Treatment and Epidemiology of Third-Generation Cephalosporin-Resistant Urinary Tract Infections.

BACKGROUND AND OBJECTIVES: Limited data are available on the contemporary epidemiology, clinical management, and health care utilization for pediatric urinary tract infection (UTI) due to third-generation cephalosporin-resistant Enterobacterales (G3CR) in the United States. The objective is to describe the epidemiology, antimicrobial treatment and response, and health care utilization associated with G3CR UTI. METHODS: Multisite, matched cohort-control study including children with G3CR UTI versus non-G3CR UTI. UTI was defined as per American Academy of Pediatrics guidelines, and G3CR as resistance to ceftriaxone, cefotaxime, or ceftazidime. We collected data from the acute phase of illness to 6 months thereafter. RESULTS: Among 107 children with G3CR UTI and 206 non-G3CR UTI with documented assessment of response, the proportion with significant improvement on initial therapy was similar (52% vs 57%; odds ratio [OR], 0.81; 95% confidence interval [CI], 0.44-1.50). Patients with G3CR were more frequently hospitalized at presentation (38% vs 17%; OR, 3.03; 95% CI, 1.77-5.19). In the follow-up period, more patients with G3CR had urine cultures (75% vs 53%; OR, 2.61; 95% CI, 1.33-5.24), antimicrobial treatment of any indication (53% vs 29%; OR, 2.82; 95% CI, 1.47-5.39), and subspecialty consultation (23% vs 6%; OR, 4.52; 95% CI, 2.10-10.09). In multivariate analysis, previous systemic antimicrobial therapy remained a significant risk factor for G3CR UTI (adjusted OR, 1.91; 95% CI, 1.06-3.44). CONCLUSIONS: We did not observe a significant difference in response to therapy between G3CR and susceptible UTI, but subsequent health care utilization was significantly increased.

Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.

BACKGROUND: No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per µL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUCtau of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUClast of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per µL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9). INTERPRETATION: The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight. FUNDING: Gilead Sciences.

Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.

BACKGROUND: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS: We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per µL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUCtau for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUClast for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults. INTERPRETATION: The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children. FUNDING: Gilead Sciences.

Low Third-Trimester Serum Levels of Lamivudine/Zidovudine and Lopinavir/Ritonavir in an HIV-Infected Pregnant Woman with Gastric Bypass.

Pharmacokinetics of lamivudine (3TC)/zidovudine (ZDV) and lopinavir/ritonavir (LPV/r) are described in a gravid 27-year-old HIV-infected woman with gastric bypass. Blood levels were obtained for these medications at time points 0 (predose) and 1, 2, 4, 6, 8, and 12 hours postdose. For these times, the levels (µg/mL) of 3TC were 0.0801, 0.69, 0.339, 0.237, 0.202, 0.108, and 0.0461; the levels of ZDV were 0.0153, 0.433, 0.0717, 0.0481, 0.0107, 0.0214, and 0.00864; the levels of lopinavir (LPV) were 2.45, 2.64, 1.95, 2.78, 3.83, 3.20, and 1.92; and the levels of ritonavir (RTV) were 0.09, 0.10, 0.07, 0.11, 0.15, 0.15, and 0.06. These data suggest that gastric bypass affected these antiretroviral drug levels. A functional, intact small bowel is responsible for absorption of these medications.

Evaluation of vaccine coverage for low birth weight infants during the first year of life in a large managed care population.

OBJECTIVE: There are few recent population-based assessments of vaccine coverage in premature infants available. This study assesses and compares age- and dose-specific immunization coverage in children of different birth weight categories during the first year of life. METHODS: We performed a retrospective cohort analysis of computerized vaccination data from a large managed care organization in southern California. The participants were children born between January 1, 1997, and December 31, 2002, and continuously enrolled from birth to at least 12 months of age in the Southern California Kaiser Permanente health plan. We measured age-specific up-to-date and age-appropriate immunization rates according to birth weight (extremely low birth weight: <1000 g; very low birth weight: 1000-1499 g; low birth weight: 1500-2499 g; normal birth weight: >/=2500 g) for 4 vaccines (hepatitis B, diphtheria and tetanus toxoids with pertussis, Haemophilus influenzae type b, and poliovirus) through the first year of life. RESULTS: We identified 127 833 infants born during the study period and continuously enrolled through the first year of life; 120 048 were normal birth weight infants; 6491 were low birth weight infants; 788 were very low birth weight infants; and 506 were extremely low birth weight infants. Vaccine-specific age-appropriate immunization rates were 3% to 15% lower for low birth weight infants and 17% to 33% lower for extremely low birth weight infants compared with the rates for normal birth weight infants in the first 6 months of life. Extremely low birth weight infants had the lowest age-specific up-to-date immunization levels (5%-31% lower) compared with normal birth weight infants at each age assessed. By 12 months, extremely low birth weight infants still had significantly lower up-to-date levels (87%) compared with very low birth weight, low birth weight, and normal birth weight infants (91%-92%). CONCLUSIONS: Despite recommendations that lower birth weight infants be vaccinated as the same chronological age as normal birth weight infants, extremely low birth weight and very low birth weight infants are immunized at significantly lower rates relative to low birth weight and normal birth weight infants at 2, 4, and 6 months of age. However, by 12 months of age this finding persists only in extremely low birth weight infants.