George K. Siberry

Failure of Clindamycin Treatment of Methicillin-Resistant Staphylococcus aureus Expressing Inducible Clindamycin Resistance In Vitro

We report a case of a surgical site infection caused by clindamycin-susceptible, erythromycin-resistant methicillin-resistant Staphylococcus aureus (MRSA) that did not respond to treatment with clindamycin. The MRSA isolate obtained after treatment was resistant to clindamycin but was found to be identical by pulsed-field gel electrophoresis to the clindamycin-susceptible isolate obtained before treatment. A post hoc erythromycin-induction test (D test) confirmed the presence of in vitro inducible macrolide-lincosamide-streptogramin B resistance (iMLS) in the pretreatment isolate. Erythromycin induction testing confirmed in vitro iMLS in 90 (56%) of 161 erythromycin-resistant, clindamycin-susceptible clinical S. aureus isolates overall and in a significantly higher proportion (78%) of methicillin-susceptible S. aureus isolates from pediatric patients. Our clinical laboratory currently tests all S. aureus isolates for iMLS before reporting clindamycin susceptibility.

Growing Up with HIV: Children, Adolescents, and Young Adults with Perinatally Acquired HIV Infection

Tremendous success in the prevention and treatment of pediatric HIV in high-resource countries has changed the face of the epidemic. A perinatally HIV-infected child now faces a chronic disease rather than a progressive, fatal one. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. These include maintaining adherence to long-term, likely life-long therapy; selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations and the lack of pharmacokinetic and safety data in children; and overcoming extensive drug resistance in multi-drug-experienced children. Pediatric HIV care now focuses on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high-resource countries encourages expansion of pediatric treatment programs in low-resource countries, where most HIV-infected children live, and provides important lessons about how the epidemic changes with increasing access to antiretroviral therapy for children.

Safety of tenofovir use during pregnancy: Early growth outcomes in HIV-exposed uninfected infants

Objective:To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants. Design:US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure. Methods:We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5 kg); weight-for-age z-scores (WAZ), length-for-age z-scores (LAZ), and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age 1 year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ, and HCAZ by TDF exposure. Results:Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with vs. without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age 1 year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, P = 0.04; HCAZ: 0.17 vs. 0.42, P = 0.02). Conclusion:TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age 1 year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.

Continued Production of Drug-Sensitive Human Immunodeficiency Virus Type 1 in Children on Combination Antiretroviral Therapy Who Have Undetectable Viral Loads

ABSTRACT Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4+ T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.

The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men.

Background:This study examined the feasibility of a combination prevention intervention for young men who have sex with men (YMSM), an anticipated target population for HIV preexposure prophylaxis (PrEP). Methods:Project PrEPare, a pilot study using a randomized 3-arm design, compared an efficacious behavioral HIV prevention intervention (Many Men, Many Voices—3 MV) alone, 3 MV combined with PrEP (tenofovir/emtricitabine), and 3 MV combined with placebo. Eligible participants were 18- to 22-year-old HIV-uninfected men who reported unprotected anal intercourse in the past year. Participants were screened for preliminary eligibility at youth venues and community organizations and were also referred through social networks. Laboratory screening determined final eligibility. Behavioral and biomedical data were collected at baseline and every 4 weeks thereafter for 24 weeks. Results:Sixty-eight youth (mean age = 19.97 years; 53% African American, 40% Latino) were enrolled; 58 were randomized. Self-reported medication adherence averaged 62% (range, 43%–83%), whereas rates of detectable tenofovir in plasma of participants in the emtricitabine/tenofovir disoproxil fumarate arm ranged from 63.2% (week 4) to 20% (week 24). There were 5 ≥ grade 2 adverse events possibly/probably related to the study medication. Sexual risk behavior declined from baseline to week 24 in all study arms. Conclusions:The feasibility of enrolling at-risk youth, particularly young men who have sex with men of color, into Project PrEPare has been demonstrated. The acceptability of the group intervention along with counseling and testing was high. Self-reported medication adherence and corresponding plasma drug concentrations were low indicating the need for enhanced adherence counseling. Exploration of PrEP use among youth in nonrandomized open label trials is warranted.

Mental health functioning among children and adolescents with perinatal HIV infection and perinatal HIV exposure

Mental health problems (MHPs) among children with perinatal HIV infection have been described prior to and during the highly active antiretroviral therapy (HAART) era. Yet child, caregiver and socio-demographic factors associated with MHPs are not fully understood. We examined the prevalence of MHPs among older children and adolescents with perinatal HIV exposure, including both perinatally HIV-infected (PHIV + ) and perinatally HIV-exposed but uninfected (PHEU) youth. Our aims were to identify the impact of HIV infection by comparing PHIV+ and PHEU youth and to delineate risk factors associated with MHPs, in order to inform development of appropriate prevention and intervention strategies. Youth and their caregivers were interviewed with the Behavior Assessment System for Children, 2nd edition (BASC-2) to estimate rates of at-risk and clinically significant MHPs, including caregiver-reported behavioral problems and youth-reported emotional problems. The prevalence of MHPs at the time of study entry was calculated for the group overall, as well as by HIV status and by demographic, child health, and caregiver characteristics. Logistic regression models were used to identify factors associated with youth MHPs. Among 416 youth enrolled between March 2007 and July 2009 (295 PHIV+, 121 PHEU), the overall prevalence of MHPs at entry was 29% and greater than expected based on recent national surveys of the general population. MHPs were more likely among PHEU than among PHIV+ children (38% versus 25%, p<0.01). Factors associated with higher odds of MHPs at p<0.10 included caregiver characteristics (psychiatric disorder, limit-setting problems, health-related functional limitations) and child characteristics (younger age and lower IQ). These findings suggest that PHEU children are at high risk for MHPs, yet current models of care for these youth may not support early diagnosis and treatment. Family-based prevention and intervention programs for HIV affected youth and their caregivers may minimize long-term consequences of MHPs.

Patient-, Provider-, and Clinic-Level Predictors of Unrecognized Elevated Blood Pressure in Children

OBJECTIVE: The goal was to determine patient-, provider-, and clinic-level predictors of unrecognized elevated blood pressure (BP) in children. We hypothesized that being of healthy weight, having a BP of <120/80 mmHg, and being seen by a less experienced provider would result in decreased recognition. METHODS: A cross-sectional study of clinic visits for children 3 to 20 years of age at an urban, pediatric primary care practice between January 1, 2006, and June 30, 2006, was performed. Children with elevated systolic or diastolic BP (≥90th percentile or ≥120/80 mmHg) were included. Recognition was defined as having any of the following documented: repeat BP measurement, elevated-BP/hypertension diagnosis, plan to recheck BP, or initiation of hypertension evaluation. Multivariate logistic regression analysis was used to identify characteristics associated with underrecognition. RESULTS: Elevated BP occurred in 779 (39%) of 2000 visits. Of 726 cases included in the analysis, 87% were not recognized by providers. Patient-level predictors of underrecognition included systolic BP of <120 mmHg (odds ratio: 7.7 [95% confidence interval: 3.2–18.6]), diastolic BP of <80 mmHg (odds ratio: 2.4 [95% confidence interval: 1.1–5.0]), decreasing BMI z score, male gender, older age, lack of family history of cardiovascular disease, and negative medical history findings. Being seen by a nurse practitioner and being seen by a less-experienced provider also were significant predictors. CONCLUSIONS: Most BP elevations were not recognized by providers. Poor recognition was most influenced by the absence of obviously elevated BP, obesity, and family history of cardiovascular disease.

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

RATIONALE Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

The future role of CD4 cell count for monitoring antiretroviral therapy

For more than two decades, CD4 cell count measurements have been central to understanding HIV disease progression, making important clinical decisions, and monitoring the response to antiretroviral therapy (ART). In well resourced settings, the monitoring of patients on ART has been supported by routine virological monitoring. Viral load monitoring was recommended by WHO in 2013 guidelines as the preferred way to monitor people on ART, and efforts are underway to scale up access in resource-limited settings. Recent studies suggest that in situations where viral load is available and patients are virologically suppressed, long-term CD4 monitoring adds little value and stopping CD4 monitoring will have major cost savings. CD4 cell counts will continue to play an important part in initial decisions around ART initiation and clinical management, particularly for patients presenting late to care, and for treatment monitoring where viral load monitoring is restricted. However, in settings where both CD4 cell counts and viral load testing are routinely available, countries should consider reducing the frequency of CD4 cell counts or not doing routine CD4 monitoring for patients who are stable on ART.

Evolving epidemiology of pediatric Staphylococcus aureus cutaneous infections in a Baltimore hospital.

Objectives: To examine the epidemiology, antibiotic susceptibility profiles, and outcomes in pediatric Staphylococcus aureus (SA) cutaneous infections at a time when community-associated (CA) methicillin-resistant SA (CA-MRSA) infections seemed to be increasing in our community. Methods: The hospital microbiology database was searched for unique skin and wound SA isolates among pediatric patients between November 2002 and October 2003. Demographic and clinical data were abstracted from medical records. Cases were classified as either health care-associated (HA) or CA. Results: Among 181 pediatric SA cutaneous infections, 81 (45%) were caused by MRSA. Most (84%) of these MRSA were CA. Between the first 6 months and second 6 months of the study period, CA-MRSA increased from 15% to 45% (P < 0.001) of all SA cutaneous infections. Ninety-eight percent and 94% of CA-MRSA were susceptible to trimethoprim/sulfamethoxazole and clindamycin (confirmed by D test), respectively. Hospitalization occurred for 25% of CA-MRSA and 75% of HA-MRSA (P = 0.004). Drainage procedures were performed for 70% of CA-MRSA. No cases of CA-MRSA skin infections were accompanied by bacteremia. Conclusions: The CA-MRSA cutaneous infections increased in children in our urban Baltimore hospital in 2003. These CA-MRSA were erythromycin resistant, clindamycin susceptible, and trimethoprim/sulfamethoxazole susceptible. The CA-MRSA cutaneous infections frequently required drainage and were not associated with bacteremia. Children with cutaneous MRSA infections were less likely to have traditional health care risk factors than children with cutaneous methicillin-sensitive SA infections-an inversion of past patterns of MRSA infections-but were equally likely to be hospitalized when other factors were considered. These CA-MRSA cutaneous infections can be managed with abscess drainage and culture, careful follow-up, and empirical clindamycin therapy when clinically indicated.