. Clin Infect Dis 2001; 32:105561. 3. Harris AD, Samore MH, Lipsitch M, Kaye KS, Perencevich E, Carmeli Y. Control-group selection importance in studies of antimicrobial resistance: examples applied to Pseudomonas aeruginosa, Enterococci, and Escherichia coli. Clin Infect Dis 2002; 34:155863. 4. Paterson DL. Looking for risk factors for the acquisition of antibiotic resistance: a 21st-century approach. Clin Infect Dis 2002; 34:15647. 5. Harbarth S, Harris AD, Carmeli Y, Samore MH. Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli. Clin Infect Dis 2001; 33:14628. 6. Donskey CJ, Hanrahan JA, Hutton RA, Rice LB. Effect of parenteral antibiotic administration on the establishment of colonization with vancomycin-resistant Enterococcus faecium in the mouse gastrointestinal tract. J Infect Dis 2000; 181:18303. 7. Pallares R, Pujol M, Pena C, Ariza J, Martin R, Gudiol F. Cephalosporins as risk factor for nosocomial Enterococcus faecalis bacteremia. A matched case-control study. Arch Intern Med 1993; 153:15816. 8. Dahms RA, Johnson EM, Statz CL, Lee JT, Dunn DL, Beilman GJ. Third-generation cephalosporins and vancomycin as risk factors for postoperative vancomycin-resistant enterococcus infection. Arch Surg 1998; 133:13436. 9. Ostrowsky BE, Venkataraman L, DAgata EM, Gold HS, DeGirolami PC, Samore MH. Vancomycin-resistant enterococci in intensive care units: high frequency of stool carriage during a non-outbreak period. Arch Intern Med 1999; 159:146772. 10. Loeb M, Salama S, Armstrong-Evans M, Capretta G, Olde J. A casecontrol study to detect modiable risk factors for colonization with vancomycin-resistant enterococci. Infect Control Hosp Epidemiol 1999; 20:7603. 11. Fridkin SK, Edwards JR, Courval JM, et al. The effect of vancomycin and third-generation cephalosporins on prevalence of vancomycinresistant enterococci in 126 US adult intensive care units. Ann Intern Med 2001; 135:17583. 12. Lautenbach E, LaRosa LA, Marr AM, Nachamkin I, Bilker WB, Fish-

man NO. Changes in the prevalence of vancomycin-resistant enterococci in response to antimicrobial formulary interventions: impact of progressive restrictions on use of vancomycin and third-generation cephalosporins. Clin Infect Dis 2003; 36:4406. 13. Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000; 343:192532. 14. Bradley SJ, Wilson AL, Allen MC, Sher HA, Goldstone AH, Scott GM. The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage. J Antimicrob Chemother 1999; 43:2616. 15. Washio M, Mizoue T, Kajioka T, et al. Risk factors for methicillinresistant Staphylococcus aureus (MRSA) infection in a Japanese geriatric hospital. Public Health 1997; 111:18790. 16. Landman D, Chockalingam M, Quale JM. Reduction in the incidence of methicillin-resistant Staphylococcus aureus and ceftazidime-resistant Klebsiella pneumoniae following changes in a hospital antibiotic formulary. Clin Infect Dis 1999; 28:10626. 17. Landman D, Quale JM, Mayorga D, et al. Citywide clonal outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY: the preantibiotic era has returned. Arch Intern Med 2002; 162:151520. 18. Quale JM, Landman D, Bradford PA, et al. Molecular epidemiology of a citywide outbreak of extended-spectrum b-lactamaseproducing Klebsiella pneumoniae infection. Clin Infect Dis 2002; 35:83441. 19. Manikal VM, Landman D, Saurina G, Oydna E, Lal H, Quale J. Endemic carbapenem-resistant Acinetobacter species in Brooklyn, New York: citywide prevalence, interinstitutional spread, and relation to antibiotic usage. Clin Infect Dis 2000; 31:1016. 20. Saurina G, Quale JM, Manikal VM, Oydna E, Landman D. Antimicrobial resistance in Enterobacteriaceae in Brooklyn, NY: epidemiology and relation to antibiotic usage patterns. J Antimicrob Chemother 2000; 45:8958. 21. Asensio A, Oliver A, Gonzalez-Diego P, et al. Outbreak of a multiresistant Klebsiella pneumoniae strain in an intensive care unit: antibiotic use as risk factor for colonization and infection. Clin Infect Dis 2000;30: 5560. 22. Schiappa DA, Hayden MK, Matushek MG, et al. Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation. J Infect Dis 1996; 174:52936. 23. Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extended-spectrum b-lactamaseproducing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 2001; 32:116271. 24. Arifn H, Navaratnam P, Mohamed M, et al. Ceftazidime-resistant Klebsiella pneumoniae bloodstream infection in children with febrile neutropenia. Int J Infect Dis 2000; 4:215. 25. Paterson DL, Ko WC, Von Gottberg A, et al. International prospective study of Klebisella pneumoniae bacteremia: implications of extendedspectrum beta-lactamase production in nosocomial infections. Ann Intern Med 2004; 140:2632. 26. Paterson DL, Singh N, Rihs JD, Squier C, Rihs BL, Muder RR. Control of an outbreak of infection due to extended-spectrum b-lactamaseproducing Escherichia coli in a liver transplantation unit. Clin Infect Dis 2001; 33:1268. 27. Patterson JE, Hardin TC, Kelly CA, Garcia RC, Jorgensen JH. Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae. Infect Control Hosp Epidemiol 2000; 21:4558. 28. Rice LB, Eckstein EC, DeVente J, Shlaes DM. Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center. Clin Infect Dis 1996; 23:11824. 29 Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 1998; 280:12337. 30. Nelson DE, Auerbach SB, Baltch AL, et al. Epidemic Clostridium dif-

Downloaded from cid.oxfordjournals.org by guest on August 31, 2011

S344 CID 2004:38 (Suppl 4) Paterson

31.

32. 33. 34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

cileassociated diarrhea: role of second- and third-generation cephalosporins. Infect Control Hosp Epidemiol 1994; 15:8894. de Lalla F, Privitera G, Ortisi G, et al. Third generation cephalosporins as a risk factor for Clostridium difcileassociated disease: a four-year survey in a general hospital. J Antimicrob Chemother 1989; 23:62331. Golledge CL, McKenzie T, Riley TV. Extended spectrum cephalosporins and Clostridium difcile. J Antimicrob Chemother 1989; 23:92931. Zadik PM, Moore AP. Antimicrobial associations of an outbreak of diarrhoea due to Clostridium difcile. J Hosp Infect 1998; 39:18993. Settle CD, Wilcox MH, Fawley WN, Corrado OJ, Hawkey PM. Prospective study of the risk of Clostridium difcile diarrhoea in elderly patients following treatment with cefotaxime or piperacillin-tazobactam. Aliment Pharmacol Ther 1998; 12:121723. Mody LR, Smith SM, Dever LL. Clostridium difcileassociated diarrhea in a VA medical center: clustering of cases, association with antibiotic usage, and impact on HIV-infected patients. Infect Control Hosp Epidemiol 2001; 22:425. Schwaber MJ, Simhon A, Block C, Roval V, Ferderber N, Shapiro M. Factors associated with nosocomial diarrhea and Clostridium difcileassociated disease on the adult wards of an urban tertiary care hospital. Eur J Clin Microbiol Infect Dis 2000; 19:915. Lai KK, Melvin ZS, Menard MJ, Kotilainen HR, Baker S. Clostridium difcileassociated diarrhea: epidemiology, risk factors, and infection control. Infect Control Hosp Epidemiol 1997; 18:62832. Shek FW, Stacey BS, Rendell J, Hellier MD, Hanson PJ. The rise of Clostridium difcile: the effect of length of stay, patient age, and antibiotic use. J Hosp Infect 2000; 45:2357. Ludlam H, Brown N, Sule O, Redpath C, Coni N, Owen G. An antibiotic policy associated with reduced risk of Clostridium difcileassociated diarrhoea. Age Ageing 1999; 28:57880. Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother 2002; 49: 9991005. Campillo B, Dupeyron C, Richardet JP. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillinresistant Staphylococcus aureus and inuence of previous antibiotic therapy and noroxacin prophylaxis. Epidemiol Infect 2001; 127: 44350. Dziekan G, Hahn A, Thune K, et al. Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study. J Hosp Infect 2000; 46:26370. Weber SG, Gold HS, Hooper DC, Karchmer AW, Carmeli Y. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis 2003; 9:141522. Zervos M, Hershberger E, Nicolau DP, et al. Relationship between uoroquinolone use and changes in susceptibility to uoroquinolones of selected pathogens in 10 United States teaching hospitals, 19912000. Clin Infect Dis 2003; 37:16438. Bisognano C, Vaudaux P, Rohner P, Lew DP, Hooper DC. Induction of bronectin-binding proteins and increased adhesion of quinoloneresistant Staphylococcus aureus by subinhibitory levels of ciprooxacin. Antimicrob Agents Chemother 2000; 44:142837.

46. Bisognano C, Vaudaux PE, Lew DP, Ng EY, Hooper DC. Increased expression of bronectin-binding proteins by uoroquinolone-resistant Staphylococcus aureus exposed to subinhibitory levels of ciprooxacin. Antimicrob Agents Chemother 1997; 41:90613. 47. Yoo JH, Huh DH, Choi JH, et al. Molecular epidemiological analysis of quinolone-resistant Escherichia coli causing bacteremia in neutropenic patients with leukemia in Korea. Clin Infect Dis 1997; 25: 138591. 48 Campillo B, Dupeyron C, Richardet JP, Mangeney N, Leluan G. Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: effect of long-term administration of noroxacin. Clin Infect Dis 1998; 26:106670. 49. Dupeyron C, Mangeney N, Sedrati L, Campillo B, Fouet P, Leluan G. Rapid emergence of quinolone resistance in cirrhotic patients treated with noroxacin to prevent spontaneous bacterial peritonitis. Antimicrob Agents Chemother 1994; 38:3404. 50. Lautenbach E, Strom BL, Bilker WB, Patel JB, Edelstein PH, Fishman NO. Epidemiological investigation of uoroquinolone resistance in infections due to extended-spectrum b-lactamaseproducing Escherichia coli and Klebsiella pneumoniae. Clin Infect Dis 2001; 33:128894. 51. Paterson DL, Mulazimoglu L, Casellas JM, et al. Epidemiology of ciprooxacin resistance and its relationship to extended-spectrum b-lactamase production in Klebsiella pneumoniae isolates causing bacteremia. Clin Infect Dis 2000; 30:4738. 52. Villers D, Espaze E, Coste-Burel M, et al. Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology. Ann Intern Med 1998; 129:1829. 53. Wiener J, Quinn JP, Bradford PA, et al. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA 1999; 281: 51723. 54. Fink MP, Snydman DR, Niederman MS, et al. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprooxacin with imipenem-cilastatin. The Severe Pneumonia Study Group. Antimicrob Agents Chemother 1994; 38:54757. 55. Neuhauser MM, Weinstein RA, Rydman R, Danizger LH, Karam G, Quinn JP. Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for uoroquinolone use. JAMA 2003; 289:8858. 56. Golledge CL, Carson CF, ONeill GL, Bowman RA, Riley TV. Ciprooxacin and Clostridium difcileassociated diarrhoea. J Antimicrob Chemother 1992; 30:1417. 57. Yip C, Loeb M, Salama S, Moss L, Olde J. Quinolone use as a risk factor for nosocomial Clostridium difcileassociated diarrhea. Infect Control Hosp Epidemiol 2001; 22:5725. 58. Gerding DN. Clindamycin, cephalosporins, uoroquinolones, and Clostridium difcile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis 2004; 38:6468. 59. Gaynes R, Rimland D, Killum E, et al. Outbreak of Clostridium difcile infection in a long-term care facility: association with gatioxacin use. Clin Infect Dis 2004; 38:6405.

Downloaded from cid.oxfordjournals.org by guest on August 31, 2011

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