From the *Pediatric Infectious Diseases consultant, Children’s Hospital at the Saarland University Medical Center, Homburg/Saar; and †Pediatric Infectious Diseases, University Children’s Hospital, Heidelberg University, Heidelberg, Germany.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Arne Simon, MD, Pediatric Infectious Disease Consultant, University Children’s Hospital, Kirrberger Str. Building 9, 66421 Homburg/Saar, Germany. E-mail: Arne.Simon@uks.eu.
Classification of Multidrug-resistant Gram-negative Pathogens
Prematurely born infants treated in a neonatal intensive care units (NICUs) face an increased risk of colonization and subsequent local or systemic infection caused by multidrug-resistant Gram-negative pathogens (MDRGN).1 Current definitions of multidrug-resistant Gram-negative pathogens do not allocate these isolates to a certain class of resistance due to the underlying resistance mechanism (eg, the expression of extended spectrum β-lactamases)2 but focus on their in vitro sensitivity to 4 different classes of bactericidal antibiotics: broad spectrum penicillins (piperacillin–tazobactam), third or fourth generation cephalosporines (cefotaxime, ceftazidime and cefepime), carbapenems (in neonates meropenem) and fluoroquinolones (ciprofloxacin).3,4
A Gram-negative pathogen in vitro resistant to 3 of those classes is defined as “3MDRGN,” a pathogen with in vitro resistance to all of them, including carbapenems, as “4 MDRGN.”5
This approach seems very reasonable in terms that from a clinical perspective the underlying molecular mechanism of resistance is not as important as the remaining alternatives for first line treatment in case of infection.
One obstacle in adjusting those categories (“3 MDRGN, 4 MDRGN”) to neonatal and pediatric patients is that fluoroquinolones are not licensed for first line treatment except in selected cases such as oral treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis6 or oral outpatient treatment of pediatric cancer patients with fever and neutropenia.7 Taking into account the recommendation to use fluoroquinolones only in selected patients and not empirically in neonates, the risk of colonization with a “2MRGN,” resistant to cephalosporines and broad spectrum penicillins, needs consideration that differs substantially from that in adult intensive care unit patients.
Acquisition of Facultative Pathogens
MDRGN microflora may be acquired to a small extent from the mother in particular during the clinical setting of prolonged rupture of membranes, during labor or through direct (hands, kangarooing) and indirect (eg, breast milk)8 contacts after birth. One “open door” through which MDRGNs intrude into the NICU could easily be closed, if maternity ward personnel performed a microbiological workup (including nasal, vaginal and rectal swabs) in all pregnant women expected to deliver their child prematurely and if they communicated the results to the neonatologists.
Nosocomially acquired MDRGN are easily transmitted from patient to patient because they are capable of surviving for prolonged time periods on the hands of healthcare workers, on medical products,9 in hospital water supplies and sinks and on inanimate surfaces.10 Thus, most MDRGN pathogens colonizing premature neonates derive from the hospital environment11,12 during specialized neonatal intensive care, including mechanical ventilation, handling of vascular catheters, administration of breast milk,13 formula14 or oral medication through feeding tubes,15 skin and wound care and surgical interventions. Overcrowding and understaffing of NICUs have been determined as 1 critical environmental factor increasing the risk of an outbreak.2,16
MDRGN colonization may persist in premature infants for the complete duration of inpatient treatment. Six month after discharge, Millar et al17 detected in 26.5% of all infants colonized with multidrug resistant (MDR) Escherichia coli and in 7.1% of those with MDR Klebsiella spp colonization strains indistinguishable (by random amplified polymorphic DNA typing) from those acquired in the NICU. Until now, no decolonization regimen with proven efficacy is available for MDRGN. In 1 recent study, the oral administration of colistin resulted in the selection of colistin-resistant Klebisella spp in NICU patients.18 Empirical treatment with broad spectrum antibiotics for suspected early19 and late onset sepsis20 may foster the colonization with MDRGN, but their definite role is still controversial.17,21 During empirical treatment of suspected late onset infection, MDRGN display a selective advantage over the sensitive gastrointestinal flora of the patient.22
From Colonization to Infection
Recently published studies describe the gastrointestinal colonization pattern of premature infants treated in the NICU environment as substantially different from that of healthy breastfed newborns. Some of those studies on high-risk neonates confirmed the relatedness of pathogens isolated in regular screening programs and pathogens detected in subsequent bloodstream infections.11,23–27 This risk is of particular relevance in children colonized with Klebsiella pneumoniae,28 Klebsiella oxytoca,16 Enterobacter cloacae and Serratia marcescens.29
The choice of empiric first line therapy is of critical importance in a patient colonized with an MDRGN pathogen and developing a systemic infection. If the choice of antibiotics is not guided by the results of former colonization, the patient’s outcome may be complicated or even fatal due to inadequate first line treatment. The therapeutic mismatch during the first 2 to 3 days of the infection (until the MRD status of the pathogen has been defined in initial cultures) may be the most important reason for a complicated course, an increased length of stay in the intensive care unit, a negative long-term neurodevelopmental outcome and higher infection-related mortality in infections due to MRGN.30,31 However, the uncritical use of second or third line antibiotics (eg, carbapenems) in all patients with suspected late onset sepsis should be avoided.
Resistance to first line antibiotics may increase the probability of an epidemic isolate to survive and be transmitted from patient to patient, but it does not per se define the virulence of a pathogen.8 In a study investigating the molecular epidemiology of MDRGN in a NICU,26 clustering was detected for 78% of the 46 Enterobacter aerogenes isolates, 45% of the 49 E. cloacae isolates and 59% of the 22 K. pneumoniae isolates. Both patient-to-patient transmission and de novo acquisition of resistance played a role in the acquisition of these organisms, and the clinical significance of such acquisition varied by species. The risk of developing an invasive infection was much higher in those neonates colonized with S. marcescens (1:6) compared with E. aerogenes (1:11), K. pneumoniae (1:27) or E. cloacae (1:41). Active surveillance cultures identified colonized patients who represented the most important reservoir of MDRGN. In this regard, Härtel et al32 have recently shown that a significant proportion of all Gram-negative late onset bloodstream infections (most of them due to Klebsiella spp) occur in microclusters within 30 days after the first patient has been diagnosed.
Continuous Surveillance for MDRGN
In January 2012, the German Commission on Hospital Hygiene and Infection Prevention at the Robert Koch Institute, Berlin, extended their recommendations for neonatal intensive care (published in 2007) and announced that weekly screening for MDR pathogens should be performed in NICUs.33
This recommendation aims at 3 principal purposes: to describe the local epidemiology of MDR pathogens not only relying on results of clinical cultures; to adjust empirical treatment in colonized patients and to allow for hygiene interventions in those patients identified as colonized to prevent nosocomial transmission.
Infectious disease and hospital hygiene experts and by the public perception of recently documented outbreaks in German NICUs focus on the allocation of resources to proactive containment of MDRGNs in high-risk patient populations (“prevent disasters instead of just counting them”).34 A recent survey in 47 NICUs from the German Neonatal Network revealed that 98% of the participating units have implemented such a screening program. Thirteen percent of the participating units changed their empiric antibiotic regimen for late onset sepsis due to screening results (Härtel et al in press). Prospective data are awaited describing the epidemiology of MDRGN in German NICUs and confirming the effects of proactive hygiene interventions35 based on surveillance results36 and clinical isolates. One obstacle is that not all studies have found an acceptable positive predictive values of MDRGN detected in screening cultures.11 In addition, there is hitherto no study available, investigating the cost effectiveness of this approach.
To our knowledge, only 1 landmark study has been published, describing active continuous surveillance combined with appropriate institution of isolation precautions as potential mechanisms to control colonization and reduce infection with MDRGN in NICU patients. Benenson et al37 invented this concept reacting to a nationwide increase in patients colonized and infected with extended spectrum betalactamase-producing K. pneumonia (ESBL-KP) strains38 in Israel. Fecal ESBL-KP cultures were performed weekly on all neonates (n = 1763) over a time period of 4 years. Neonates with positive cultures were managed with contact precautions by dedicated nurses separately from other neonates. ESBL-KP acquisition decreased continuously from 94 of the 397 (24%) neonates in 2006 to 33 of the 304 (11%) in 2009 (P < 0.001, hazard ratio: 0.75, 95% confidence interval: 0.66–0.85, P < 0.001 for comparison of years). Hospital-wide ESBL-KP acquisition did not decrease outside the NICU. Pulse field gel electrophoresis identified as well-identical ESBL-KP strains as different strains from single neonates on 7 occasions. The authors concluded that ESBL-KP is probably both imported into and transmitted within the NICU. Continuous long-term surveillance with cohorting was associated with a decrease in ESBL-KP acquisition within the NICU. Clinical infection with ESBL-KP in this NICU was too infrequent for statistical analyses, appearing in 8 neonates (6 with bacteraemia and 2 with positive urine cultures).
With regard to the severe consequences of invasive infections due to MDRGN pathogens in premature neonates, every effort should be made to prevent colonization and nosocomial transmission with these bacteria. Colonized infants are at risk for MDRGN infection and represent the most important reservoir for subsequent nosocomial transmission. Surveillance may be an important part of a proactive intervention in a NICU, directing isolation procedures and the choice of empirical therapy in case of a systemic infection. Future studies should show whether monitoring of mucosal cultures prevents invasive disease.
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