Jennifer Le

Urinary Tract Infections During Pregnancy

OBJECTIVE To provide a comprehensive review of urinary tract infections (UTIs) during pregnancy. All aspects of UTIs, including epidemiology, pathogenesis, resistance, clinical features, diagnosis, treatment, and prevention, were reviewed. DATA SOURCES MEDLINE (1966–August 2003) and Cochrane Library searches were performed using the key search terms urinary tract infection, pyelonephritis, cystitis, asymptomatic bacteriuria, and resistance. STUDY SELECTION AND DATA EXTRACTION All article abstracts were evaluated for relevance. Only articles pertaining to pregnancy were included. The majority of published literature were review articles; the number of original clinical studies was limited. DATA SYNTHESIS UTIs are the most common bacterial infections during pregnancy. They are characterized by the presence of significant bacteria anywhere along the urinary tract. Pyelonephritis is the most common severe bacterial infection that can lead to perinatal and maternal complications including premature delivery, infants with low birth weight, fetal mortality, preeclampsia, pregnancy-induced hypertension, anemia, thrombocytopenia, and transient renal insufficiency. Enterobacteriaceae account for 90% of UTIs. The common antibiotics used are nitrofurantoin, cefazolin, cephalexin, ceftriaxone, and gentamicin. CONCLUSIONS Therapeutic management of UTIs in pregnancy requires proper diagnostic workup and thorough understanding of antimicrobial agents to optimize maternal outcome, ensure safety to the fetus, and prevent complications that lead to significant morbidity and mortality in both the fetus and the mother.

Adverse Drug Reactions Among Children Over a 10-Year Period

OBJECTIVES. This study was designed to evaluate (1) the incidence and common types of adverse drug reactions among hospitalized children, (2) the frequency of adverse drug reaction reporting by health care providers, and (3) the follow-up processes resulting from adverse drug reactions. METHODS. A retrospective cohort study of pediatric patients who experienced an adverse drug reaction between January 1, 1995, and December 31, 2004, was conducted at a community-based, tertiary care, childrens teaching hospital. RESULTS. A total of 1087 adverse drug reactions were reported; the overall incidence was 1.6%. The severity of most adverse drug reactions was low (levels 1–3: 89%; high levels 4–6: 11%). Adverse drug reactions with low severity were significantly more common in both the general pediatric unit and the NICU. Adverse reactions resulting from use of antibiotics (particularly penicillins, cephalosporins, and vancomycin) were usually mild. In contrast, adverse drug reactions rated high in severity were significantly more common among reactions that led to hospital admission or occurred during surgery and among certain drug classes, including anticonvulsants and antineoplastic agents. Adverse drug reactions were reported by pharmacists (89%), nurses (10%), and physicians (<1%). Although documentation of physician notification occurred for 93% of adverse drug reactions, only 29% of cases were documented in the patients medical chart, 13% included follow-up education for individuals involved, and 10% were updated in the allergy profile of the hospital computer system. CONCLUSION. Measures to improve detection and reporting of adverse drug reactions by all health care professionals should be undertaken, to enhance our understanding of the nature and impact of these reactions in children.

Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children.

OBJECTIVE To determine the incidence of vancomycin-associated nephrotoxicity in children and to examine potential risk factors for nephrotoxicity, including average serum trough concentrations ≥ 15 mg/L. STUDY DESIGN Patients ≥ 1 week old to ≤ 19 years with normal baseline serum creatinine values who received vancomycin for ≥ 48 hours between December 2007 and April 2009 were retrospectively evaluated. Nephrotoxicity was defined as a serum creatinine increase of ≥ 0.5 mg/dL or ≥ 50% baseline increase over 2 days. Patients with average serum trough concentrations ≥ 15 mg/L were compared with a lower trough group. RESULTS Nephrotoxicity occurred in 14% of 167 patients. More patients who attained high average (≥ 15 mg/L) rather than low average (<15 mg/L) vancomycin troughs had nephrotoxicity (28% versus 7.3%, P = .0001). Using multivariable regression analysis, patients with high troughs and those receiving furosemide in the intensive care unit were more likely to have nephrotoxicity (OR, 3.27 [95% CI, 1.19 to 8.95], P = .021, and odds ratio, 9.45 [95% confidence interval, 3.44 to 26.00], P < .0001, respectively). CONCLUSIONS Renal function and serum troughs in children receiving vancomycin, especially those with targeted troughs of ≥ 15 mg/L, in intensive care, and receiving furosemide, should be closely monitored.

Improved Vancomycin Dosing in Children Using Area-Under-the-Curve Exposure

Background: Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL. Methods: The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. Results: Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2–13.4) years, weight 22.7 (12.6–46) kg and baseline serum creatinine 0.40 (0.30–0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt0.75 * (0.48/serum creatinine)0.361 * (ln(age)/7.8)0.995 and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39–52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL. Conclusions: Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.

The Epithelium-specific ETS Protein EHF/ESE-3 Is a Context-dependent Transcriptional Repressor Downstream of MAPK Signaling Cascades

Exon trapping and cDNA selection procedures were used to search for novel genes at human chromosome 11p13, a region previously associated with loss of heterozygosity in epithelial carcinomas. Using these approaches, we found the ESE-2 and ESE-3 genes, coding for ETS domain-containing transcription factors. These genes lie in close proximity to the catalase gene within a ∼200-kilobase genomic interval. ESE-3 mRNA is widely expressed in human tissues with high epithelial content, and immunohistochemical analysis with a newly generated monoclonal antibody revealed that ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and that it is absent in the epithelial carcinomas tested. In transient transfections, ESE-3 behaves as a repressor of the Ras- or phorbol ester-induced transcriptional activation of a subset of promoters that contain ETS and AP-1 binding sites. ESE-3-mediated repression is sequence- and context-dependent and depends both on the presence of high affinity ESE-3 binding sites in combination with AP-1 cis-elements and the arrangement of these sites within a given promoter. We propose that ESE-3 might be an important determinant in the control of epithelial differentiation, as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence based pharmacotherapy. Further research with well designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.

Treatment of Meningitis Caused by Vancomycin-Resistant Enterococcus faecium: High-Dose and Combination Daptomycin Therapy

Objective: To report 3 successful treatments of vancomycin-resistant Enterococcus faecium meningitis in adults using daptomycin and either linezolid or gentamicin. Case Summary: Three case reports involving males (aged 58-78 years) are presented; in each case (trigeminal nerve microvascular decompression and subdural hygroma; paraspinal abscess; and hydrocephalus with subsequent craniotomy and ventriculo-peritoneal shunt placement) CSF examination revealed vancomycin-resistant Enterococcus (VRE) susceptible to daptomycin, gentamicin, and/or linezolid. Three- to four-week treatment regimens with daptomycin 6-12 mg/kg and either gentamicin or linezolid led to clinical resolution and microbiological clearance of infection. Discussion: Daptomycin has previously been shown to be successful in treating methicillin-resistant Staphylococcus aureus–associated meningitis and other serious VRE and enterococcal infections. Higher than approved doses of daptomycin were used in 2 cases where in theory higher CSF concentrations would thus be obtained. Gentamicin and linezolid were added to daptomycin therapy based on in vitro data synergy results and because of documented successful treatment for VRE meningitis, respectively. Conclusions: The difficulty in treating VRE CSF infections involves both drug kinetics and microbial resistance factors, as well as external factors such as foreign bodies like shunts. This report highlighted 3 cases where daptomycin use in concert with either gentamicin or linezolid was successful in treating this infection. Additional controlled trials will be helpful in identifying the best strategies when using daptomycin to treat CSF infections.

Nephrotoxicity associated with amphotericin B deoxycholate in neonates.

Background: The prevalence of nephrotoxicity in neonates receiving amphotericin B deoxycholate (amphoB) is not well-defined. While some studies report a lack of toxicity, others claim a frequency as high as 85%. Methods: We reviewed medical records of all infants ≤90 days of age in the neonatal intensive care unit who received at least 3 doses of amphoB between January 1990 and December 2004. A standardized form was used to collect demographic, therapeutic, microbiologic, and laboratory data for each patient. Nephrotoxicity was defined as a rise in serum creatinine (SCr) of at least 0.4 mg/dL any time during amphoB therapy. Results: A total of 92 infants met entry criteria. Median gestational age was 26 (range: 23–41) weeks and median birth weight was 863 (range: 546–4000) grams. Overall, 15 (16%) infants experienced nephrotoxicity, and 16 (17%) developed hypokalemia (<3.0 mmol/L). There were no differences between infants who did or did not develop nephrotoxicty in terms of gestational age, birth weight, gender, underlying medical conditions, or use of other potentially nephrotoxic medications. AmphoB exposure and duration of therapy were similar between infants who developed nephrotoxicity and those who did not, with a mean cumulative dose of 13.5 ± 9.6 mg/kg and duration of 16.3 ± 10.4 days. With the exception of 1 infant, the elevated SCr values resolved in all infants by the end of amphoB therapy. Conclusion: AmphoB administration does not appear to be associated with lasting measurable nephrotoxicity in neonates. Because of changes in serum creatinine and potassium, renal function and potassium levels should be monitored closely in infants receiving amphoB.

Management of community-associated methicillin-resistant Staphylococcus aureus infections in children.

In recent years, community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA) has emerged as a pathogen in children without established risk factors, and its prevalence in the United States is increasing. Although many CA‐MRSA infections are mild, primarily involving the skin and soft tissues, the organism can cause serious, invasive, and life‐threatening infections. To provide a comprehensive review of the epidemiology, clinical features, therapy, and prevention of CA‐MRSA infections in children, we performed MEDLINE (1966–January 2006) and Cochrane Library searches, and reviewed abstracts for relevance to S. aureus infections. Only articles pertaining to CA‐MRSA infections in pediatrics were closely examined. As a genetically distinct pathogen, CA‐MRSA is generally susceptible to multiple non–β‐lactam antimicrobials. The optimal treatment for CA‐MRSA infections in pediatric patients has not been well studied. Common antibiotics used include clindamycin, trimethoprim‐sulfamethoxazole, vancomycin, and rifampin. Rational empiric antimicrobial therapy for infections caused by S. aureus requires consideration of the possibility of methicillin resistance. The local prevalence and susceptibilities of CA‐MRSA, severity of infection, and individual risk factors should be considered in selecting treatment.

Impact of Empiric Antibiotic Use on Development of Infections caused by Extended-Spectrum ??-Lactamase Bacteria in a Neonatal Intensive Care Unit

Background: The neonatal intensive care unit at Miller Childrens Hospital changed from empiric use of cefotaxime and vancomycin (CEF) to tobramycin and vancomycin (TOB) for hospital-acquired infections in November 1999 because of an increase in infections caused by extended-spectrum β-lactamase (ESBL)-producing bacteria. The objectives of this study were to evaluate the incidence and impact of this change on the development of ESBL infections. Methods: We retrospectively reviewed medical records of infants who received CEF or TOB between January 1998 and December 2002. A standardized form was used to collect demographic data, information on antibiotic use, and culture results. Results: The mean gestational age and birth weight of the 250 infants were 28.8 ± 4.0 weeks and 1213.1 ± 662 g, respectively. There were no differences between infants who received CEF (N = 130) or TOB (N = 120) in terms of gestational age, birth weight, device use, invasive procedures, or prior antibiotic use. There were 11 ESBL infections. Infants in the CEF group were more likely than those in the TOB group to develop ESBL infection (7.8% versus 0.8%, P = 0.008). There were 11 deaths, with none attributed to ESBL infection. In a multivariate analysis, duration of prior ampicillin and gentamicin use and exposure to CEF were associated with ESBL infection [odds ratio (OR): 3.1, 95% confidence interval (CI): 1.28–7.49, P = 0.012; and OR: 33.7; 95% CI: 1.02–1136, P = 0.05, respectively]. Conclusions: The change from empiric use of CEF to TOB was associated with a significant decrease in the incidence of ESBL infections.