Cluster of bloodstream infections caused by KPC-2 carbapenemase-producing Klebsiella pneumoniae in Manhattan

Cluster of bloodstream infections caused by KPC-2 carbapenemaseproducing Klebsiella pneumoniae in Manhattan Abhijeet S. Nadkarni, MD, Tjark Schliep, MD, Lamia Khan, MD, and Cosmina B. Zeana, MD, MPH New York, New York

Background: Carbapenems are considered the agents of choice for treatment of serious infections caused by resistant gramnegative organisms. A new group of class A b-lactamases, known as KPC-type carbapenemases, has recently been described and poses a serious clinical challenge. Methods: Seven patients with bloodstream infections caused by Klebsiella pneumoniae isolates with decreased susceptibility to carbapenems were identified between January and April 2005 in the intensive care units of a hospital in Manhattan. Isolate identification and susceptibility testing were performed according to National Committee for Clinical Laboratory Standards methodology. All isolates were ribotyped and screened for blaKPC by polymerase chain reaction. The polymerase chain reaction product underwent nucleotide sequencing for one of the isolates. Medical records were reviewed retrospectively. Results: Six isolates were carbapenem-resistant with minimum inhibitory concentrations for imipenem of .8 mg/mL. Ribotyping showed that all isolates belonged to a single clone. All isolates possessed blaKPC and nucleotide sequencing identified the allelic type KPC-2. Patients’ median age was 68 years. The median duration of hospitalization was 25.5 days before the first positive blood culture. Five of 6 patients received previous broad-spectrum b-lactam antibiotics but none received prior carbapenems. Five of 6 isolates were susceptible to polymyxin B. Three of the 5 patients were treated with polymyxin B and 1 survived. Overall, only 2 of the 6 patients survived. Conclusion: This report describes the first outbreak of KPC-2 carbapenemase-producing K pneumoniae bloodstream infections in a hospital in Manhattan. Copyright ª 2009 Association for Professionals in Infection Control and Epidemiology, Inc. (Am J Infect Control 2009;37:121-6.)

Klebsiella pneumoniae is a well-described health care-associated pathogen causing 2% to 5% of nosocomial infections particularly those of the lower respiratory and urinary tracts.1-4 K pneumoniae ranks fourth as a cause of hospital-acquired pneumonia in the United States.5 Strains of multidrug-resistant Klebsiella have become increasingly prevalent in health care institutions in the United States and Europe.6-12 Klebsiella species carrying extended-spectrum b-lactamases are resistant to third-generation cephalosporins and other classes of antibiotics, such as monobactams, aminoglycosides, fluoroquinolones, and sulfonamides.13,14 Carbapenems are considered the agents of choice for the treatment of serious infections because of extended-spectrum b-lactamase-producing From the Harlem Hospital Center, New York, NY. Address Correspondence to Abhijeet S. Nadkarni, MD, 111 East 210th St, Bronx, NY 10467. E-mail: [email protected]. Conflicts of interest: The authors report no conflicts of interest. 0196-6553/$36.00 Copyright ª 2009 by the Association for Professionals in Infection Control and Epidemiology, Inc. doi:10.1016/j.ajic.2007.10.013

Klebsiella species. The recent emergence and spread of acquired carbapenem resistance is therefore a major concern and has been described as a ‘‘global sentinel event.’’15 Recently, 3 different new enzymes that confer resistance to carbapenems have been described in K pneumoniae isolates. These enzymes are categorized as Ambler class A and Bush functional group 2 f b-lactamases and are called KPC-enzymes.16,17 The first of these enzymes, known as KPC-1, was found in a K pneumoniae isolate from North Carolina.18 KPC-2 was found in isolates of K pneumoniae from Baltimore, Maryland,19 as well as in K oxytoca and K pneumoniae isolates from New York.20,21 More recently, an outbreak of K pneumoniae producing a new enzyme, KPC-3, was described in K pneumoniae isolates from a hospital in New York City.21 Outbreaks are often difficult to control. Sparse data exist on optimal strategies for controlling outbreaks of colonization and infection with carbapenemase-producing K pneumoniae. In this report, we describe the first outbreak of bloodstream infections caused by KPC-2 producing K pneumoniae strains that occurred in a hospital in Manhattan. Unlike the other published reports,22,23 all our isolates were recovered from blood. 121

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Table 1. Animicrobial susceptibility data for Klebsiella pneumoniae isolates from incident cases

Isolate HHKPdl1 (case 1) HHKPbl2 (case 2) HHKPBD3 (case 3) HHKPSE4 (case 4) HHKPAE5 (case 5) HHKPES6 (case 6) HHKPWF7 (case 7)

Imipenem, Meropenem, Ticarcillin/clavu- Cefepime, Amikacin, Gentamicin, Levofloxacin, Tetracycline, Susceptibility MIC MIC lanate, MIC MIC MIC MIC MIC to (mg/mL) (mg/mL) MIC (mg/mL) (mg/mL) (mg/mL) (mg/mL) (mg/mL) (mg/mL) Polymyxin B R (.16)

R (.16)

R (256)

R (.32)

R (.64)

R (.16)

R (.8)

S (2)

Not tested

I (8)

I (8)

R ($256)

R (.32)

R ($64)

R (.16)

R ($8)

S (2)

S

R ($16)

R ($16)

R ($256)

R ($32)

R ($64)

S (4)

R ($8)

R ($16)

S

R (.16)

S (,2)

R (.256)

S (,8)

R (.64)

S (,2)

R (.8)

I (8)

S

R (.4)

S (,2)

R ($256)

R ($32)

S (,8)

R ($16)

R ($8)

R ($16)

S

R ($16)

S (,2)

R ($256)

R (.32)

R ($64)

I (8)

R ($8)

R ($16)

S

R ($16)

R ($16)

R ($256)

R ($32)

R ($64)

S (4)

R ($8)

R ($16)

S

R, Resistant; S, susceptible.

MATERIALS AND METHODS The outbreak Between January 2005 and April 2005, 7 patients in the intensive care units (ICUs) at a 500-bed communityteaching hospital in Manhattan were noted to have K pneumoniae bacteremia with reduced susceptibility to carbapenems. The outbreak affected patients in the surgical and medical ICUs (SICU and MICU, respectively). There are a total of 12 beds in the SICU, 3 of which are in isolation rooms. The medical ICU contains 6 beds, 1 of which is in an isolation room. Both units are located on the same floor of the hospital. Medical residents and nursing staff often move among the 2 units, providing an opportunity for potential nosocomial spread of pathogens.

Case definition An incident case was defined as any patient in the ICUs with a noscomial infection (pneumonia, urinary tract infection, bacteremia) and with at least 1 blood culture positive for K pneumoniae expressing reduced carbapenem susceptibility. Nosocomial pneumonia, urinary tract infection, and nosocomial bloodstream infection were defined as per Centers for Disease Control and Preventon24 and National Nosocomial Surveillance System guidelines.25

Determination of clonality Isolates of K pneumoniae were identified by means of standard criteria, and susceptibility testing was performed according to National Committee for Clinical Laboratory Standards (NCCLS) methodology using the Vitek microdilution technique. Susceptibility results were defined according to established break points.26

All isolates of K pneumoniae were ribotyped with the Riboprinter Microbial Characterization System (Qualicon, Wilmington, DE). This was performed in collaboration with the division of Microbiology at SUNY-Downstate, New York.

Identification of mechanism of resistance b-lactamases were characterized by isoelectric focusing according to established methods.27 Supernatants from selected isolates were also analyzed for spectrophotometric evidence of carbapenemase activity in 50 mmol/L HEPES (pH 7.0) with 1 mmol/L ZnCl2.28 Nucleotide sequencing was performed on both the strands of the DNA from clones resulting from at least 3 independent polymerase chain reactions with the Big Dye sequencing kit and an automated DNA sequencing system 3700 (Applied Biosystems, Foster City, CA). The DNA sequences were identified by the BLAST program from the National Center for Biotechnology Information Web site (http:// www.ncbi.nlm.nih.gov/BLAST).

Review of records We performed a retrospective review of medical records, computerized medical data, and laboratory information of the 7 cases for the duration of January 2005 to April 2005. The study was reviewed and approved by the hospital Institutional Review Board. This period was chosen because of the notable increase in the number of K pneumoniae isolates with reduced carbapenem susceptibility from patients in the ICUs. Demographic and clinical data collected from each chart/ computer included age, gender, diagnosis, underlying medical conditions, clinical presentation, surgical procedures, and instrumentation. Acute Physiologic and

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Chronic Health Evaluation (APACHE II) scores were calculated for all patients. Antimicrobial use (prior and current) was examined. Antibiotics were defined as appropriate when consistent with susceptibility testing of the isolates. Information such as type of ICU, duration of ICU stay prior to the development of bacteremia, and total length of ICU stay was obtained for each patient. The final outcome of hospitalization was also noted for all cases.

RESULTS A total of 7 isolates of Klebsiella species with reduced susceptibility to carbapenems were recovered from January 2005 to April 2005 in blood cultures of patients admitted to the MICU and SICU. There were no specific rooms or locations in the SICU or MICU that were more likely to be affected. No breakdown in infection control measures has been identified. All isolates were identified as K pneumoniae. The antimicrobial susceptibilities of these isolates are shown in Table 1. Six out of 7 isolates had minimum inhibitory concentrations (MICs) $8 mg/mL for imipenem. Five out of the 6 isolates had MICs $16 mg/mL. Three out of the 7 isolates were sensitive to meropenem with MICs ,2 mg/mL while being resistant to imipenem. MICs for meropenem ranged from 8 to 16 mg/mL in 3 out of 7 isolates. Most isolates were resistant to aminoglycosides and tetracyclines. All 7 isolates were resistant to fluoroquinolones (MIC for levofloxacin, .8 mg/mL) and ticarcillin/clavulanate (MIC $ 256 mg/mL), whereas 6 out of 7 isolates were resistant to fourth-generation cephalosporins (MIC for cefepime, $8 mg/mL). The results of ribotyping revealed that 6 out of 7 isolates belonged to the same ribotype (Fig 1). The isolate HHKPAE5 was further analyzed for carbapenem susceptibility by performing an E-test and was found to be susceptible to carbapenems (MIC , 2 mg/mL), unlike the initial result obtained by the Vitek method. All the other 6 carbapenem-resistant K pneumoniae isolates belonged to a single clone. Characterization of the b-lactamases by isoelectric focusing revealed that 1 enzyme with an isoelectric point (pI) of 6.7 was present in all the 6 isolates. Nucleotide sequencing of this enzyme subsequently identified it as KPC-2, identical to the one described in the Brooklyn and Queens isolates.20 Clinical characteristics of the cases, obtained from a retrospective review of the charts/computers, are summarized in Table 2. The median age of the case patients was 68 years. All isolates were recovered from the blood and represented active infections. All isolates were acquired nosocomially, with a median duration of hospitalization of 25.5 days prior to the positive blood culture. The average APACHE II score for these patients was 27.1. The

Fig 1. Ribotyping of Klebsiella pneumoniae clinical isolates with the RiboPrinter System (Qualicon) with EcoR1 as the restriction enzyme. average length of stay in the hospital was 65 days. Two out of the 6 patients survived hospitalization. No patient had prior carbapenem use. Five out of 6 patients received broad-spectrum b-lactams (b-lactam/ b-lactamase inhibitor combination antibiotics or cephalosporins). Five out of 6 isolates were susceptible to polymyxin B. Three patients were treated with polymyxin B based on the susceptibility profile. Only 1 patient treated with polymyxin B had a successful outcome. The isolate HHKPdl1 was not tested for polymyxin B susceptibility. This patient was successfully treated with a combination of tetracycline and aminoglycoside. To our knowledge, this is the first large cluster of KPC-2 carbapenemase-producing K pneumoniae bloodstream infections reported from a hospital in Manhattan, New York.

DISCUSSION The increasing rate of resistance of gram-negative bacilli to cephalosporins and fluroquinolones29 has placed greater emphasis on carbapenems for the treatment of serious nosocomial infections. Until recently, carbapenem resistance in gram-negative pathogens was predominantly confined to Pseudomonas aeruginosa and Acinetobacter baumannii. The recent emergence of carbapenem-resistant K pneumoniae species is of major concern, posing a significant therapeutic challenge. Nosocomially acquired carbapenem-resistant K pneumoniae isolates were first seen in our institution in mid-2004. The present report describes the first outbreak of KPC-2-producing K pneumoniae bloodstream infections in a hospital in Manhattan. Over a span of 4 months, we identified 6 bloodstream infections

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Table 2. Clinical characteristics of incident cases with carbapenem-resistant K pneumoniae isolates expressing KPC-2

Case

Age/ sex Location

Comorbidities

Diagnosis

APACHE II Score

Surgeries/ instrumentation

63/M

SICU Diabetes mellitus, renalin sufficiency

Status epilepticus, stroke, acute respiratory failure, pneumonia

30

Intubation and mechanical ventilation, central venous/arterial lines, EGD, PEG,tracheostomy

HHKPbl2 (case 2)

62/F

MICU Hypertension, old stroke, pacemaker, atrial fibrillation

Altered mental status, status epilepticus, new stroke

18

HHKPBD3 (case 3)

67/F

Upper GI bleed, acute respiratory failure, pneumonia

32

HHKPSE4 (case 4)

80/F

SICU Hypertension, diabetes mellitus, CAD,CHF, end-stage renal disease SICU Hypertension, old stroke

New stroke, acute respiratory failure, pleural effusion upper GI bleed

28

HHKPAE5 (case 5)

60/F

MICU Hypertension, diabetes mellitus, gout

Altered mental status, new stroke, perforated bowel

30

HHKPES6 (case 6)

63/F

Hepatic encephalopahthy, pneumonia, pneumothorax

32

HHKPWF7 (case 7)

75/M

MICU Cirrhosis, diabetes mellitus, hypertension, pacemaker MICU Hypertension, diabetes mellitus, peptic ulcer, postpartial gastrectomy

Intubation and mechanical ventilation, central venous/arterial lines, tracheostomy Intubation and mechanical ventilation, central venous/areterial lines, IVC filter, hemodialysis Intubation and mechanical ventilation, central venous/arterial lines, EGD, tracheostomy Intubation and mechanical ventilation, tracheostomy, central venous/arterial lines, PEG, laparotomy Intubation and mechanical ventilation, central venous/arterial lines

GI bleed, acute respiratory failure, pneumonia

20

Intubation and mechanical ventilation, tracheostomy, central venous/arterial lines, EGD, colonoscopy

Hospital stay prior to bacteremia (days)

Total stay (days) Outcome

Ceftriaxone Ampicillin Ticarcillin/ clavulanate Tobramycin Ceftriaxone Ampicillin Cefepime Clindamycin Cefepime Gatifloxacin Gentamicin

18

97

Expired

15

42

Survived

42

101

Expired

Gatifloxacin Vancomycin

11

20

Expired

Ceftriaxone Cefepime Gatifloxacin Clindamycin Cefepime Gatifloxacin Vancomycin Linezolid Ampicillin Gatifloxacin Cefepime Azithromycin Aztreonam Vancomycin

16

38

Survived

51

57

Expired

16

75

Survived

APACHE, Acute Physiology and Chronic Health Evaluation; EGD, esophagogastroduodenoscopy; PEG, percutaneous esophagogastrostomy; GI, gastrointestinal; CAD, coronary artery disease; CHF, congestive heart failure; IVC, interior vena cava; SICU, surgical intensive care unit; MICU, medical intensive care unit.

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HHKPdl1 (case 1)

Antibiotics used prior to bacteremia

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caused by this multidrug-resistant K pneumoniae. All isolates belonged to a single clone. Lomaetsro et al described the spread of KPC-2 carbapenemase-producing K pneumoniae in upstate New York; only 3 cases of bacteremia were reported.30 Bratu et al31 described outbreaks in 2 hospitals in Brooklyn, New York, with KPC-2 carbapenemase-producing K pneumoniae: 9 and 13 isolates were recovered from blood in each institution, respectively. Unlike prior published reports,19,32 the isolates from our hospital had MICs for imipenem that were clearly above the break point for resistance.26 All of our 6 cases were elderly patients with multiple underlying medical comorbidities. The average hospital stay prior to the development of K pneumoniae bloodstream infection was approximately 2 weeks. All patients received broad-spectrum antibiotics, but none was treated with carbapenems prior to the development of KPC-2-producing K pneumoniae bacteremia. Treatment of infections caused by KPC-2-producing K pneumoniae is very difficult because most isolates are resistant to all b-lactam antibiotics, fluoroqinolones, and aminoglycosides. The only potentially useful drugs are polymyxin B and tigecycline. Bratu et al reported in vitro susceptibility of carbapenemresistant K pneumoniae isolates to tigecycline and polymyxin B and synergy between polymyxin B and rifampin.31 Tigecycline is the only bacteriostatic for K pneumoniae, and blood levels are very low, raising concerns about the efficacy of this drug for the treatment of bloodstream infections. Polymyxin B is currently the only available therapeutic agent with adequate blood levels for the treatment of carbapenem-resistant K pneumoniae. In our outbreak, 5 out of 6 isolates tested were susceptible to polymyxin B. Only 1 out of 3 patients treated with polymyxin B survived. The mortality associated with bloodstream infections caused by KPC-2-producing K pneumoniae is very high. Our mortality rate was 66%, which is even higher when compared with a recent report with 47% mortality in bacteremic patients.32 Carbapenem-resistant K pneumoniae possessing KPC enzymes appear to be spreading through hospitals in New York City.32 Previous studies have documented that these enzymes reside on transmissible plasmids allowing for rapid spread.33,34 No specific source or mechanism of spread was identified in this outbreak. Environment and hand cultures of employees who were in contact with the patients have not been performed. Coordinated infection control strategies such as contact isolation precautions and hand hygiene along with continued restriction of third- and fourthgeneration cephalosporins, fluroquinolones, and carbapenems were eventually successful in curbing our outbreak in April 2005.

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