Implementation of a PCR-based strategy to control an outbreak by Serratia marcescens in a Neonatal Intensive Care Unit.

OBJECTIVES: To evaluate the clinical and epidemiological impact of a new molecular surveillance strategy based on qPCR to control an outbreak by Serratia marcescens in a Neonatal Intensive Care Unit (NICU). METHODS: We design a specific qPCR for the detection of S. marcescens in rectal swabs of patients admitted to a NICU. We divided the surveillance study into two periods: (a) the pre-PCR, from the outbreak declaration to the qPCR introduction, and (b) the PCR period, from the introduction of the qPCR until the outbreak was solved. In all cases, S. marcescens isolates were recovered and their clonal relationship was analysed by PFGE. Control measures were implemented during the outbreak. Finally, the number of bloodstream infections (BSI) was investigated in order to evaluate the clinical impact of this molecular strategy. RESULTS: Nineteen patients colonized/infected by S. marcescens were detected in the pre-PCR period (October 2020-April 2021). On the contrary, after the PCR implementation, 16 new patients were detected. The PFGE revealed 24 different pulsotypes belonging to 7 different clonal groups, that were not overlapping at the same time. Regarding the clinical impact, 18 months after the qPCR implementation, no more outbreaks by S. marcescens have been declared in the NICU of our hospital, and only 1 episode of BSI has occurred, compared with 11 BSI episodes declared previously to the outbreak control. CONCLUSIONS: The implementation of this qPCR strategy has proved to be a useful tool to control the nosocomial spread of S. marcescens in the NICU.

Association between Vancomycin Pharmacokinetic Parameters and Clinical and Microbiological Efficacy in a Cohort of Neonatal Patients.

Vancomycin pharmacokinetic/pharmacodynamic (PK/PD) targets have not been validated in the neonatal population as no specifically designed studies are available. The main goal of this study was to analyze the therapeutic vancomycin regimen, the 24-h area under the curve (AUC24), and the trough plasma concentration (Ct) obtained that achieved clinical and microbiological effectiveness in a cohort of neonates. This was an observational, prospective, single-center study covering a period of 2 years. Eligible patients were neonates and young infants who were undergoing treatment with intravenous vancomycin for ≥72 h with ≥1 Ct available. The primary outcome was the association of Ct and AUC24 with clinical and microbiological efficacy at the beginning (early clinical evolution [ECE]) and the end (late clinical evolution [LCE]) of treatment with vancomycin. A total of 43 patients were included, 88.4% of whom were cured. In ECE, the cutoff points of the receiver operating characteristic (ROC) curve were 238 mg · h/L (sensitivity of 61% and specificity of 88%) for AUC24 and 6.8 µg/mL (sensitivity of 61% and specificity of 92%) for Ct. In LCE, the Ct value was 11 µg/mL, with a sensitivity of 80% and a specificity of 92%. In this analysis, AUC24 was not considered a good predictor. Logistic regression showed that a vancomycin Ct of ≤6.8 µg/mL was associated with an unfavorable ECE (P = 0.001), being 18 times more likely to progress poorly compared to those with higher levels. AUC24 and Ct are good predictors of ECE in this population. Concentrations close to 7 µg/mL and an AUC24 of around 240 mg · h/L 48 h after antibiotic initiation seem to be sufficient to achieve clinical cure in most cases.

Antimicrobial Defined Daily Dose in Neonatal Population: Validation in the Clinical Practice.

BACKGROUND: Currently, there is no validated method for estimating antimicrobial consumption in the neonatal population, as it exists for adults using Defined Daily Doses (DDD). In neonatology, although there are different methods, each one with advantages and disadvantages, there is no unified criterion for use. The aim of this study is to validate the neonatal DDD designed as a new standardised form of antimicrobial consumption over this population. METHODS: The validation of the neonatal DDD, Phase II of the research project, was carried out through a descriptive observational study. Periodic cut-offs were performed to collect antimicrobial prescriptions of neonates admitted to the neonatology and intensive care units of nine Spanish hospitals. The data collected included demographic variables (gestational age, postnatal age, weight and sex), antimicrobial dose, frequency and route of administration. The selection of the optimal DDD value takes into account power value, magnitude obtained from the differences in the DDD, statistical significance obtained by the Wilcoxon test and degree of agreement in the stipulated doses. RESULTS: Set of 904 prescriptions were collected and finally 860 were analysed based on the established criteria. The antimicrobials were mostly prescribed in the intensive care unit (63.1%). 32 different antimicrobials were collected, and intravenous administration was the most commonly used route. Neonatal DDD were defined for 11 different antimicrobials. A potency > 80% was obtained in 7 antibiotics. The 57.1% of the selected DDD correspond to phase I and 21.4% from phase II. CONCLUSION: DDD validation has been achieved for the majority of intravenously administered antimicrobials used in clinical practice in the neonatal population. This will make it possible to have an indicator that will be used globally to estimate the consumption of antimicrobials in this population, thus confirming its usefulness and applicability.

Antimicrobial defined daily dose in neonatal population.

BACKGROUND: Antimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates. METHODS: Neonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method. RESULTS: A total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01). CONCLUSIONS: A useful method for antimicrobial DDD measurement in neonatology has been designed to monitor antimicrobial consumption in hospital settings. It should be validated in further studies and thereby included in the design for neonatal antimicrobial stewardship programs in the future.

[Drug interactions in critically-ill patients. An important factor in the use of micafungin?]. / Interacciones farmacológicas en el paciente crítico. ¿Un factor relevante para usar micafungina?

Currently there are three main drug groups for the prevention and treatment of fungal infections: polyenes (amphotericin B deoxycholate or its lipid formulations), azoles (fluconazole, itraconazole or posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin). However, a major characteristic to be evaluated when choosing an antifungal agent -apart from antifungal spectrum, pharmacokinetics and adverse effects- is the absence of significant drug interactions. Amphotericin B lacks interactions but may cause renal dysfunction, leading to the accumulation of renally metabolized drugs. Nephrotoxicity is significantly lower with lipid formulations, especially with liposomal amphotericin B. Azoles modify the metabolism of a wide range of drugs by inhibiting their biotransformation or altering their distribution and elimination. These drugs are metabolized in the liver through the P450 cytochrome complex, inhibiting several isoenzymes, especially CYP3A4, the main drug-metabolizing enzyme. Moreover, itraconazole and posaconazole are substrates and inhibitors of the transporter protein, P-glycoprotein. Fluconazole is the azole with the fewest drug-drug interactions. The echinocandins have increased the therapeutic arsenal and a particular feature of these drugs is their safety, due to the absence of severe adverse effects and the scarce number of interactions. The echinocandin with the highest number of interactions is caspofungin. Micafungin is an echinocandin lacking in relevant interactions and consequently its dosage requires no adjustment in any of its indications. This drug can be used both in adults and in the pediatric population, including neonates.

Antimicrobial defined daily dose in neonatal population.

BACKGROUND: Antimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates. METHODS: Neonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method. RESULTS: A total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01). CONCLUSIONS: A useful method for antimicrobial DDD measurement in neonatology has been designed to monitor antimicrobial consumption in hospital settings. It should be validated in further studies and thereby included in the design for neonatal antimicrobial stewardship programs in the future.