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Ciprofloxacin and imipenem resistance and cross-resistance in Pseudomonas aeruginosa: A single institution experience
ARTICLE IN PRESS American Journal of Infection Control ■■ (2016) ■■-■■
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
Brief Report
Ciprofloxacin and imipenem resistance and cross-resistance in Pseudomonas aeruginosa: A single institution experience Nadim El Kary MD *, Elie El Rassy MD, MSc, Nadim Azar PhD, Jacques Choucair MD Department of Infectious Diseases, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
We conducted a pilot study to evaluate the resistance and cross-resistance of Pseudomonas aeruginosa to imipenem and ciprofloxacin. Our results highlight the importance of the judicious use of antibiotics, particularly fluoroquinolones, amidst the limited arsenal of effective antibiotics against Pseudomonas aeruginosa and the risk of cross-resistance induction. © 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
Pseudomonas aeruginosa is a pathogen that is well known for its natural resistance and various acquired resistances to many families of antibiotics.1 Its resistance to imipenem and ciprofloxacin is evolving worldwide and contributing to high morbidity and mortality rates.2 Moreover, the resistance profile of P aeruginosa varies between countries, which renders the adoption of foreign treatment recommendations inefficacious in certain circumstances. Therefore, we conducted a pilot study of the resistance and crossresistance of P aeruginosa to imipenem and ciprofloxacin in a clinical setting.
PATIENTS AND METHODS We performed a case–control study to evaluate the risk factors associated with ciprofloxacin- and imipenem-resistant P aeruginosa infections at our institution (Hotel Dieu de France University Hospital). Our study included all inpatients diagnosed with a P aeruginosa infection, defined according to Centers for Disease Control and Prevention criteria, between January and July 2013. Patients with more than a 1-month interval between 2 P aeruginosa infections were reenrolled in the study. Colonized patients were excluded. Information on age, gender, site of infection, and predetermined risk factors were obtained from the hospital medical records. Risk factors included prior antibiotic administration and hospitalization within the past 3 months, mechanical ventilation, use of immunosuppressive agents (eg, chemotherapy within the past 2
* Address correspondence to Nadim El Kary, MD, Department of Infectious Diseases, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon. E-mail address: [email protected] (N. El Kary). Conflicts of Interest: None to report.
weeks or long-term corticosteroid treatment), cancer, neutropenia, and second- or third-degree burns. Cultures were performed on a MacConkey agar. Identification and minimal inhibitory concentrations were determined by the BD Phoenix Automated Microbiology System (Franklin Lakes, NJ) and were interpreted for ciprofloxacin and imipenem (CA-SFM 2007). SPSS version 20.0 (IBM-SPSS Inc, Armonk, NY) was used for statistical analysis. Binomial variables were assessed using odds ratios (ORs) and 95% confidence intervals (CIs). Categorical data were analyzed using χ2 test or Fisher exact test, and Student t test or Wilcoxon rank-sum test were used for continuous data. A 2-tailed P value < .05 was considered statistically significant. Logistic regression method Forward LR was used for multivariate analysis. RESULTS Our study enrolled 135 patients with a mean age of 60.6 ± 21.3 years and a male-to-female ratio of 1.8. Infection with P aeruginosa most commonly occurred in the respiratory and urinary tracts (40%, and 25.9%, respectively). Other localizations included cutaneous and hematogenic infections (21.5% and 3.7%, respectively). Resistance to imipenem occurred in 18.5%, to ciprofloxacin in 8.9%, and to both antibiotics in 28.9% of cases. Univariate analysis did not demonstrate any statistically significant association between the studied risk factors and ciprofloxacin resistance. Imipenem resistance occurred in patients receiving fluoroquinolone (OR, 3.0; 95% CI, 1.1-7.6; P = .017), carbapenem (OR, 4.3; 95% CI, 1.4-12.5; P = .005), or various other antibiotics (OR, 4.4; 95% CI, 1.1-20.1; P = .038) within the past 3 months. Patients hospitalized within the past 3 months were also at risk for imipenem resistance (OR, 9.6; 95% CI, 1.2-74.5; P = .008). Combined resistance to both ciprofloxacin and imipenem occurred more often in patients who received fluoroquinolone (OR, 2.2; 95% CI, 1.0-5.1;
0196-6553/© 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc. http://dx.doi.org/10.1016/j.ajic.2016.04.246
ARTICLE IN PRESS 2
N. El Kary et al. / American Journal of Infection Control ■■ (2016) ■■-■■
P = .044) or carbapenem (OR, 6.3; 95% CI, 2.4-16.0; P < .001) within the past 3 months, patients who were hospitalized within the past 3 months (OR, 3.7, 95% CI, 1.2-11.6; P = .015), and immunocompromised patients (OR, 3.5; 95% CI, 1.5-8.0; P = .002). Multivariate analysis showed an increased resistance to imipenem (OR, 4.5; CI, 1.5-13.1; P = .006) and ciprofloxacin and imipenem (OR, 5.3; 95% CI, 2.0-13.9; P = .001) in patients with carbapenem administration within the past 3 months. On the other hand, these patients had a decreased trend for ciprofloxacin resistance (OR, 0.2; 95% CI, 0.1-1.1; P = .075). Immunocompromised patients had increased resistance to both drugs (OR, 3.3; 95% CI, 1.2-8.5; P = .013).
outer membrane proteins.11 These results explain to a large extent our findings of combined resistance to both ciprofloxacin and imipenem occurring in patients who received fluoroquinolone or carbapenem within the past 3 months. To our knowledge, this is the first clinical study that evaluates the risk factors for ciprofloxacin and imipenem resistance and crossresistance of P aeruginosa. In contrast to other, similar studies, we took into consideration colonizers and outpatient antibiotic use. We are aware that our results are limited by the small sample size and the possibility for selection bias (by allowing subjects to be included more than once). CONCLUSIONS
DISCUSSION One antibiotic of choice for P aeruginosa infections is fluoroquinolone because of its high oral bioavailability, convenient dosing, and favorable safety profile.3 Unfortunately, resistance to fluoroquinolone is associated with several risk factors, including its use during the previous 7 and 30 days, diabetes mellitus, nosocomial acquisition, and resistance to other antibiotics.4 In line with Krcmery et al,5 our data did not correlate the previous use of fluoroquinolones in P aeruginosa infections to subsequent ciprofloxacin resistance. Imipenem is another treatment option characterized by its stability to most β-lactamases secreted by P aeruginosa.6 Published literature associates imipenem resistance to previous carbapenem and vancomycin treatment, mechanical ventilation, and hospital admission during the previous year.7 Imipenem resistance occurred in our patients who received fluoroquinolone or carbapenem within the past 3 months and those hospitalized within the past 3 months. P aeruginosa may become resistant to ciprofloxacin via alteration of DNA-gyrase or topoisomerase IV, reduction in outer membrane proteins, or increased expression of multidrug-resistance efflux pumps.3 Possible mechanisms of P aeruginosa resistance to imipenem include chromosomal β-lactamase activity and reduction of outer membrane proteins.8 When dealing with 2 different antibiotic families, the most plausible mechanism is membrane permeability alterations.9 In vivo studies demonstrated that ciprofloxacin and imipenem select imipenem-resistant P aeruginosa strains. Unlike ciprofloxacin, exposure to imipenem did not induce ciprofloxacin and imipenem cross-resistance.9,10 However, more recent data attribute ciprofloxacin and imipenem cross-resistance to at least 2 independent mechanisms, where gyrA mutations induce fluoroquinolone resistance in P aeruginosa even in strains lacking
The results of this study underline the importance of judicious use of antibiotics amidst the limited arsenal of efficient antibiotic agents. The epidemiologic outcome of these resistance patterns should be assessed in prospective, randomized controlled studies, especially where antibiotic prescriptions are poorly controlled. References 1. Mérens A, Delacour H, Plésiat P, Cavallo J-D, Jeannot K. Pseudomonas aeruginosa et résistance aux antibiotiques. Rev Francoph Lab 2011;2011:49-62. 2. King A, Shannon K, Phillips I. Resistance to imipenem in Pseudomonas aeruginosa. J Antimicrob Chemother 1995;36:1037-41. 3. Piddock LJ. Mechanisms of resistance to fluoroquinolones: state-of-the-art 1992-1994. Drugs 1995;49(Suppl 2):29-35. 4. Hsu DI, Okamoto MP, Murthy R, Wong-Beringer A. Fluoroquinolone-resistant Pseudomonas aeruginosa: risk factors for acquisition and impact on outcomes. J Antimicrob Chemother 2005;55:535-41. 5. Krcmery V, Mateicka F, Krupova I, Trupl J, Kunova A. Bacteremia due to ciprofloxacin-resistant Pseudomonas aeruginosa in cancer patients: risk factors for resistance and outcome of 25 episodes. A case-control study. Infect Dis Clin Pract 1999;8:158-61. 6. Gaynes RP, Culver DH. Resistance to imipenem among selected gram-negative bacilli in the United States. Infect Control Hosp Epidemiol 1992;13:10-4. 7. Zavascki AP, Cruz RP, Goldani LZ. Risk factors for Imipenem-resistant Pseudomonas aeruginosa: a comparative analysis of two case-control studies in hospitalized patients. J Hosp Infect 2005;59:96-101. 8. Livermore DM. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1992;36:2046-8. 9. Rådberg G, Nilsson LE, Svensson S. Development of quinolone-imipenem cross-resistance in Pseudomonas aeruginosa during exposure to ciprofloxacin. Antimicrob Agents Chemother 1990;34:2142-7. 10. Michéa-Hamzehpour M, Auckenthaler R, Regamey P, Pechère JC. Resistance occurring after fluoroquinolone therapy of experimental Pseudomonas aeruginosa peritonitis. Antimicrob Agents Chemother 1987;31:1803. 11. Cambau E, Perani E, Dib C, Petinon C, Trias J, Jarlier V. Role of mutations in DNA gyrase genes in ciprofloxacin resistance of Pseudomonas aeruginosa susceptible or resistant to imipenem. Antimicrob Agents Chemother 1995;39:2248-52.
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
Brief Report
Ciprofloxacin and imipenem resistance and cross-resistance in Pseudomonas aeruginosa: A single institution experience Nadim El Kary MD *, Elie El Rassy MD, MSc, Nadim Azar PhD, Jacques Choucair MD Department of Infectious Diseases, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
We conducted a pilot study to evaluate the resistance and cross-resistance of Pseudomonas aeruginosa to imipenem and ciprofloxacin. Our results highlight the importance of the judicious use of antibiotics, particularly fluoroquinolones, amidst the limited arsenal of effective antibiotics against Pseudomonas aeruginosa and the risk of cross-resistance induction. © 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.
Pseudomonas aeruginosa is a pathogen that is well known for its natural resistance and various acquired resistances to many families of antibiotics.1 Its resistance to imipenem and ciprofloxacin is evolving worldwide and contributing to high morbidity and mortality rates.2 Moreover, the resistance profile of P aeruginosa varies between countries, which renders the adoption of foreign treatment recommendations inefficacious in certain circumstances. Therefore, we conducted a pilot study of the resistance and crossresistance of P aeruginosa to imipenem and ciprofloxacin in a clinical setting.
PATIENTS AND METHODS We performed a case–control study to evaluate the risk factors associated with ciprofloxacin- and imipenem-resistant P aeruginosa infections at our institution (Hotel Dieu de France University Hospital). Our study included all inpatients diagnosed with a P aeruginosa infection, defined according to Centers for Disease Control and Prevention criteria, between January and July 2013. Patients with more than a 1-month interval between 2 P aeruginosa infections were reenrolled in the study. Colonized patients were excluded. Information on age, gender, site of infection, and predetermined risk factors were obtained from the hospital medical records. Risk factors included prior antibiotic administration and hospitalization within the past 3 months, mechanical ventilation, use of immunosuppressive agents (eg, chemotherapy within the past 2
* Address correspondence to Nadim El Kary, MD, Department of Infectious Diseases, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon. E-mail address: [email protected] (N. El Kary). Conflicts of Interest: None to report.
weeks or long-term corticosteroid treatment), cancer, neutropenia, and second- or third-degree burns. Cultures were performed on a MacConkey agar. Identification and minimal inhibitory concentrations were determined by the BD Phoenix Automated Microbiology System (Franklin Lakes, NJ) and were interpreted for ciprofloxacin and imipenem (CA-SFM 2007). SPSS version 20.0 (IBM-SPSS Inc, Armonk, NY) was used for statistical analysis. Binomial variables were assessed using odds ratios (ORs) and 95% confidence intervals (CIs). Categorical data were analyzed using χ2 test or Fisher exact test, and Student t test or Wilcoxon rank-sum test were used for continuous data. A 2-tailed P value < .05 was considered statistically significant. Logistic regression method Forward LR was used for multivariate analysis. RESULTS Our study enrolled 135 patients with a mean age of 60.6 ± 21.3 years and a male-to-female ratio of 1.8. Infection with P aeruginosa most commonly occurred in the respiratory and urinary tracts (40%, and 25.9%, respectively). Other localizations included cutaneous and hematogenic infections (21.5% and 3.7%, respectively). Resistance to imipenem occurred in 18.5%, to ciprofloxacin in 8.9%, and to both antibiotics in 28.9% of cases. Univariate analysis did not demonstrate any statistically significant association between the studied risk factors and ciprofloxacin resistance. Imipenem resistance occurred in patients receiving fluoroquinolone (OR, 3.0; 95% CI, 1.1-7.6; P = .017), carbapenem (OR, 4.3; 95% CI, 1.4-12.5; P = .005), or various other antibiotics (OR, 4.4; 95% CI, 1.1-20.1; P = .038) within the past 3 months. Patients hospitalized within the past 3 months were also at risk for imipenem resistance (OR, 9.6; 95% CI, 1.2-74.5; P = .008). Combined resistance to both ciprofloxacin and imipenem occurred more often in patients who received fluoroquinolone (OR, 2.2; 95% CI, 1.0-5.1;
0196-6553/© 2016 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc. http://dx.doi.org/10.1016/j.ajic.2016.04.246
ARTICLE IN PRESS 2
N. El Kary et al. / American Journal of Infection Control ■■ (2016) ■■-■■
P = .044) or carbapenem (OR, 6.3; 95% CI, 2.4-16.0; P < .001) within the past 3 months, patients who were hospitalized within the past 3 months (OR, 3.7, 95% CI, 1.2-11.6; P = .015), and immunocompromised patients (OR, 3.5; 95% CI, 1.5-8.0; P = .002). Multivariate analysis showed an increased resistance to imipenem (OR, 4.5; CI, 1.5-13.1; P = .006) and ciprofloxacin and imipenem (OR, 5.3; 95% CI, 2.0-13.9; P = .001) in patients with carbapenem administration within the past 3 months. On the other hand, these patients had a decreased trend for ciprofloxacin resistance (OR, 0.2; 95% CI, 0.1-1.1; P = .075). Immunocompromised patients had increased resistance to both drugs (OR, 3.3; 95% CI, 1.2-8.5; P = .013).
outer membrane proteins.11 These results explain to a large extent our findings of combined resistance to both ciprofloxacin and imipenem occurring in patients who received fluoroquinolone or carbapenem within the past 3 months. To our knowledge, this is the first clinical study that evaluates the risk factors for ciprofloxacin and imipenem resistance and crossresistance of P aeruginosa. In contrast to other, similar studies, we took into consideration colonizers and outpatient antibiotic use. We are aware that our results are limited by the small sample size and the possibility for selection bias (by allowing subjects to be included more than once). CONCLUSIONS
DISCUSSION One antibiotic of choice for P aeruginosa infections is fluoroquinolone because of its high oral bioavailability, convenient dosing, and favorable safety profile.3 Unfortunately, resistance to fluoroquinolone is associated with several risk factors, including its use during the previous 7 and 30 days, diabetes mellitus, nosocomial acquisition, and resistance to other antibiotics.4 In line with Krcmery et al,5 our data did not correlate the previous use of fluoroquinolones in P aeruginosa infections to subsequent ciprofloxacin resistance. Imipenem is another treatment option characterized by its stability to most β-lactamases secreted by P aeruginosa.6 Published literature associates imipenem resistance to previous carbapenem and vancomycin treatment, mechanical ventilation, and hospital admission during the previous year.7 Imipenem resistance occurred in our patients who received fluoroquinolone or carbapenem within the past 3 months and those hospitalized within the past 3 months. P aeruginosa may become resistant to ciprofloxacin via alteration of DNA-gyrase or topoisomerase IV, reduction in outer membrane proteins, or increased expression of multidrug-resistance efflux pumps.3 Possible mechanisms of P aeruginosa resistance to imipenem include chromosomal β-lactamase activity and reduction of outer membrane proteins.8 When dealing with 2 different antibiotic families, the most plausible mechanism is membrane permeability alterations.9 In vivo studies demonstrated that ciprofloxacin and imipenem select imipenem-resistant P aeruginosa strains. Unlike ciprofloxacin, exposure to imipenem did not induce ciprofloxacin and imipenem cross-resistance.9,10 However, more recent data attribute ciprofloxacin and imipenem cross-resistance to at least 2 independent mechanisms, where gyrA mutations induce fluoroquinolone resistance in P aeruginosa even in strains lacking
The results of this study underline the importance of judicious use of antibiotics amidst the limited arsenal of efficient antibiotic agents. The epidemiologic outcome of these resistance patterns should be assessed in prospective, randomized controlled studies, especially where antibiotic prescriptions are poorly controlled. References 1. Mérens A, Delacour H, Plésiat P, Cavallo J-D, Jeannot K. Pseudomonas aeruginosa et résistance aux antibiotiques. Rev Francoph Lab 2011;2011:49-62. 2. King A, Shannon K, Phillips I. Resistance to imipenem in Pseudomonas aeruginosa. J Antimicrob Chemother 1995;36:1037-41. 3. Piddock LJ. Mechanisms of resistance to fluoroquinolones: state-of-the-art 1992-1994. Drugs 1995;49(Suppl 2):29-35. 4. Hsu DI, Okamoto MP, Murthy R, Wong-Beringer A. Fluoroquinolone-resistant Pseudomonas aeruginosa: risk factors for acquisition and impact on outcomes. J Antimicrob Chemother 2005;55:535-41. 5. Krcmery V, Mateicka F, Krupova I, Trupl J, Kunova A. Bacteremia due to ciprofloxacin-resistant Pseudomonas aeruginosa in cancer patients: risk factors for resistance and outcome of 25 episodes. A case-control study. Infect Dis Clin Pract 1999;8:158-61. 6. Gaynes RP, Culver DH. Resistance to imipenem among selected gram-negative bacilli in the United States. Infect Control Hosp Epidemiol 1992;13:10-4. 7. Zavascki AP, Cruz RP, Goldani LZ. Risk factors for Imipenem-resistant Pseudomonas aeruginosa: a comparative analysis of two case-control studies in hospitalized patients. J Hosp Infect 2005;59:96-101. 8. Livermore DM. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1992;36:2046-8. 9. Rådberg G, Nilsson LE, Svensson S. Development of quinolone-imipenem cross-resistance in Pseudomonas aeruginosa during exposure to ciprofloxacin. Antimicrob Agents Chemother 1990;34:2142-7. 10. Michéa-Hamzehpour M, Auckenthaler R, Regamey P, Pechère JC. Resistance occurring after fluoroquinolone therapy of experimental Pseudomonas aeruginosa peritonitis. Antimicrob Agents Chemother 1987;31:1803. 11. Cambau E, Perani E, Dib C, Petinon C, Trias J, Jarlier V. Role of mutations in DNA gyrase genes in ciprofloxacin resistance of Pseudomonas aeruginosa susceptible or resistant to imipenem. Antimicrob Agents Chemother 1995;39:2248-52.