An Outbreak of Extended-Spectrum β-Lactamase–Producing Klebsiella pneumoniae in aNeonatal Intensive Care UnitAuthor(s): Pranita D. Tamma, MD; Patrice Savard, MD, MSc, FRCPC; Tibor Pál, MD, PhD, DSc;Ágnes Sonnevend, MD, PhD; Trish M. Perl, MD, MSc; Aaron M. Milstone, MD, MHSSource: Infection Control and Hospital Epidemiology, Vol. 33, No. 6 (June 2012), pp. 631-634Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiologyof AmericaStable URL: http://www.jstor.org/stable/10.1086/665715 .

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infection control and hospital epidemiology june 2012, vol. 33, no. 6

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

An Outbreak of Extended-Spectrumb-Lactamase–Producing Klebsiellapneumoniae in a Neonatal IntensiveCare Unit

Pranita D. Tamma, MD;1 Patrice Savard, MD, MSc, FRCPC;2

Tibor Pal, MD, PhD, DSc;3 Agnes Sonnevend, MD, PhD;3

Trish M. Perl, MD, MSc;4 Aaron M. Milstone, MD, MHS1

We present a large outbreak of ESBL-producing Klebsiella pneumo-niae in a neonatal intensive care unit that resulted in 31 colonizedinfants, 10 invasive infections, and 5 attributable deaths over a 5-month period. Although the source of infection was unknown, over-crowding and understaffing appeared to have been aggravatingfactors.

Infect Control Hosp Epidemiol 2012;33(6):631-634

In recent years, extended spectrum b-lactamase (ESBL)–pro-ducing Klebsiella pneumoniae have emerged in healthcare fa-cilities.1,2 Antimicrobial prescribing practices and lapses ininfection control measures have likely contributed to a risingprevalence of ESBL-producing organisms.3 Because these or-ganisms are resistant to multiple antimicrobial agents, ther-apeutic options for infections caused by these organisms arelimited and the resulting morbidity and mortality alarming.4-6

The neonatal intensive care unit (NICU) can be an idealsetting for the spread of ESBL-producing organisms becauseof the prolonged hospital stays of infants, lengthy antimicro-bial courses, proximity of isolettes, and protracted use ofinvasive devices. Outbreaks in NICUs can have disastrousconsequences due to the relative immaturity of a neonate’simmune system and the lack of normal, protective intestinalflora.7 We present a NICU outbreak of ESBL-producing K.pneumoniae that resulted in 31 colonized infants, 10 invasiveinfections, and 5 attributable deaths over a 5-month period.

methods

Epidemiological Investigation

In 2011, 2 infants died within 24 hours of each other fromoverwhelming sepsis due to ESBL K. pneumoniae. Both ap-peared to be well in the preceding days, and neither infanthad a central line in place within 48 hours before the timethat ESBL K. pneumoniae was cultured from blood samples.These events occurred in a 235-bed obstetrics, gynecology,and neonatology hospital located in the Middle East, with∼9,000 deliveries per year. The 42-bed NICU has the resourcesto care for extremely premature infants. Further investiga-

tions were undertaken to identify additional cases. Cases weredefined as infants colonized or infected with K. pneumoniaesusceptible only to meropenem and amikacin. Microbiologyreports were queried, and perirectal surveillance cultures wereobtained from all infants to determine the point prevalenceof colonization with ESBL K. pneumoniae. Weekly cultureswere obtained thereafter to identify additional cases. Medicalrecords were reviewed for all colonized infants to assess acommon source. Contact precautions for all infants and strictcohorting of colonized infants were implemented with des-ignated nursing staff. Environmental samples, multidosemedication vials, and shared carrier fluid bags were cultured.Compliance with hand hygiene, contact precautions, line in-sertion, cleaning and disinfection, and breast milk storageand preparation were observed. Nursing-to-patient ratios andthe daily census were documented. Microbiology databaseswere queried as far back as January 2010 to identify additionalK. pneumoniae organisms isolated with similar susceptibilitypatterns.

Microbiological Methods

Carriage of ESBL K. pneumoniae was established by culturingperirectal swabs on blood agar plates containing cefpodoxime.Organisms growing in the presence of cefpodoxime were iso-lated and further identified using API 20E strips (Biomer-ieux). ESBL production was tested by double disk diffusionmethods. Twenty-two isolates with identical susceptibility pat-terns were available for molecular fingerprinting by pulsed fieldgel electrophoresis (PFGE) of Xba I digested chromosome.8

results

Epidemiological Investigation

Over a 13-week period in 2011, 26 infants were colonizedwith ESBL K. pneumoniae (Figure 1). At the onset of theoutbreak investigation, ESBL K. pneumoniae was isolatedfrom 35% of neonates in the NICU. After reviewing the mi-crobiology database, an additional 5 infants were identifiedas colonized or infected with ESBL K. pneumoniae in the 4previous months. No K. pneumoniae organisms meeting thecase definition were identified in 2010. Of the 31 infants fromwhom ESBL K. pneumoniae was isolated, there were 10 in-fections (Table 1). Of the 24 identified by active surveillanceas colonized with ESBL K. pneumoniae, 6 (25%) developeda subsequent infection. Overall, 1 neonate was diagnosed withmeningitis and bacteremia, 7 with bacteremia, 1 with ven-tilator-associated pneumonia, and 1 with an intraabdominalabscess. Of the 10 infants with infection, 6 died, with 5 deathsdirectly attributable to ESBL K. pneumoniae. During the firstweek of outbreak investigation, compliance with alcohol-based hand gels and use of contact precautions were ∼40%.

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632 infection control and hospital epidemiology june 2012, vol. 33, no. 6

figure 1. Extended-spectrum b-lactamase–producing Klebsiella pneumoniae colonizations and infections during the outbreak period, withblack bars representing colonization and gray bars representing infection. Neonatal intensive care unit (NICU) census during the sametime period is also shown.

Although there was an expectation for routine cleaning, therewas no written protocol for cleaning shared patient equip-ment and no documentation of compliance. Equipment likelyto be contaminated (eg, scales for weighing diapers) was ad-jacent to “clean” items (eg, medication scales). During thetime the outbreak was recognized and in the preceding 3months, the NICU routinely exceeded its daily capacity byat least 20% (Figure 1). On average, there was a 4 : 1 patient-to-nurse ratio and 3 : 1 patient-to-nurse ratio for low-acuityand high-acuity patients, respectively. Besides traditionalnursing duties, nurses were also responsible for inserting pe-ripheral intravenous lines, obtaining labs, and maintainingventilators. PFGE analysis completed on the first 22 isolates(including 7 invasive isolates) demonstrated identical strains,and the remaining isolates had indistinguishable antimicro-bial susceptibility patterns. The ESBL enzyme produced bythe outbreak strain was a cefotaximase (CTX-M). No envi-ronmental cultures yielded ESBL K. pneumoniae, despite ex-tensive sampling.

Infection Control Interventions

Daily hand hygiene observations were implemented, and ed-ucation and weekly feedback were provided. Compliance withhand disinfection and contact precautions improved dra-matically, in the range of 82%–92%, on the basis of docu-mentation by infection control practitioners. Clean equip-ment was physically separated from easily contaminatedequipment and was cleaned at scheduled intervals. Multidosevials and shared carrier fluids were discarded and no longerpermitted.

In August 2011, the NICU expanded to a capacity of 64

beds. The census ranged from 43 to 52, allowing for increasedbed space between infants and more effective cohorting. Ad-ditional ancillary healthcare workers were assigned to theNICU. Previous nursing responsibilities were shared betweenunit attendants, pharmacists, and environmental services.Rigorous efforts to recruit qualified nurses continued andreduced the ratio to 1 : 3 for low-acuity patients and 1 : 2 forthe sickest patients. Admission of new neonates was restrictedto critically ill infants who could not receive the necessarycare at neighboring healthcare facilities, and nonessential ma-ternal admissions were diverted to neighboring hospitals.There were no further cases of ESBL K. pneumoniae colonizedneonates meeting the case definition after August 2011.

discussion

We describe the management of a large NICU outbreak ofan ESBL-producing organism with a high attributable mor-tality rate. Although K. pneumoniae is part of a neonate’snormal intestinal flora, it seldom causes invasive infections.9

In contrast, the ESBL K. pneumoniae identified in the currentoutbreak was extremely aggressive as it had an attack ratefrom colonization to infection of ∼25%. The risk of infectionin colonized infants exceeds reports of infection with otherorganisms, highlighting the importance of control effortswhen ESBL organisms are identified. ESBL organisms havebeen previously shown to have mortality rates in the rangeof 22%–40%.4-6 As the world witnesses a rise in multidrug-resistant organisms coupled with a decrease in new agents totreat these infections, outbreaks due to ESBL organisms arelikely to continue. Because of their lengthy hospital stays,

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esbl outbreak in a nicu 633

table 1. Baseline Characteristics and Clinical Outcomes of the 10 Infants with Invasive Extended-Spectrumb-Lactamase–Producing Klebsiella pneumoniae Infection

InfantGestationalage, weeks

CVC ≤48 hoursbefore first

positiveclinical isolate

Type ofinfection

Age at firstpositive clinical

isolate, days

Vital status within10 days of firstpositive culture

1 28 No Bacteremia, meningitis 6 Alive2 36 No Bacteremia 15 Dead—not attributable3 25 Yes Bacteremia 4 Dead—attributable4 26 No Bacteremia 19 Dead—attributable5 32 No Bacteremia 5 Dead—attributable6 25 Yes Bacteremia 12 Alive7 30 No VAP 47 Alive8 25 Yes Intraabominal abscess 14 Dead—attributable9 28 Yes Bacteremia 39 Dead—attributable10 30 No Bacteremia 30 Alive

note. CVC, central venous catheter; VAP, ventilator-associated pneumonia.

exposure to multiple courses of antimicrobials, prolongedrequirement for invasive devices, and lack of protective en-teric flora, neonates are an especially vulnerable populationto develop colonization and infection with highly resistantgram-negative organisms and are a reservoir for ongoingtransmission.7 This may have large implications for both em-piric antibiotic choices and infection control practices, suchas cohorting, screening, and universal contact precautions.

Despite an extensive epidemiological investigation, a pointsource could not be identified in the current outbreak. Theinvestigation revealed that overcrowding and understaffingmay have been contributing factors. NICU occupation rou-tinely exceeded the standard maximum capacity by at least20%, providing conditions that likely increased the risk ofcross-transmission of pathogens. With more patients to carefor, lapses in healthcare worker aseptic technique and poorcompliance with hand hygiene and universal precautions wereevident, as observed in past outbreaks.10 The outbreak finallysubsided by increasing the interpatient distance, improvingnursing-to-patient ratios, reducing the census, and redistrib-uting the work load. In the current outbreak, understaffingwas due to challenges in employee recruitment. However, asother hospitals consider staff reductions to contain costs, theyshould ensure that attempts to decrease costs do not comeat the expense of quality patient care. Understaffing may ac-tually increase hospital expenses due to rises in nosocomialinfections from lapses in infection control practices by over-burdened employees.

acknowledgments

We thank the hospital administration and all the nurses and physicians caringfor the infants in the NICU during the time of the outbreak.

Financial support. This study was funded by a National Institutes ofHealth grant KL2RR025006 awarded to P.D.T.

Potential conflicts of interest. T.M.P. is on the advisory board for Hospiraand Pfizer and receives grant support from Merck and Sage. All other authors

report no conflicts of interest relevant to this article. All authors submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest, and theconflicts that the editors consider relevant to this article are disclosed here.

Affiliations: 1. Johns Hopkins Medical Institutions, Division of PediatricInfectious Diseases, Baltimore, Maryland; 2. Johns Hopkins Medical Insti-tutions, Department of Hospital Epidemiology and Infection Control, Bal-timore, Maryland; 3. United Arab Emirates University, Department of Mi-crobiology and Immunology, Al Ain, United Arab Emirates; 4. JohnsHopkins Medical Institutions, Departments of Medicine, Pathology, and Ep-idemiology, Baltimore, Maryland.

Address correspondence to Pranita D. Tamma, MD, Johns Hopkins Med-ical Institutions, Division of Pediatric Infectious Diseases, 200 North WolfeStreet, Suite 3155, Baltimore, MD 21287 (ptamma1@jhmi.edu).

Received December 6, 2011; accepted January 19, 2012; electronically pub-lished April 16, 2012.� 2012 by The Society for Healthcare Epidemiology of America. All rightsreserved. 0899-823X/2012/3306-0016$15.00. DOI: 10.1086/665715

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