- Email: [email protected]
Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult
International Journal of Infectious Diseases (2009) 13, e295—e298
http://intl.elsevierhealth.com/journals/ijid
CASE REPORT
Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult Successful treatment with gentamicin and colistin Shmuel Benenson a,*, Shiri Navon-Venezia b, Yehuda Carmeli c, Amos Adler a, Jacob Strahilevitz a, Allon E. Moses a, Colin Block a a Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew University Medical Center, Kiryat Hadassah, POB 12000, il-91120, Jerusalem, Israel b The Laboratory for Molecular Epidemiology and Antibiotic Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Division of Epidemiology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received 22 June 2008; received in revised form 1 January 2009; accepted 20 January 2009 Corresponding Editor: Craig Lee, Ottawa, Canada
KEYWORDS Carbapenem-resistant Klebsiella pneumoniae; Infective endocarditis; blaKPC3 gene; Colistin; Gentamicin
Summary Introduction: Enterobacteriaceae are rarely the etiologic agents of endocarditis, with Klebsiella species being especially rare. From the end of 2005, isolates of carbapenem-resistant Klebsiella pneumoniae began to appear in various hospitals across Israel, sensitive only to colistin and gentamicin. We present a case of hospital-acquired endocarditis caused by carbapenem-resistant K. pneumoniae in a young adult. Case report: An 18-year-old man with 40% full thickness burns developed acute bacterial endocarditis complicated by embolic myocardial infarction. Carbapenem-resistant K. pneumoniae carrying the blaKPC3 gene was isolated from multiple blood cultures. He recovered fully after antibiotic treatment with colistin and gentamicin. Conclusions: To our knowledge, this is the first reported case of acute bacterial endocarditis caused by carbapenem-resistant K. pneumoniae. The combination of intravenous colistin and gentamicin was effective and resulted in the cure of this patient’s endocarditis without the need for surgical intervention. # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Introduction
* Corresponding author. Tel.: +972 2 677 6543; fax: +972 2 641 9545. E-mail address: [email protected] (S. Benenson).
Klebsiella pneumoniae is a frequent cause of nosocomial bloodstream infections where the primary source is usually pneumonia, intravascular catheters or the urinary tract.
1201-9712/$36.00 # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.01.006
e296 During the 1990s, resistance to various broad-spectrum antibiotics emerged among K. pneumoniae, including resistance to the extended spectrum b-lactamases (ESBL), aminoglycosides and fluoroquinolones, leaving carbapenems as the agents of choice for the treatment of serious infections caused by these organisms. In 2000, carbapenem-resistant K. pneumoniae (CRKP) first appeared and spread rapidly in New York City hospitals.1 In late 2005 a national epidemic of nosocomial CRKP infections caused by a single strain, as determined by pulsed-field electrophoresis (PFGE), emerged in Israel. The epidemic strain was susceptible only to colistin sulfomethate sodium and gentamicin.2 Herein we present our first recognized encounter with the epidemic CRKP at our hospital–—a case that manifested itself in an unusual way: acute myocardial infarction as the presenting sign of infective endocarditis in a young adult. The patient was successfully treated with colistin and gentamicin.
Case presentation A healthy 18-year-old man was admitted to plastic surgery with 40% full thickness burns. On day 10 of his hospitalization, he underwent skin grafts to his legs and abdomen. A Pseudomonas aeruginosa burn wound infection was treated with cefepime through a peripheral venous catheter for five days postoperatively. On the 17th hospital day, high fever, chest pain, and shortness of breath supervened. On physical examination no obvious source of infection was seen. Hematological investigations revealed a white blood cell count of 31.4 109/l with 95% neutrophils and a platelet count of 1085 109/l. The serum creatinine level was 65 mmol/l and troponin was 3.47 (normal range 0—0.1 ng/ml). An electrocardiogram showed anterolateral ST elevation, consistent with anteroseptal wall acute myocardial infarction. Transthoracic echocardiography revealed segmental akinesis of the anteroseptal walls and a large 24 19 mm mobile mass under the mitral valve. Repeated peripheral blood cultures taken 12 hours apart and a culture from a burned area grew K. pneumoniae that was susceptible only to gentamicin and colistin. He was diagnosed with hospital-acquired CRKP mitral valve endocarditis with suspected emboli to the coronary artery. The patient was treated with gentamicin (1.7 mg/kg) and colistin (two million units), both every 8 hours. Trough plasma gentamicin levels were between 1 and 2 mg/ml. Because the patient was planned for additional debridement of burns, with its attendant risk of repeated bacteremic episodes, a decision was made in favor of conservative therapy of the endocarditis. After three weeks of antibiotic treatment, acute renal failure developed (creatinine 427 mmol/l) and gentamicin treatment was stopped. Colistin treatment was continued for a total duration of six weeks and renal function returned to normal. Follow-up blood cultures were negative. Echocardiography done one year later showed billowing of the mitral valve, mildly global hypokinesia of the left ventricle, and complete disappearance of the vegetation.
Methods and results Antibiotic susceptibilities were determined by disk diffusion assay and also by Vitek-2 (BioMerieux Inc., Marcy l’Etoile,
S. Benenson et al. France). Minimum inhibitory concentrations (MICs) of carbapenems, colistin, gentamicin and tigecycline were determined by E-test (AB Biodisk, Solna, Sweden). CLSI breakpoints3 were used for carbapenems and gentamicin, the BSAC breakpoint for colistin (http://www.bsac.org.uk), and the EUCAST value for tigecycline (http://www.eucast.org), since CLSI has no definitions for the latter two. The susceptibility results for the K. pneumoniae isolate are presented in Table 1. The isolate was resistant to cephalosporins, piperacillin/tazobactam, quinolones and amikacin, as well as highly resistant to carbapenems. The organism was susceptible only to colistin and gentamicin with intermediate susceptibility to tigecycline. Genomic DNA of the clinical isolate was analyzed by PFGE and revealed a SpeI endonuclease-restricted DNA profile identical to clone Q, the major CRKP clone reported in Israel.2 Identification of carbapenemase genes was performed on cell lysates by PCR using specific primers designed to identify known class A b-lactamase genes, including blaKPC, blaSME, blaIMI, and blaNMC, as previously described.4 The K. pneumoniae isolate had the carbapenemase gene blaKPC, which was characterized by nucleotide acid and deduced protein sequences as KPC-3.
Discussion We have presented what is, to the best of our knowledge, the first reported case of endocarditis caused by carbapenemresistant K. pneumoniae. We assume that the source of the CRKP bacteremia was preceding burned skin colonization. PFGE showed the isolate to be identical to the epidemic Israeli clone of CRKP, carrying the KPC-3 gene. Infection by this resistant pathogen is an emerging problem in hospitals across Israel; it mainly affects the elderly and is a predictor of death.5 There are few antibiotic options because it is susceptible only to colistin and gentamicin and on the breakpoint of susceptibility to tigecycline, as demonstrated by the present case. Detection of KPC-mediated resistance to carbapenems by some routine clinical microbiology techniques is not straightforward. Some automated and non-automated methods have sensitivities for KPC detection as low as about 40% when imipenem or meropenem are tested alone.6,7 Among the Table 1 Susceptibility results for the Klebsiella pneumoniae isolate Antibiotic
Susceptibility break point, mg/ml a
MIC mg/ml b
Colistin Gentamicin Tigecycline Meropenem Imipenem Ertapenem
4 2 1 4 4 2
0.5 2.0 1.5 >32 >32 >32
MIC, minimum inhibitory concentration. a CLSI breakpoints3 were used for the carbapenems and gentamicin, the BSAC breakpoint for colistin (http://www.bsac.org.uk), and the EUCAST value for tigecycline (http:// www.eucast.org). CLSI has no definitions for the latter two. b Tested with E-test.
Carbapenem-resistant K. pneumoniae endocarditis carbapenems, ertapenem is probably the best indicator, with sensitivities and specificities of 90% and 84%, respectively, by a range of methods. Hence, ertapenem should be included in susceptibility testing of all clinical isolates of Enterobacteriaceae. Endocarditis is a rare complication of major burn injury, with an incidence of 1.3% in one study.8 Although nonsalmonella Enterobacteriaceae are common pathogens in nosocomial bloodstream infections, they rarely cause endocarditis, possibly due to their low affinity to endocardial tissue.9 K. pneumoniae endocarditis is particularly rare, yet, the associated mortality is 49%.10 When endocarditis is caused by an ESBL-producing K. pneumoniae, a carbapenem is likely the antibiotic of choice.11 Because many patients fail to respond to medical treatment alone, early cardiac surgery, in combination with prolonged courses of combined antibiotic therapy, is a cornerstone of treatment.12 The choice of a combination of gentamicin and colistin in our patient was based on the lack of other options and the dearth of information regarding monotherapy with either agent alone. Gentamicin monotherapy was not effective in sterilizing vegetations caused by Enterobacteriaceae in animal models of infective endocarditis, but was synergistic with cell wall active drugs in clearing the infection.13,14 Thus, a combination of gentamicin with a b-lactam is recommended for K. pneumoniae endocarditis.12 Data on the efficacy of colistin for the treatment of endocarditis are scarce. The in vivo activity of colistin was evaluated in an experimental rabbit model of Acinetobacter baumannii endocarditis with a strain susceptible to colistin and intermediate to imipenem. Compared to a control group, colistin was effective ( p < 0.05) in bacterial clearance from the blood, but was less effective in clearing the bacteria from vegetations.15 Colistin increases the permeability of the outer membrane of Gram-negative bacteria, thereby it might be synergistic with other antibiotics, such as aminoglycosides, by facilitating the penetration of the latter through the membrane. Few clinical studies have evaluated the synergistic activity of colistin with other antimicrobial agents; most of them are limited by the lack of a control group. There are two case reports of successful treatment of P. aeruginosa endocarditis by a regimen comprising colistin with either tobramycin and rifampin or amikacin.16,17 Another antimicrobial regimen that has demonstrated synergy against CRKP during in vitro testing is the combination of polymyxin B and rifampin.18 Since CRKP isolates are not universally susceptible to polymyxin and gentamicin, the therapeutic regimens should definitely be based on isolate-specific susceptibility data. The most notable finding of the present study is that the combination of colistin and gentamicin was effective and resulted in the cure of this patient’s endocarditis, without the need for surgical intervention. In the era of multi-drug resistance, this combination, which should be given cautiously because of its nephrotoxic potential, is a rational option for severe infections. Conflict of interest: No conflict of interest to declare.
e297
2.
3.
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
References 1. Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M, et al. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in
New York City: a new threat to our antibiotic armamentarium. Arch Intern Med 2005;165:1430—5. Leavitt A, Navon-Venezia S, Chmelnitsky I, Schwaber MJ, Carmeli Y. Emergence of KPC-2 and KPC-3 in carbapenem-resistant Klebsiella pneumoniae strains in an Israeli hospital. Antimicrob Agents Chemother 2007;51:3026—9. Clinical Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 15th Informational supplement (M100-S17). Wayne, PA: CLSI; 2007. Navon-Venezia S, Chmelnitsky I, Leavitt A, Schwaber MJ, Schwartz D, Carmeli Y. Plasmid-mediated imipenem-hydrolyzing enzyme KPC-2 among multiple carbapenem-resistant Escherichia coli clones in Israel. Antimicrob Agents Chemother 2006;50:3098— 101. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother 2008;52:1028—33. Tenover FC, Kalsi RK, Williams PP, Carey RB, Stocker S, Lonsway D, et al. Carbapenem resistance in Klebsiella pneumoniae not detected by automated susceptibility testing. Emerg Infect Dis 2006;12:1209—13. Anderson KF, Lonsway DR, Rasheed JK, Biddle J, Jensen B, McDougal LK, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J Clin Microbiol 2007;45:2723—5. Baskin TW, Rosenthal A, Pruitt BA. Acute bacterial endocarditis: a silent source of sepsis in the burn patient. Ann Surg 1976;184:618—21. Trexler Hessen M, Abrutyn E. Gram-negative bacterial endocarditis. In: Kaye D, editor. Infective endocarditis. New York: Raven Press; 1992. Anderson MJ, Janoff EN. Klebsiella endocarditis: report of two cases and review. Clin Infect Dis 1998;26:468—74. Zimhony O, Chmelnitsky I, Bardenstein R, Goland S, Hammer Muntz O, Navon Venezia S, et al. Endocarditis caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae: emergence of resistance to ciprofloxacin and piperacillin—tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother 2006;50:3179—82. Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Bolger AF, Levison ME, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394—434. Mentec H, Vallois JM, Bure A, Saleh-Mghir A, Jehl F, Carbon C. Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant. Antimicrob Agents Chemother 1992;36:1883—9. Kobasa WD, Kaye D. Aztreonam, cefoperazone, and gentamicin in the treatment of experimental Enterobacter aerogenes endocarditis in rabbits. Antimicrob Agents Chemother 1983;24:321—4. Rodriguez-Hernandez MJ, Jimenez-Mejias ME, Pichardo C, Cuberos L, Garcia-Curiel A, Pachon J. Colistin efficacy in an experimental model of Acinetobacter baumannii endocarditis. Clin Microbiol Infect 2004;10:581—4. Dor V, Gioanni T, Mermet B, Diesnis P, Kreitmann P, Schmitt R, et al. [Pseudomonas endocarditis on aortic valve prosthesis. Successful treatment by association of tobramycin—rifampicin—colistin and two reinterventions. Follow-up of 5 years (author’s transl)]. Ann Chir 1981;35:163—5.
e298 17. Tascini C, Ferranti S, Messina F, Menichetti F. In vitro and in vivo synergistic activity of colistin, rifampin, and amikacin against a multiresistant Pseudomonas aeruginosa isolate. Clin Microbiol Infect 2000;6:690—1.
S. Benenson et al. 18. Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, et al. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother 2005;56:128—32.
http://intl.elsevierhealth.com/journals/ijid
CASE REPORT
Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult Successful treatment with gentamicin and colistin Shmuel Benenson a,*, Shiri Navon-Venezia b, Yehuda Carmeli c, Amos Adler a, Jacob Strahilevitz a, Allon E. Moses a, Colin Block a a Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew University Medical Center, Kiryat Hadassah, POB 12000, il-91120, Jerusalem, Israel b The Laboratory for Molecular Epidemiology and Antibiotic Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Division of Epidemiology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received 22 June 2008; received in revised form 1 January 2009; accepted 20 January 2009 Corresponding Editor: Craig Lee, Ottawa, Canada
KEYWORDS Carbapenem-resistant Klebsiella pneumoniae; Infective endocarditis; blaKPC3 gene; Colistin; Gentamicin
Summary Introduction: Enterobacteriaceae are rarely the etiologic agents of endocarditis, with Klebsiella species being especially rare. From the end of 2005, isolates of carbapenem-resistant Klebsiella pneumoniae began to appear in various hospitals across Israel, sensitive only to colistin and gentamicin. We present a case of hospital-acquired endocarditis caused by carbapenem-resistant K. pneumoniae in a young adult. Case report: An 18-year-old man with 40% full thickness burns developed acute bacterial endocarditis complicated by embolic myocardial infarction. Carbapenem-resistant K. pneumoniae carrying the blaKPC3 gene was isolated from multiple blood cultures. He recovered fully after antibiotic treatment with colistin and gentamicin. Conclusions: To our knowledge, this is the first reported case of acute bacterial endocarditis caused by carbapenem-resistant K. pneumoniae. The combination of intravenous colistin and gentamicin was effective and resulted in the cure of this patient’s endocarditis without the need for surgical intervention. # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Introduction
* Corresponding author. Tel.: +972 2 677 6543; fax: +972 2 641 9545. E-mail address: [email protected] (S. Benenson).
Klebsiella pneumoniae is a frequent cause of nosocomial bloodstream infections where the primary source is usually pneumonia, intravascular catheters or the urinary tract.
1201-9712/$36.00 # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.01.006
e296 During the 1990s, resistance to various broad-spectrum antibiotics emerged among K. pneumoniae, including resistance to the extended spectrum b-lactamases (ESBL), aminoglycosides and fluoroquinolones, leaving carbapenems as the agents of choice for the treatment of serious infections caused by these organisms. In 2000, carbapenem-resistant K. pneumoniae (CRKP) first appeared and spread rapidly in New York City hospitals.1 In late 2005 a national epidemic of nosocomial CRKP infections caused by a single strain, as determined by pulsed-field electrophoresis (PFGE), emerged in Israel. The epidemic strain was susceptible only to colistin sulfomethate sodium and gentamicin.2 Herein we present our first recognized encounter with the epidemic CRKP at our hospital–—a case that manifested itself in an unusual way: acute myocardial infarction as the presenting sign of infective endocarditis in a young adult. The patient was successfully treated with colistin and gentamicin.
Case presentation A healthy 18-year-old man was admitted to plastic surgery with 40% full thickness burns. On day 10 of his hospitalization, he underwent skin grafts to his legs and abdomen. A Pseudomonas aeruginosa burn wound infection was treated with cefepime through a peripheral venous catheter for five days postoperatively. On the 17th hospital day, high fever, chest pain, and shortness of breath supervened. On physical examination no obvious source of infection was seen. Hematological investigations revealed a white blood cell count of 31.4 109/l with 95% neutrophils and a platelet count of 1085 109/l. The serum creatinine level was 65 mmol/l and troponin was 3.47 (normal range 0—0.1 ng/ml). An electrocardiogram showed anterolateral ST elevation, consistent with anteroseptal wall acute myocardial infarction. Transthoracic echocardiography revealed segmental akinesis of the anteroseptal walls and a large 24 19 mm mobile mass under the mitral valve. Repeated peripheral blood cultures taken 12 hours apart and a culture from a burned area grew K. pneumoniae that was susceptible only to gentamicin and colistin. He was diagnosed with hospital-acquired CRKP mitral valve endocarditis with suspected emboli to the coronary artery. The patient was treated with gentamicin (1.7 mg/kg) and colistin (two million units), both every 8 hours. Trough plasma gentamicin levels were between 1 and 2 mg/ml. Because the patient was planned for additional debridement of burns, with its attendant risk of repeated bacteremic episodes, a decision was made in favor of conservative therapy of the endocarditis. After three weeks of antibiotic treatment, acute renal failure developed (creatinine 427 mmol/l) and gentamicin treatment was stopped. Colistin treatment was continued for a total duration of six weeks and renal function returned to normal. Follow-up blood cultures were negative. Echocardiography done one year later showed billowing of the mitral valve, mildly global hypokinesia of the left ventricle, and complete disappearance of the vegetation.
Methods and results Antibiotic susceptibilities were determined by disk diffusion assay and also by Vitek-2 (BioMerieux Inc., Marcy l’Etoile,
S. Benenson et al. France). Minimum inhibitory concentrations (MICs) of carbapenems, colistin, gentamicin and tigecycline were determined by E-test (AB Biodisk, Solna, Sweden). CLSI breakpoints3 were used for carbapenems and gentamicin, the BSAC breakpoint for colistin (http://www.bsac.org.uk), and the EUCAST value for tigecycline (http://www.eucast.org), since CLSI has no definitions for the latter two. The susceptibility results for the K. pneumoniae isolate are presented in Table 1. The isolate was resistant to cephalosporins, piperacillin/tazobactam, quinolones and amikacin, as well as highly resistant to carbapenems. The organism was susceptible only to colistin and gentamicin with intermediate susceptibility to tigecycline. Genomic DNA of the clinical isolate was analyzed by PFGE and revealed a SpeI endonuclease-restricted DNA profile identical to clone Q, the major CRKP clone reported in Israel.2 Identification of carbapenemase genes was performed on cell lysates by PCR using specific primers designed to identify known class A b-lactamase genes, including blaKPC, blaSME, blaIMI, and blaNMC, as previously described.4 The K. pneumoniae isolate had the carbapenemase gene blaKPC, which was characterized by nucleotide acid and deduced protein sequences as KPC-3.
Discussion We have presented what is, to the best of our knowledge, the first reported case of endocarditis caused by carbapenemresistant K. pneumoniae. We assume that the source of the CRKP bacteremia was preceding burned skin colonization. PFGE showed the isolate to be identical to the epidemic Israeli clone of CRKP, carrying the KPC-3 gene. Infection by this resistant pathogen is an emerging problem in hospitals across Israel; it mainly affects the elderly and is a predictor of death.5 There are few antibiotic options because it is susceptible only to colistin and gentamicin and on the breakpoint of susceptibility to tigecycline, as demonstrated by the present case. Detection of KPC-mediated resistance to carbapenems by some routine clinical microbiology techniques is not straightforward. Some automated and non-automated methods have sensitivities for KPC detection as low as about 40% when imipenem or meropenem are tested alone.6,7 Among the Table 1 Susceptibility results for the Klebsiella pneumoniae isolate Antibiotic
Susceptibility break point, mg/ml a
MIC mg/ml b
Colistin Gentamicin Tigecycline Meropenem Imipenem Ertapenem
4 2 1 4 4 2
0.5 2.0 1.5 >32 >32 >32
MIC, minimum inhibitory concentration. a CLSI breakpoints3 were used for the carbapenems and gentamicin, the BSAC breakpoint for colistin (http://www.bsac.org.uk), and the EUCAST value for tigecycline (http:// www.eucast.org). CLSI has no definitions for the latter two. b Tested with E-test.
Carbapenem-resistant K. pneumoniae endocarditis carbapenems, ertapenem is probably the best indicator, with sensitivities and specificities of 90% and 84%, respectively, by a range of methods. Hence, ertapenem should be included in susceptibility testing of all clinical isolates of Enterobacteriaceae. Endocarditis is a rare complication of major burn injury, with an incidence of 1.3% in one study.8 Although nonsalmonella Enterobacteriaceae are common pathogens in nosocomial bloodstream infections, they rarely cause endocarditis, possibly due to their low affinity to endocardial tissue.9 K. pneumoniae endocarditis is particularly rare, yet, the associated mortality is 49%.10 When endocarditis is caused by an ESBL-producing K. pneumoniae, a carbapenem is likely the antibiotic of choice.11 Because many patients fail to respond to medical treatment alone, early cardiac surgery, in combination with prolonged courses of combined antibiotic therapy, is a cornerstone of treatment.12 The choice of a combination of gentamicin and colistin in our patient was based on the lack of other options and the dearth of information regarding monotherapy with either agent alone. Gentamicin monotherapy was not effective in sterilizing vegetations caused by Enterobacteriaceae in animal models of infective endocarditis, but was synergistic with cell wall active drugs in clearing the infection.13,14 Thus, a combination of gentamicin with a b-lactam is recommended for K. pneumoniae endocarditis.12 Data on the efficacy of colistin for the treatment of endocarditis are scarce. The in vivo activity of colistin was evaluated in an experimental rabbit model of Acinetobacter baumannii endocarditis with a strain susceptible to colistin and intermediate to imipenem. Compared to a control group, colistin was effective ( p < 0.05) in bacterial clearance from the blood, but was less effective in clearing the bacteria from vegetations.15 Colistin increases the permeability of the outer membrane of Gram-negative bacteria, thereby it might be synergistic with other antibiotics, such as aminoglycosides, by facilitating the penetration of the latter through the membrane. Few clinical studies have evaluated the synergistic activity of colistin with other antimicrobial agents; most of them are limited by the lack of a control group. There are two case reports of successful treatment of P. aeruginosa endocarditis by a regimen comprising colistin with either tobramycin and rifampin or amikacin.16,17 Another antimicrobial regimen that has demonstrated synergy against CRKP during in vitro testing is the combination of polymyxin B and rifampin.18 Since CRKP isolates are not universally susceptible to polymyxin and gentamicin, the therapeutic regimens should definitely be based on isolate-specific susceptibility data. The most notable finding of the present study is that the combination of colistin and gentamicin was effective and resulted in the cure of this patient’s endocarditis, without the need for surgical intervention. In the era of multi-drug resistance, this combination, which should be given cautiously because of its nephrotoxic potential, is a rational option for severe infections. Conflict of interest: No conflict of interest to declare.
e297
2.
3.
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
References 1. Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M, et al. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in
New York City: a new threat to our antibiotic armamentarium. Arch Intern Med 2005;165:1430—5. Leavitt A, Navon-Venezia S, Chmelnitsky I, Schwaber MJ, Carmeli Y. Emergence of KPC-2 and KPC-3 in carbapenem-resistant Klebsiella pneumoniae strains in an Israeli hospital. Antimicrob Agents Chemother 2007;51:3026—9. Clinical Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 15th Informational supplement (M100-S17). Wayne, PA: CLSI; 2007. Navon-Venezia S, Chmelnitsky I, Leavitt A, Schwaber MJ, Schwartz D, Carmeli Y. Plasmid-mediated imipenem-hydrolyzing enzyme KPC-2 among multiple carbapenem-resistant Escherichia coli clones in Israel. Antimicrob Agents Chemother 2006;50:3098— 101. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality. Antimicrob Agents Chemother 2008;52:1028—33. Tenover FC, Kalsi RK, Williams PP, Carey RB, Stocker S, Lonsway D, et al. Carbapenem resistance in Klebsiella pneumoniae not detected by automated susceptibility testing. Emerg Infect Dis 2006;12:1209—13. Anderson KF, Lonsway DR, Rasheed JK, Biddle J, Jensen B, McDougal LK, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J Clin Microbiol 2007;45:2723—5. Baskin TW, Rosenthal A, Pruitt BA. Acute bacterial endocarditis: a silent source of sepsis in the burn patient. Ann Surg 1976;184:618—21. Trexler Hessen M, Abrutyn E. Gram-negative bacterial endocarditis. In: Kaye D, editor. Infective endocarditis. New York: Raven Press; 1992. Anderson MJ, Janoff EN. Klebsiella endocarditis: report of two cases and review. Clin Infect Dis 1998;26:468—74. Zimhony O, Chmelnitsky I, Bardenstein R, Goland S, Hammer Muntz O, Navon Venezia S, et al. Endocarditis caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae: emergence of resistance to ciprofloxacin and piperacillin—tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother 2006;50:3179—82. Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Bolger AF, Levison ME, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394—434. Mentec H, Vallois JM, Bure A, Saleh-Mghir A, Jehl F, Carbon C. Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant. Antimicrob Agents Chemother 1992;36:1883—9. Kobasa WD, Kaye D. Aztreonam, cefoperazone, and gentamicin in the treatment of experimental Enterobacter aerogenes endocarditis in rabbits. Antimicrob Agents Chemother 1983;24:321—4. Rodriguez-Hernandez MJ, Jimenez-Mejias ME, Pichardo C, Cuberos L, Garcia-Curiel A, Pachon J. Colistin efficacy in an experimental model of Acinetobacter baumannii endocarditis. Clin Microbiol Infect 2004;10:581—4. Dor V, Gioanni T, Mermet B, Diesnis P, Kreitmann P, Schmitt R, et al. [Pseudomonas endocarditis on aortic valve prosthesis. Successful treatment by association of tobramycin—rifampicin—colistin and two reinterventions. Follow-up of 5 years (author’s transl)]. Ann Chir 1981;35:163—5.
e298 17. Tascini C, Ferranti S, Messina F, Menichetti F. In vitro and in vivo synergistic activity of colistin, rifampin, and amikacin against a multiresistant Pseudomonas aeruginosa isolate. Clin Microbiol Infect 2000;6:690—1.
S. Benenson et al. 18. Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, et al. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother 2005;56:128—32.