David M. Mushatt

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 Generals 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.

Tolerance and Pharmacokinetic Interactions of Rifabutin and Azithromycin

ABSTRACT This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.

Non-epidermidis coagulase-negative staphylococcal bacteremia: clinical predictors of true bacteremia

In order to explore the clinical significance and risk factors for true bacteremia caused by coagulase-negative staphylococci (CNS) other than Staphylococcus epidermidis, a retrospective cohort study of 160 patients with at least one blood culture positive for non-epidermidis CNS was performed. True bacteremia was diagnosed in 32 (20%) of the patients. On multivariate analysis the following factors were associated with true bacteremia: (i) more than one positive blood culture, (ii) presence of a central venous catheter, and (iii) methicillin resistance. The results of this study indicate that non-epidermidis CNS can cause significant bloodstream infections.

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.

Infected total knee arthroplasty due to Actinomyces naeslundii.

A case of a total knee arthroplasty infection with Actinomyces naeslundii is described. The difficulties of therapeutic decision-making are emphasized.A case of a total knee arthroplasty infection with Actinomyces naeslundii is described. The difficulties of therapeutic decision-making are emphasized.

High-Level Penicillin-Nonsusceptible Streptococcus pneumoniae Bacteremia: Identification of a Low-Risk Subgroup

High-level penicillin resistance has been associated with treatment failure in patients with Streptococcus pneumoniae infections. To identify a subgroup of patients at low risk for high-level penicillin-nonsusceptible S. pneumoniae bacteremia, a cross-sectional study of 303 patients was performed. For the total study population, penicillin resistance was observed in 98 (32%) of 303 patients; high-level resistance was seen in 33 (11%). A predictive model was created by using 3 baseline variables that were independently associated with high-level penicillin resistance: previous beta -lactam antibiotic use, previous stay in a risk area (defined as stay in day care facilities, prisons, homeless shelters, nursing homes, or other long-term care facilities), and previous respiratory tract infection. The model was used to identify patients at low and high risk for high-level penicillin-resistant pneumococcal bacteremia. None of the isolates of patients in the low-risk subgroup had ceftriaxone resistance. Patients in the low-risk subgroup could be empirically treated with fluoroquinolone-sparing regimens.

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

Summary 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.

Gender Differences in HIV Drug Resistance Mutations and Virological Outcome

BACKGROUND Previous studies have shown that female gender has higher odds of developing HIV drug resistance mutations. We aimed to evaluate the gender differences in HIV drug resistance mutation patterns and outcomes in a cohort of an HIV-infected population who underwent genotype resistance testing (GRT). METHODS We conducted a retrospective study from January 2004 to April 2007 of patients >12 years of age who underwent GRT in the HIV Outpatient Program Clinic (HOP) at the Medical Center of Louisiana at New Orleans. RESULTS Among 391 patients included in the analysis, 130 were females and 261 were males. There were no major statistically significant differences in the baseline demographic, clinical, or genotypic characteristics between males and females before GRT except for race, presence of coexisting hepatitis B and C infection, prior diagnosis of tuberculosis, presence of thymidine analogue mutations (TAMs), and protease inhibitor (PI) mutations L90M and I84V (p < 0.05). Females showed a 1.6 fold probability of carrying nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.02-2.6), whereas males showed a 2-fold probability of carrying PI mutations (OR 2, 95% CI 1.12-3.8). Sixty-seven percent of males achieved virological suppression compared with 57% of females at 1 year (±6 months). Independent of history of optimal treatment and race, females showed 2-fold odds of having virological failure compared with males at 1 year (±6 months) after GRT (OR 2.0, 95% CI 1.04-3.8). CONCLUSIONS Females did worse than males in regard to viral load suppression at the end of 1 year if they had documented HIV drug resistance at baseline. Further longitudinal studies are needed to confirm our findings.