Large Outbreak of Infection and Colonization with Gram‐Negative Pathogens Carrying theMetallo‐β‐Lactamase Gene bla IMP‐4 at a 320‐Bed Tertiary Hospital in Australia • Author(s): Sophie Herbert , MBChB, BSc, MRCP; Dag S. Halvorsen , MD, MPH; Tim Leong ,FJFICM; Clare Franklin , BSc; Glenys Harrington , RN, RM; Denis Spelman , FRACP, FRCPA,MPHSource: Infection Control and Hospital Epidemiology, Vol. 28, No. 1 (January 2007), pp. 98-101Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiologyof AmericaStable URL: http://www.jstor.org/stable/10.1086/508841 .

Accessed: 16/05/2014 15:46

Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp

.JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact support@jstor.org.

.

The University of Chicago Press and The Society for Healthcare Epidemiology of America are collaboratingwith JSTOR to digitize, preserve and extend access to Infection Control and Hospital Epidemiology.

http://www.jstor.org

This content downloaded from 193.105.154.110 on Fri, 16 May 2014 15:46:28 PMAll use subject to JSTOR Terms and Conditions

infection control and hospital epidemiology january 2007, vol. 28, no. 1

c o n c i s e c o m m u n i c a t i o n

Large Outbreak of Infectionand Colonization with Gram-NegativePathogens Carrying the Metallo-b-Lactamase Gene blaIMP-4 at a 320-BedTertiary Hospital in Australia

Sophie Herbert, MBChB, BSc, MRCP;Dag S. Halvorsen, MD, MPH; Tim Leong, FJFICM;Clare Franklin, BSc; Glenys Harrington, RN, RM;Denis Spelman, FRACP, FRCPA, MPH

A large outbreak of infection and colonization with multiple generaof gram-negative bacilli carrying the metallo-b-lactamase geneblaIMP-4 occurred in a 36-bed intensive care unit at a tertiary hos-pital in Australia. The organisms emerged rapidly, caused severeinfections, and contributed to mortality. Controlling the spread ofthese organisms remains a challenge for all staff involved.

Infect Control Hosp Epidemiol 2007; 28:98-101

The prevalence of gram-negative bacilli with acquired metallo-b-lactamase (MBL) genes is increasing worldwide.1-4 The genesconfer medium- to high-level resistance to carbapenems andall b-lactams except for aztreonam in vitro.1 MBLs are notinhibited by clavulanic acid, tazobactam, or sulbactam, but areuniversally inhibited by EDTA, which is a hallmark of thelaboratory identification.5 MBLs are encoded by transferablegenes, located on integrons, and may disseminate not onlywithin a given species of bacteria but also between differentgenera of gram-negative bacteria.1,6 MBL gene transfer isthought to be driven by extensive use of broad-spectrum ceph-alosporins and carbapenems.1

Our hospital has recently experienced a large outbreak ofinfection and colonization with multiple genera of gram-neg-ative bacilli carrying the MBL gene blaIMP-4. The objective ofthis report is to describe the outbreak, to extend the infor-mation provided in the initial report,7 and to discuss infectioncontrol aspects of the outbreak.

methods

Setting. The Alfred Hospital (Melbourne, Australia) is a320-bed, tertiary care institution with a 36-bed intensive careunit (ICU) that includes 7 isolation rooms. The ICU is dividedinto medical and surgical ICUs and specializes in trauma,burns, and heart-lung transplantation. There are approxi-mately 1,600 admissions annually, and 60% of ICU bed-daysare used by complex state-wide services.

Definitions, laboratory methods, and data collection. A pa-tient’s acquisition of an MBL-producing isolate was classifiedas “ICU related” if the organism was isolated in the ICU or

within 48 hours after ICU discharge between January 2004and August 2005; otherwise acquisition was classified as“non–ICU related” (Figure). The microbiological method-ology, the molecular typing protocols, and the clinical defi-nitions have been described elsewhere.7 Data were collectedfrom administrative and laboratory computerized databasesand clinical information from medical records and antibioticcharts.

Ongoing infection control strategies in the ICU. Infectioncontrol measures in the ICU underwent changes because ofa contemporaneous outbreak of Acinetobacter baumannii col-onization and infection. A multidisciplinary containmentgroup had been established, which emphasized enhancedcompliance with hand hygiene with alcohol-based gel, as wellas environmental cleaning. Information on the number ofnew isolates was given monthly to all staff, with reinforcementof preventive strategies. In January 2004, standard precau-tions were practiced in the ICU, and all staff wore gloveswhen caring for patients who had acquired A. baumannii.Beginning in June 2004, the following strategies were en-forced: all staff were required to wear gloves and gowns onentry to a new patient area, all staff were required to changeto new protective gear when moving to care for the nextpatient, and (beginning in March 2005) single-room isolationwas used in all wards (Figure).

Regular review of antibiotic prescriptions resulted in re-striction of the use of carbapenems: the combination of van-comycin and tobramycin replaced the combination of van-comycin and meropenem for empirical therapy for patientswith acute sepsis in March 2004. Beginning in May 2005, theprotocol for empirical therapy was changed to ticarcillin–clavulanic acid and gentamicin for inpatients with a lengthof stay of less than 7 days; vancomycin, cefepime, and cip-rofloxacin for inpatients with a length of stay of 7-28 days;and vancomycin and amikacin for inpatients with a lengthof stay of more than 28 days.

results

Sixty-two patients had an MBL-producing organism isolatedfrom a clinical sample (Table); for 40 of these 62 patients,acquisition of the organism was ICU related, according toour definition. Of the 22 patients with non–ICU related ac-quisition, 12 had a prior ICU stay, and the median time fromICU discharge to isolation of the organisms was 18 days(range, 5-54 days). Two patients had 4 different genera iso-lated in the ICU, and 3 patients had 2 different genera isolatedin the ICU, whereas 1 patient had 2 different genera isolated9 days after ICU discharge. The most commonly diagnosedinfections were ventilator-associated pneumonia among pa-tients with ICU-related acquisition (15 patients) and urinarytract infection among patients with non–ICU-related acqui-

This content downloaded from 193.105.154.110 on Fri, 16 May 2014 15:46:28 PMAll use subject to JSTOR Terms and Conditions

outbreak involving multiple genera of mbl-producing bacilli 99

figure. Epidemic curve of nosocomial spread of gram-negative bacilli harboring the metallo-b-lactamase (MBL) gene blaIMP-4. Patientsare classified into those with intensive care unit–related acquisition (ICU) and patients with non–intensive care unit–related acquisition(non–ICU) (as defined in Methods). Horizontal lines indicate time frames of implemented infection control measures, as follows: ∗restrictionof carbapenem use, ∗∗wearing of gloves and gowns by all staff when entering a new patient area in the intensive care unit, and ∗∗∗isolationof all patients with an MBL-producing organism in single-bed rooms in all wards.

sition (4 patients). The presence of MBL-producing organ-isms may have contributed to death for 12 (66.7%) of 18patients with ICU-related acquisition and for 3 (60%) of 5patients with non–ICU-related acquisition.

Seventy-two isolates of MBL-producing organisms be-longing to 8 different genera were recovered and identified(Table). Genotypic characterization confirmed the presenceof an IMP-type MBL gene in all isolates, and DNA sequencingconfirmed the presence of the MBL gene blaIMP-4 in the first19 isolates recovered. Organisms were isolated from sputumsamples ( ), wound and tissue specimens ( ),n p 28 n p 14catheter tips ( ), blood ( ), urine ( ), andn p 11 n p 8 n p 7bronchial lavage fluid ( ). Among patients with ICU-n p 4related acquisition, Serratia marcescens was the pathogen mostfrequently isolated (from sputum samples), whereas amongpatients with non–ICU-related acquisition, Pseudomonas aeru-ginosa was the pathogen most frequently isolated (from woundand tissue specimens). Resistance to carbapenems was vari-able (minimum inhibitory concentration range, 2 to x32mg/L), except among P. aeruginosa isolates, all of which dem-onstrated high-level resistance. All isolates were susceptibleto colistin except for the S. marcescens isolates.

discussion

We report a large outbreak of infection and colonization withmultiple genera of gram-negative bacilli harboring the MBLgene blaIMP-4. The outbreak commenced in the ICU, involving62 patients hospital-wide, of whom 40 had a first clinicalisolate directly associated with their ICU stay (Figure 1). The

proportion of patients with ICU-related acquisition is prob-ably an underestimate, because for 6 of the patients with non–ICU acquisition, the first clinical sample was obtained within11 days after ICU discharge, although cross-transmission be-tween patients in wards cannot be ruled out. The organismscaused severe infections and contributed to mortality.

To our knowledge, this is the largest such multigenera out-break reported and the first report to describe such a rapiddissemination of an acquired blaIMP-4 MBL determinant in 8different genera. Hirakata et al.6 reported P. aeruginosa andS. marcescens haboring blaIMP-type genes; in the outbreak wedescribe, these organisms were also the most prevalent ones.

Because of the complexity of transmission routes, the lackof identifiable risk factors, and the paucity of published re-ports on infection control issues, there is no agreement onthe optimal infection control strategy to prevent or to limitthe spread of MBL genes and/or MBL-producing organisms.

Besides restriction of carbapenem use, the introduction ofand compliance with contact precautions for all ICU patients(irrespective of culture results) was a major change. Beginningin June 2004, all staff entering a new-patient area wore glovesand gowns, and they changed protective gear when theymoved to care for the next patient. The only specific changein infection control practice that was adopted because of theoutbreak was isolation of patients in single rooms in wardsoutside the ICU. Although we had the opportunity to observea hospital-wide decline in the prevalence of MBL-producingorganisms, it was impossible to determine the effectivenessof the individual infection control measures. Use of gloves,

This content downloaded from 193.105.154.110 on Fri, 16 May 2014 15:46:28 PMAll use subject to JSTOR Terms and Conditions

100 infection control and hospital epidemiology january 2007, vol. 28, no. 1

table. Demographic and Clinical Characteristics of Patients With Nosocomially AcquiredGram-Negative Bacilli Harboring the Metallo-b-Lactamase (MBL) Gene blaIMP-4.

Characteristic

Patients withICU-relatedacquisition(n p 40)

Patients withnon–ICU-related

acquisition(n p 22)a

Male sex 28 14Age, years 48 (17-85) 48.5 (18-84)Diagnostic category

Trauma 5 6Burns 12 4Severe infection 9 2Cardiovascular surgery 7 5Others 7 5

Total length of stay, daysIn the hospital 47 (18-202) 42 (1-265)In the ICU 35 (9-124) 12 (1-70)

APACHE II score 18.5 (7-36) 16 (0-30)Time undergoing ventilation, hours 585 (1-1767) 84.5 (0-677)Length of stay before first clinical sample obtained, days

In the hospital 20.5 (6-113) 24 (1-162)In the ICU 19 (3-112) …

Clinical outcomeColonization 15 (37.5) 11 (50.0)Infection 25 (62.5) 11 (50.0)In-hospital mortality 18 (45.0) 5 (22.7)

Antibiotics received in the 14 d before first clinicalsample obtainedb

b-Lactamsc 33 (84.6) 13 (65.0)Vancomycin 29 (74.4) 14 (70.0)Quinolones 16 (41.0) 7 (35.0)Aminoglycosides 22 (56.4) 9 (45.0)Carbapenems 12 (30.8) 2 (10.0)

MBL-producing organism isolated, no. of isolatesSerratia marcescens 26 6Pseudomonas aeruginosa 6 12Klebsiella pneumoniae 7 1Escherichia coli 3 3Enterobacter cloacae 5 0Acinetobacter junii 0 1Citrobacter koseri 1 0Klebsiella oxytoca 1 0

Total no. of isolates 49 23

note. Data are no. (%) of patients or median value (range), unless indicated otherwise. “First clinicalsample” indicates the first sample from which an MBL-producing organism was isolated. APACHE II,Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit.a Twelve patients were discharged from the ICU prior to isolation of an MBL-producing organism.b Antibiotics were prescribed for 39 ICU patients and 20 non–ICU patients prior to isolation of an MBL-producing organism.c Penicillins, cephalosporins, or inhibitor-protected b-lactams.

gowns, and improved compliance with hand gel use probablylimited cross-transmission between patients.

The spread of MBL-producing organisms is thought to bedriven by use of broad-spectrum cephalosporins and car-bapenems.1 Interestingly, only 30% of the patients with ICU-related acquisition and 10% of the patients with non–ICUrelated acquisition had received carbapenem therapy within

the 2 weeks before the first clinical sample positive for anMBL-producing organism was obtained. Nouer et al.3 re-ported that quinolone use was a risk factor for acquisitionof P. aeruginosa haboring blaSPM-type and blaIMP-type genes,whereas Hirakata et al.8 did not identify use of any antibioticas a risk factor for this. The role of selective antibiotic pressurehas been questioned, as horizontal MBL gene transfer seems

This content downloaded from 193.105.154.110 on Fri, 16 May 2014 15:46:28 PMAll use subject to JSTOR Terms and Conditions

outbreak involving multiple genera of mbl-producing bacilli 101

to be the main mechanism of spread.6,8,9 Studies of antibioticrisk factors have also been criticized for having small samplesizes, for lack of molecular characterization of resistancemechanisms, and for analyzing colonizations and infectionstogether.9

An undetected environmental reservoir or a significantnumber of colonized patients may have contributed to themagnitude of the outbreak we describe; surveillance cultureswere not performed. At present, identification by means ofa molecular screening method is unrealistic, and culture withselective agar or broth is less efficient because of variablecarbapenem minimum inhibitory concentration values. Wedo not know whether a pool of organisms with the MBL genehas been established in our facility, but 6 new cases of in-fection with such organisms were identified in ICU in the 8months following the study period. There is a need for well-designed studies to identify risk factors for acquisition ofMBL-producing organisms,9 so that optimal infection controlmeasures can be directed effectively.

acknowledgment

We thank Kerrie Watson for assisting the presentation of the epidemiolog-ical data.

From the Infectious Diseases and Microbiology Department (S.H., D.S.H.,C.F., D.S.), the Intensive Care Unit (T.L.), and the Infection Control and Ep-idemiology Unit (G.H.), The Alfred Hospital, Melbourne, Victoria, Australia.

Address reprint requests to Denis Spelman, FRACP, FRCPA, MPH, InfectiousDiseases and Microbiology Department, The Alfred Hospital, CommercialRoad, Melbourne, Victoria 3004 Australia (D.Spelman@alfred.org.au).

Received February 22, 2006; accepted June 14, 2006; electronically publishedDecember 20, 2006.

� 2007 by The Society for Healthcare Epidemiology of America. All rightsreserved. 0899-823X/2007/2801-0019$15.00.

references

1. Walsh TR, Toleman MA, Poirel L, Nordmann P. Metallo-b-lactamases:the quiet before the storm? Clin Microbiol Rev 2005; 18:306-325.

2. Lee K, Lee WG, Uh Y, et al. VIM- and IMP-type metallo-b-lactamase-producing Pseudomonas spp. and Acinetobacter spp. in Korean hospitals.Emerg Infect Dis 2003; 9:868-871.

3. Nouer SA, Nucci M, de-Oliveira MP, Pellegrino FLPC, Moreira BM. Riskfactors for acquisition of multidrug-resistant Pseudomonas aeruginosa pro-ducing SPM metallo-b-lactamase. Antimicrob Agents Chemother 2005; 49:3663-3667.

4. Laupland KB, Parkins MD, Church DL, et al. Population-based epidemi-ological study of infections caused by carbapenem-resistant Pseudomonasaeruginosa in the Calgary Health Region: importance of the metallo-b-lactamase (MBL)–producing strains. J Infect Dis 2005; 192:1606-1612.

5. Lee K, Lim YS, Yong D, Yum JH, Chong Y. Evaluation of the Hodge testand the imipenem-EDTA double disk synergy test for differentiating me-tallo-b-lactamase–producing isolates of Pseudomonas spp. and Acineto-bacter spp. J Clin Microbiol 2003; 41:4623-4629.

6. Hirakata Y, Izumikawa K, Yamaguchi T, et al. Rapid detection and eval-uation of clinical characteristics of emerging multiple-drug-resistantgram-negative rods carrying the metallo-b-lactamase gene blaIMP. AntimicrobAgents Chemother 1998; 42:2006-2011.

7. Peleg AY, Franklin C, Bell JM, Spelman DW. Dissemination of the metallo-b-lactamase gene blaIMP-4 among gram-negative pathogens in a clinicalsetting in Australia. Clin Infect Dis 2005; 41:1549-1556.

8. Hirakata Y, Yamaguchi T, Nakano M, et al. Clinical and bacteriologicalcharacteristics of IMP-type metallo-b-lactamase-producing Pseudomonasaeruginosa. Clin Infect Dis 2003; 37:26-32.

9. Paterson DL. Looking for risk factors for the acquisition of antibioticresistance: a 21st-century approach. Clin Infect Dis 2002; 34:1564-1567.

This content downloaded from 193.105.154.110 on Fri, 16 May 2014 15:46:28 PMAll use subject to JSTOR Terms and Conditions