Retrospective cohort study comparing two versus three blood culture sets in people who inject drugs.

BACKGROUND: The current standard of drawing two vs three blood culture sets lacks adequate guidance. Because people who inject drugs are at higher risk for bacteraemia and life-threatening infection, consideration of a third blood culture becomes more important. AIM: To investigate the risks and benefits of obtaining two versus three blood culture sets. METHODS: Retrospective cohort study of adults who inject drugs at a multicentre catch-net hospital system from 2017-2022. FINDINGS: 998 people who inject drugs and 2278 blood culture sets were analysed. There were 1618 episodes with two blood culture sets and 660 episodes with three. A potential benefit of adding a third blood culture was seen in 30 (4.5%) episodes. However, only 13 (2.0%) episodes showed pathogen-identifying benefit, as 17 (2.6%) involved known inadequately treated infections or the same pathogen in another culture. The number of blood culture sets needed to achieve diagnostic benefit was 51. There were more contaminants for three blood culture sets (65, 9.8%) than for two (114, 7.0%) (p < 0.00001). By adding a third blood culture, the risk of a contaminant increased by 39.7%; the number of blood culture sets needed to find a contaminant was 36. Of 122 episodes with only contaminants and available for analysis, 111 (91.0%) experienced at least one complication. 33 (27.0%) patients experienced either prolonged admission, readmission, or unnecessary antibiotic administration. CONCLUSIONS: The benefits of possibly isolating a pathogen from a third blood culture set do not universally outweigh the risks for contaminant growth for people who inject drugs. A third blood culture should be considered in specific clinical scenarios (i.e. inadequately treated endocarditis and osteomyelitis).

Risk Factors for Low CD4+ Count Recovery Despite Viral Suppression Among Participants Initiating Antiretroviral Treatment With CD4+ Counts > 500 Cells/mm3: Findings From the Strategic Timing of AntiRetroviral Therapy (START) Trial.

BACKGROUND: Low CD4 recovery among HIV-positive individuals who achieve virologic suppression is common but has not been studied among individuals initiating treatment at CD4 counts of >500 cells/mm. SETTING: United States, Africa, Asia, Europe and Israel, Australia, Latin America. METHODS: Among participants randomized to immediate antiretroviral therapy (ART) in the Strategic Timing of AntiRetroviral Therapy trial, low CD4 recovery was defined as a CD4 increase of <50 cells/mm from baseline after 8 months despite viral load of ≤200 copies/mL. Risk factors for low recovery were investigated with logistic regression. RESULTS: Low CD4 recovery was observed in 39.7% of participants. Male sex [odds ratio (OR), 1.53; P = 0.007], lower screening CD4 cell counts (OR, 1.09 per 100 fewer cells/mm; P = 0.004), higher baseline CD8 cell counts (OR, 1.05 per 100 more cells/mm; P < 0.001), and lower HIV RNA levels (OR, 1.93 per log10 decrease; P < 0.001) were associated with low CD4 recovery. D-dimer had a quadratic association with low CD4 recovery, with lowest odds occurring at 0.32 µg/mL. At lower HIV RNA levels, the odds of low CD4 recovery were elevated across the levels of screening CD4 count; but at higher HIV RNA levels, the odds of low CD4 recovery were higher among those with lower vs. higher screening CD4. CONCLUSIONS: Low CD4 recovery is frequent among participants starting ART at high CD4 counts. Risk factors include male sex, lower screening CD4 cell counts, higher CD8 cell counts, and lower HIV RNA levels. More follow-up is required to determine the impact of low CD4 recovery on clinical outcomes.

IKBKG (NEMO) 5' Untranslated Splice Mutations Lead to Severe, Chronic Disseminated Mycobacterial Infections.

Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing.

AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial.

BACKGROUND: Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS: We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per µL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 µL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964. FINDINGS: Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2-4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference -6·1%, 95% CI -14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI -5·6 to 23·8). INTERPRETATION: The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. FUNDING: US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

Final report of the Lyme disease review panel of the Infectious Diseases Society of America.

In April 2008, the Infectious Diseases Society of America (IDSA) entered into an agreement with Connecticut Attorney General Richard Blumenthal to voluntarily undertake a special review of its 2006 Lyme disease guidelines. This agreement ended the Attorney General's investigation into the process by which the guidelines were developed. The IDSA agreed to convene an independent panel to conduct a one-time review of the guidelines. The Review Panel members, vetted by an ombudsman for potential conflicts of interest, reviewed the entirety of the 2006 guidelines, with particular attention to the recommendations devoted to post-Lyme disease syndromes. After multiple meetings, a public hearing, and extensive review of research and other information, the Review Panel concluded that the recommendations contained in the 2006 guidelines were medically and scientifically justified on the basis of all of the available evidence and that no changes to the guidelines were necessary.

Antibiotic dosing in slow extended daily dialysis.

Slow extended daily dialysis (SLEDD) is the newest form of dialysis that is being used increasingly to replace continuous venovenous hemodialysis (CVVHD) for critically ill patients; it is less expensive to administer and has similar safety for patients who are prone to hemodynamic instability. Unfortunately, there are limited data regarding the appropriate dosing of antimicrobial agents for patients undergoing SLEDD. Furthermore, many nonnephrologists are not familiar with the differences between SLEDD, other continuous renal replacement therapies--for example, CVVHD--and routine hemodialysis. Thus, there is potential for inaccurate and, at worst, inadequate dosing of critical antimicrobial agents for this patient population. We review the available pharmacokinetic data on SLEDD and give preliminary recommendations for how to approach dosing in this situation.

Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers.

OBJECTIVES: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. DESIGN: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. SETTING: Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans. PARTICIPANTS: 126 healthy adults 21-45 years of age. INTERVENTIONS: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. OUTCOME MEASURES: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. RESULTS: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. CONCLUSIONS: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.

Head and neck manifestations in HIV infection.

Diseases of the head and neck often are the first sign of Human Immunodeficiency Virus (HIV) infection. As current treatment increases the survival time of HIV-positive patients, the physician may encounter patients with a greater variety and number of diseases related to the primary HIV infection. Some entities are harbingers of HIV infection, such as Kaposi's sarcoma and parotid cystic enlargement. Other manifestations, such as Mycobacterium avium complex infection, may be used to determine the stage of HIV infection. The advent of highly active anti-retroviral therapy (HAART) has transformed the prevalence of HIV-associated head and neck disease. This article reviews the clinical presentations and treatments of common and uncommon head and neck manifestations in HIV infection. Accurate assessment of these conditions may allow the physician to identify HIV infection in previously undiagnosed patients, and, as a result, provide more timely treatment.