Off-Label Use of Drugs and Adverse Drug Reactions in Pediatric Units: A Prospective, Multicenter Study.

BACKGROUND: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood. PATIENTS AND METHODS: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents). RESULTS: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01]. CONCLUSION: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.

MRSA infection in the neonatal intensive care unit.

Methicillin-resistant Staphylococcus aureus (MRSA) is well known as one of the most frequent etiological agents of healthcare-associated infections. The epidemiology of MRSA is evolving with emergence of community-associated MRSA, the clonal spread of some successful clones, their spillover into healthcare settings and acquisition of antibacterial drug resistances. Neonatal intensive care unit (NICU) patients are at an especially high risk of acquiring colonization and infection by MRSA. Epidemiology of MRSA in NICU can be very complex because outbreaks can overlap endemic circulation and make it difficult to trace transmission routes. Moreover, increasing prevalence of community-associated MRSA can jeopardize epidemiological investigation, screening and effectiveness of control policies. Surveillance, prevention and control strategies and clinical management have been widely studied and are still the subject of scientific debate. More data are needed to determine the most cost-effective approach to MRSA control in NICU in light of the local epidemiology.

Outbreak of colonizations by extended-spectrum ß-lactamase-producing Escherichia coli sequence type 131 in a neonatal intensive care unit, Italy.

BACKGROUND: Extended spectrum ß-lactamases (ESBLs) often associated with resistance to aminoglycosides and fluoroquinolones have recently emerged in community-associated Escherichia coli. The worldwide clonal dissemination of E. coli sequence type (ST)131 is playing a prominent role.We describe an outbreak of colonizations by ESBL-producing E. coli (ESBL-E. coli) in the neonatal intensive care unit (NICU) of the University Hospital, Palermo, Italy. METHODS: An epidemiological investigation was conducted with the support of molecular typing. All children admitted to the NICU and colonized by ESBL-E. coli between January and June 2012, were included in the study. Cases were defined as infants colonized by E. coli resistant to third generation cephalosporins and fluoroquinolones. A case-control study was also performed to identify possible risk factors. RESULTS: During the outbreak period, 15 infants were found to be colonized by ESBL-E. coli. The epidemic strain demonstrated continuous transmission throughout the outbreak period. Case-control study identified a lower birth weight as the only risk factor for colonization. The strain belonged to the sequence-type 131 community-associated clone. Transmission control interventions, including contact precautions and cohorting, restriction of the new admissions, sanitization of surfaces and equipment and targeted training sessions of the NICU staff, were successful in interrupting the outbreak. CONCLUSIONS: Although invasive infections did not develop in any of the 15 colonized neonates, our report highlights the need to strictly monitor the spill in the NICU setting of multidrug resistant community-associated organisms. Our findings confirm also the role of active surveillance in detecting the silent spread of ESBL-producing Gram negatives in a critical healthcare setting and trigging the implementation of infection control measures. As ß-lactam and fluoroquinolone resistant E. coli strains are increasingly spreading in the community, this event could become a more serious challenge.

Epidemic spread of ST1-MRSA-IVa in a neonatal intensive care unit, Italy.

BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged as an important pathogen in neonatal intensive care units (NICUs). The purposes of this study were to characterize methicillin-resistant isolates from an outbreak in a NICU, to examine the genetic traits and clonality of CA-MRSA, and to review the characteristics and outcomes of the neonatal cases and investigate the routes of entry and transmission of the MRSA outbreak strain in the NICU under study. METHODS: The study NICU practiced an active surveillance program for multidrug-resistant organisms, including weekly cultures for detection of MRSA from nasal swabs among all the admitted neonates. All first isolates from surveillance cultures and all clinical isolates were submitted for susceptibility testing and genotyping. Data from each infant's medical records were prospectively included in a database, and the clinical features and outcomes of the colonized/infected infants were assessed. RESULTS: A total of 14 infants were colonized or infected by a strain of ST1-MRSA-IVa between April and August 2011. The CA-MRSA strain appeared to have been introduced to the NICU by an infected infant transferred from another hospital. The outbreak was successfully contained by multifaceted infection control interventions. CONCLUSIONS: The results of this study confirm that NICU is a healthcare setting with a critical permeability to CA-MRSA. Active surveillance including molecular typing can help to detect and monitor the spread of antimicrobial drug-resistant organisms, and thus trigger timely control interventions.

Prevention of nosocomial infections and surveillance of emerging resistances in NICU.

Neonates hospitalized in NICU are at risk for healthcare associated infections because of their poor immune defenses, related to gestational age, colonization of mucous membranes and skin with nosocomial microorganisms, exposure to antibiotics, invasive procedures and frequent contacts with healthcare workers (HCWs). Healthcare associated infections are the major source of morbidity and mortality in NICU in the developed world. Most infections are caused by Gram-positive organisms, fulminant sepsis are often associated to Gram-negative organisms, fungal sepsis occurs frequently in ELBW infants. Hand hygiene is the most important preventive procedure, nevertheless hand hygiene compliance among HCWs remains low. Continuous educational strategies can improve hand hygiene and contribute to reducing the incidence of neonatal infections. Other important prevention strategies include early enteral feeding with human milk, minimization and safety in the use of invasive devices, limiting unnecessary empiric broadspectrum antibiotics, eventual use of lactoferrin bifidobacteria and lactobacilli, prophylactic administration of fluconazole in VLBW. Emergence of multi drug resistant organisms (MDRO) is a worrying perspective. Methicillin-resistant Staphylococcus aureus (MRSA) is an important healthcare-associated pathogen. Active surveillance culturing for MRSA carriers, in combination with contact precautions and decolonization in some hyperendemic settings, has been proved to reduce MRSA transmission and infection rates. Multidrug-resistant Gram-negatives are frequently reported. Overuse of antimicrobial drugs and crosstransmission via caregiver hands, contaminated equipment or inanimate objects are the major drivers of selection and dissemination. Strategies to control outbreaks of MDRO colonization/infection in the NICU may include performing hand hygiene, cohorting and isolating patients, screening healthcare workers and performing admission and periodic surveillance cultures.

MRSA ST22-IVa (EMRSA-15 clone) in Palermo, Italy.

Epidemic spread of methicillin-resistant Staphylococcus aureus (MRSA) strains carrying the Staphylococcal Chromosomal Cassettes (SCC) mec type IV is being increasingly reported in many geographical areas. A survey to determine the prevalence and characteristics of MRSA SCCmec IV isolates identified in four general hospitals in Palermo, Italy, was carried out. During the period February-June 2009, SCCmec type IVa has been found in 12 out of 94 isolates. Nine isolates from all hospitals and all strains from a NICU outbreak occurring in the same period were attributed with the ST22-IVa (EMRSA-15) clone. In our setting, due to the changing MRSA epidemiology, detection of SCCmec IV could be poorly predictive of CA-MRSA.

Nosocomial colonization due to imipenem-resistant Pseudomonas aeruginosa epidemiologically linked to breast milk feeding in a neonatal intensive care unit.

AIM: We describe a one-year investigation of colonization by imipenemresistant, metallo-beta-lactamase (MBL) producing Pseudomonas aeruginosa in a neonatal intensive care unit (NICU) of the University Hospital of Palermo, Italy. METHODS: A prospective epidemiological investigation was conducted in the period 2003 January to 2004 January. Rectal swabs were collected twice a week from all neonates throughout their NICU stay. MBL production by imipenem-resistant strains of P aeruginosa was detected by phenotypic and molecular methods. Pulsed field gel electrophoresis (PFGE) was carried out on all isolates of P aeruginosa. The association between risk factors and colonization by imipenem-resistant, imipenem-susceptible P aeruginosa isolates and other multidrug-resistant Gram negative (MDRGN) organisms was analyzed for variables present at admission and during the NICU stay. Data analysis was carried out by the Cox proportional hazards regression model. RESULTS: Twentytwo of 210 neonates were colonized with imipenem-resistant, MBL-producing P aeruginosa isolates and 14 by imipenem-susceptible P aeruginosa isolates. A single pulsotype, named A, was shared by all imipenem-resistant isolates. Colonization by P aeruginosa of pulsotype A was positively correlated with breast milk feeding and administration of ampicillin-sulbactam, and inversely correlated with exclusive feeding by formula. In the Cox proportional hazards regression model, birthweight of more than 2500 g and breast milk feeding were independently associated with an increased risk of colonization by MBL producing P aeruginosa. CONCLUSION: The results strongly support an association between colonization by a well-defined imipenem-resistant, MBL producing P aeruginosa strain and breast milk feeding. Such a study may highlight the need for implementation of strategies to prevent expressed breast milk from becoming a vehicle of health care-associated infections.

Surveillance of multidrug-resistant gram-negative bacilli in a neonatal intensive care unit: prominent role of cross transmission.

BACKGROUND: Multidrug-resistant gram-negative bacilli (MDRGN) are an important cause of nosocomial infections in neonatal intensive care units (NICUs). We conducted a 1-year prospective surveillance study in an NICU to assess the epidemiology of MDRGN among newborns and the relative importance of acquisition routes. METHODS: Neonates admitted at the NICU of the Dipartimento Materno-Infantile, University Hospital, Palermo, Italy, from January 7, 2003, to January 6, 2004, were included in the study. Colonization of patients with MDRGN was assessed by cultures of rectal swabs sampled twice a week. Pulsed-field gel electrophoresis was used to determine relatedness among MDRGN isolates. Extended-spectrum beta-lactamases (ESBL) and metallo-beta-lactamases (MBL) production was investigated. The association between risk factors at admission and during the NICU stay was analyzed by multivariate logistic regression analysis. RESULTS: During the 12-month period January 7, 2003, through January 6, 2004, 1021 rectal swabs were cultured from 210 infants. One hundred sixteen infants (55.2%) were colonized by MDRGN. The monthly incidence of acquisition of MDRGN ranged between 12 and 53 cases per 1000 patient-days. Eighty-four (72.4%) of the 116 patients were cross colonized. Exclusive feeding by formula was significantly associated with cross transmission (RR=1.8, P=.02). Fifty-seven (49.1%) of the 116 infants were colonized by ESBL-producing Enterobacteriaceae. Feeding by formula was significantly associated with colonization by ESBL-producing Enterobacteriaceae (RR=1.6, P=.007), whereas breastfeeding proved to be protective (RR=0.5, P=.001). Ninety-two (43.8%) of the 210 infants received antibiotics during the NICU stay, but exposure to those most frequently administered, ampicillin-sulbactam and gentamicin, was not significantly associated with MDRGN colonization. CONCLUSION: The emerging picture of this study is that spread of MDRGN in an NICU may be the result of diffuse cross transmission and, consequently, of poor infection control procedures.