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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
Oral fluoroquinolone use and serious arrhythmia (March 2016)
QT interval prolongation and torsades de pointes have been associated with fluoroquinolone use, but the degree to which fluoroquinolones block cardiac potassium channels and thereby cause QT prolongation varies by agent. The risk of serious arrhythmia during fluoroquinolone therapy was evaluated in a cohort of adults aged 40 to 79 years of age in Denmark and Sweden; arrhythmic events were compared for 909,656 courses of fluoroquinolones (ciprofloxacin in 83 percent, norfloxacin in 12 percent, ofloxacin in 3 percent, moxifloxacin in 1 percent, other in 1 percent) and 909,656 courses of penicillin, an antibiotic not associated with arrhythmia . There was no increase in the risk of serious arrhythmia with fluoroquinolones compared with penicillin. This finding conflicts with results from earlier studies, and may be explained in part by the predominant use of ciprofloxacin in this cohort, with its smaller impact on QT prolongation. (See "Fluoroquinolones", section on 'QT interval prolongation and arrhythmia'.)
Oritavancin interference with coagulation tests (February 2016)
Oritavancin is a glycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). Although oritavancin has no effect on the coagulation system in vivo, it falsely prolongs the activated partial thromboplastin time (aPTT), prothrombin time/international normalized ratio (PT/INR), and activated clotting time (ACT) by binding to phospholipid reagents used in laboratory testing. In 2016, the US Food and Drug Administration (FDA) labeling was revised to include new time frames for concern as to interference with coagulation tests of up to five days for aPTT, 12 hours for PT/INR, and 24 hours for ACT, following a single intravenous (IV) dose of oritavancin . Coagulation test interference can make the monitoring of unfractionated heparin (UFH) and warfarin unreliable within these time frames. For patients who require aPTT monitoring within five days of oritavancin, anti-factor Xa activity testing may be used. Patients who require a heparin anticoagulant and do not have access to anti-factor Xa testing could be treated with low molecular weight (LMW) heparin instead of UFH. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Prolonged baseline aPTT' and "Pharmacology of antimicrobial agents for treatment of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus", section on 'Drug interactions' and "Oritavancin: Drug information".)
Etiology of community-acquired pneumonia (April 2016)
Multiple studies of patients with community-acquired pneumonia (CAP) have identified an etiologic agent in fewer than half of cases. In a study of hospitalized adults with CAP in the United Kingdom that used both bacterial cultures and comprehensive multiplex molecular testing for bacteria and viruses of lower respiratory tract specimens, a pathogen was identified in 87 percent of cases by molecular methods . Culture-based methods detected a pathogen in only 39 percent of cases. Haemophilus influenzae and Streptococcus pneumoniae were the most common agents detected, followed by a wide variety of pathogens. Viruses were present in 30 percent of cases; 82 percent of these were detected in specimens that also tested positive for bacteria. A caveat is that contamination of specimens with upper respiratory tract secretions could cause false positive results . (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)
Indications for antibiotics in the management of skin abscess (March 2016)
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has raised uncertainty regarding the role of antimicrobial therapy for treatment of skin abscess following incision and drainage. In a randomized trial including 1220 patients >12 years of age (median 35 years) with drained skin abscess (≥2 cm in diameter) comparing trimethoprim sulfamethoxazole (TMP-SMX, 320 mg/1600 mg twice daily) with placebo, the cure rate 7 to 14 days after treatment was higher in the TMP-SMX group (80.5 versus 73.6 percent); wound cultures were positive for MRSA in 45 percent of cases . Based on these findings, abscess size ≥2 cm in diameter is a useful threshold for guiding decisions regarding use of antibiotic therapy for adjunctive treatment of skin abscess.
Additional factors for which we recommend antibiotic therapy include the presence of multiple lesions, extensive surrounding cellulitis, associated comorbidities or immunosuppression, signs of systemic infection, or inadequate clinical response to incision and drainage alone; we suggest antibiotic therapy for patients with an indwelling device or high risk for transmission of S. aureus to others. For otherwise healthy patients with none of these factors, we suggest not administering antimicrobial therapy. (See "Skin abscesses, furuncles, and carbuncles", section on 'Role of antibiotics'.)
Frozen fecal microbiota transplantation for Clostridium difficile infection (January 2016)
Treatment with fecal microbiota transplantation (FMT) has been hampered by logistic difficulties in preparation and administration of the fecal suspension. In a randomized non-inferiority trial, 219 patients with recurrent Clostridium difficile infection (CDI) or refractory CDI were assigned to receive frozen-and-thawed or fresh FMT via rectal enema . In the modified intention-to-treat population, rates of clinical resolution in the frozen FMT group were non-inferior to fresh FMT, and there were no differences in adverse events between the two groups. The use of frozen FMT also has the potential advantage of immediate availability. Frozen FMT is currently an investigational technique for the treatment of C. difficile. (See "Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection", section on 'Suggested protocol'.)
Time to return to school following treatment for streptococcal pharyngitis (December 2015)
Traditionally, patients with streptococcal pharyngitis have been considered contagious until 24 hours following antibiotic therapy and so have not been allowed to return to daycare, school, or camp until this interval has passed. In a recent study including 111 children with a sore throat and positive streptococcal rapid antigen detection test (RADT) who were treated with single-dose amoxicillin, 91 percent had a negative follow-up RADT and throat culture the following morning (12 to 23 hours later) . Based on these findings, children treated with amoxicillin for streptococcal pharyngitis by 5:00 pm are unlikely to be contagious by the next morning. When consistent with local policies, it would be reasonable to permit such children to attend school the following day if afebrile and clinically improved. (See "Treatment and prevention of streptococcal tonsillopharyngitis", section on 'Follow-up'.)
New American and European guidelines on endocarditis (October 2015)
The American Heart Association (AHA) and European Society of Cardiology (ESC) have each issued new guidelines on management of infective endocarditis (IE) that provide updated information on antimicrobial therapy for IE [8,9]. Daptomycin has been added as an alternative agent for treatment of staphylococcal IE, and gentamicin is no longer recommended for treatment of staphylococcal native valve IE. Regimens for treatment of enterococcal IE now include double beta-lactam therapy with ampicillin and high-dose ceftriaxone. In addition, high-dose daptomycin (with or without a beta-lactam) and linezolid are included as potential alternative regimens for managing IE caused by enterococci resistant to penicillin, aminoglycosides, and vancomycin. (See "Antimicrobial therapy of native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
Discretionary ICU admission and mortality in older adults with pneumonia (October 2015)
A retrospective cohort study of over one million Medicare beneficiaries (aged >64 years) admitted with pneumonia to hospitals in the United States evaluated the relationship between intensive care unit (ICU) admission and outcomes among patients whose ICU admissions appeared to be discretionary (ie, based predominantly on proximity to a hospital with high ICU admission rates) . In an adjusted analysis, among patients whose ICU admission was potentially discretionary, ICU admission was associated with lower mortality than general ward admission. There were no differences in Medicare spending or hospitalization costs between discretionary ICU and general ward patients. These results suggest a potential benefit for broader ICU admission criteria for older adults with pneumonia without substantially increased costs, but should be confirmed in a randomized trial. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Indications for hospitalization and ICU admission'.)
IDSA guidelines on the management of candidiasis (January 2016)
The Infectious Diseases Society of America released updated guidelines for the management of patients with candidiasis . A substantial change compared with previous versions is the preference for echinocandins (anidulafungin, caspofungin, micafungin) as first-line therapy for candidemia and invasive candidiasis. As an example, for both nonneutropenic and neutropenic patients with candidemia, an echinocandin is the preferred choice for initial therapy (table 1). This change is due to an increase in fluconazole-resistant Candida infections, the favorable safety profile of the echinocandins, and accumulating efficacy data and clinical experience to support the echinocandins. Important exceptions include Candida central nervous system, eye, and urinary tract infections, for which other antifungals are preferred. (See "Treatment of candidemia and invasive candidiasis in adults", section on 'Nonneutropenic patients'.)
Miscarriage risk with oral fluconazole (January 2016)
The pregnancy effects of oral azoles for treatment of vulvovaginal candidiasis is unclear. Studies have reported an increased risk of birth defects after exposure to high-dose azole therapy (400 to 800 mg/day), but not for the low dose therapy used to treat vulvovaginal infections (eg, fluconazole 150 mg). Prior studies have not reported an increased risk of miscarriage with oral fluconazole. However, a recent cohort study of over 3300 women who received 150 to 300 mg of oral fluconazole between 7 and 22 weeks of pregnancy reported an approximately 50 percent increased risk of miscarriage in exposed women compared with either unexposed women or with women treated with vaginal azole therapy . We continue to offer topical azole treatment during pregnancy and prefer to avoid oral therapy until more data on reproductive outcomes are available. (See "Candida vulvovaginitis", section on 'Pregnancy'.)
Outbreak of fungal CNS infection and septic arthritis in the United States: Long-term follow-up (November 2015)
A multistate outbreak of fungal central nervous system infection and septic arthritis associated with injections with contaminated methylprednisolone was detected in the United States in 2012 and involved >750 cases. In a long-term follow-up study, by 12 months after the initial diagnosis, 42 percent of 455 patients followed in the study were considered cured, 41 percent were no longer receiving antifungal therapy but did not meet the definition of cure, 7 percent were still receiving antifungal therapy, 8 percent had died (with 24 of 36 fatalities attributed to outbreak-associated infections), and 2 percent had incomplete follow-up data . One patient developed probable fungal meningitis 26 months after receiving an injection of contaminated methylprednisolone. In addition, eight cases of relapsed fungal infection were reported. Median time to relapse was 90 days, but one relapse occurred 21 months after cessation of therapy. (See "Outbreak of fungal central nervous system and osteoarticular infections in the United States: Epidemiology, clinical manifestations, and diagnosis", section on 'Incubation period' and "Outbreak of fungal central nervous system and osteoarticular infections in the United States: Treatment", section on 'Outcomes'.)
Adverse pregnancy effects of improved control of malaria (November 2015)
Improvements in malaria control in some endemic areas have led to declines in malaria transmission and, in turn, immunity. A recent study from Mozambique illustrated an adverse consequence of a less immune population. In this study, a large reduction in malaria transmission in recent years was associated with a large reduction in maternal levels of antimalarial IgG antibodies against both pregnancy-specific parasite lines and more general parasite lines . In addition, women who developed a malaria infection during pregnancy in recent years had greater reductions in hemoglobin level and newborn birth weight compared with pregnant women infected prior to the overall decline in malaria prevalence and reduced immunity. (See "Overview of malaria in pregnancy", section on 'Immunity'.)
Pre-exposure prophylaxis against HIV using a dapivirine-containing vaginal ring (March 2016)
For high-risk HIV-uninfected individuals, pre-exposure prophylaxis (PrEP) using antiretroviral medications can prevent new HIV infections. Among heterosexual women, clinical trials of PrEP with both oral and topical tenofovir-containing formulations have yielded variable results, thus raising interest in other PrEP modalities in this population. A randomized trial of 2692 women in Africa evaluated the efficacy of a monthly vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine . Compared with a placebo vaginal ring, dapivirine reduced the incidence of HIV infection by 27 percent, and there was no difference in adverse events between the two groups. Dapivirine efficacy was higher among those with increased adherence. The dapivirine ring is not yet clinically available but is being evaluated in an open-label study to assess real world effectiveness. (See "Pre-exposure prophylaxis against HIV infection", section on 'Heterosexual women'.)
Pregnancy risk with progestin-releasing implants in HIV-infected women using efavirenz (March 2016)
Potential drug interactions are important considerations when choosing hormonal contraception for HIV-infected women on antiretroviral therapy (ART). Two recent observational studies from Africa have suggested that drug interactions between the non-nucleoside reverse transcriptase inhibitor efavirenz and progestin-releasing implants (both levonorgestrel and etonogestrel) are associated with decreased contraceptive efficacy [16,17]. In one of these studies, the adjusted pregnancy incidence among over 6000 women using progestin-releasing implants was three times higher in those using an efavirenz- versus a nevirapine-based regimen . If a progestin-releasing implant is the preferred contraceptive method for a women taking an efavirenz-based ART regimen, a second form of contraception should also be used. (See "HIV and women", section on 'Drug interactions'.)
No benefit of routine glucocorticoids for cryptococcal meningitis in HIV-infected patients (February 2016)
The preferred treatment approach for HIV-infected patients with cryptococcal meningoencephalitis includes combination antifungal therapy for the induction phase of therapy followed by consolidation therapy with fluconazole alone. There is no role for empiric glucocorticoids during induction therapy. This is in contrast to other conditions (eg, tuberculous meningitis) in which they are routinely administered as part of initial therapy. The use of glucocorticoids for patients with cryptococcal meningitis was evaluated in a randomized trial that included 451 HIV-infected patients from Asia and Africa . Patients received amphotericin plus fluconazole with or without dexamethasone. The trial was stopped early after an interim analysis found no difference in mortality or the rate of immune reconstitution inflammatory syndromes (IRIS) between the two groups at 10 weeks. In addition, patients who received adjunctive corticosteroids were less likely to have a good neurologic outcome, had slower rates of fungal clearance, and were more likely to develop an adverse event (eg, infection, renal or cardiac event). Although glucocorticoids are not routinely recommended for induction therapy, they may have a role in the management of patients who develop IRIS following initiation of antifungal therapy. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section on 'Induction and consolidation'.)
New guidance on blood donation deferral for men who have sex with men in the United States (December 2015)
The US Food and Drug Administration has updated its guidance on blood donation for men who have sex with men (MSM). The new guidance specifies a deferral period of 12 months since the last MSM sexual contact rather than indefinite deferral . Prospective donors are instructed not to donate if they have other risk factors for human immunodeficiency virus (HIV) infection such as a recent needle stick injury or blood splash, and permanent deferral remains in place for individuals who have tested positive for HIV, used non-prescription injection drugs, or engaged in sex in exchange for money or drugs. The 12-month deferral has already been in place for other donors who have sex with at-risk individuals, and it aligns the US policy with that of Australia and the United Kingdom. Other countries have deferral periods ranging from six months to indefinite. (See "Blood donor screening: Medical history", section on 'Human immunodeficiency virus'.)
Tenofovir alafenamide as part of a coformulated antiretroviral regimen (November 2015)
Tenofovir is a preferred nucleoside to use in a combination antiretroviral regimen for the treatment of HIV infection. Until recently, tenofovir was available only as tenofovir-disoproxil fumarate (TDF), which has been associated with renal toxicity and decreased bone mineral density. In November 2015, a newer formulation, tenofovir alafenamide (TAF) became available in the United States as part of a single tablet coformulation, elvitegravir-cobicistat-emtricitabine-TAF (ECF-TAF) . This combination agent is as effective as elvitegravir-cobicistat-emtricitabine-TDF (ECF-TDF) in suppressing HIV RNA with fewer adverse renal and bone effects . ECF-TAF can be used for patients with reduced kidney function (estimated glomerular filtration rate [eGFR] ≥30 mL/min/m2), unlike ECF-TDF, which should only be used in patients with an eGFR >70 mL/min/m2. ECF-TAF is considered a recommended regimen by the United States Department of Health and Human Services . In March 2016, TAF also became available as part of the coformulated tablet rilpivirine-emtricitabine-tenofovir alafenamide. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient", section on 'Preferred regimens'.)
Risk of Pneumocystis pneumonia and cytomegalovirus infections with idelalisib (March 2016)
Idelalisib is a phosphatidylinositol 3-kinase inhibitor used for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Seven clinical trials of idelalisib used in combination with other agents have been halted due to an increase in serious adverse events and fatalities in patients receiving idelalisib . The majority of adverse events were infections, including sepsis and pneumonia. In particular, an increased number of cases of Pneumocystis pneumonia and cytomegalovirus (CMV) infection was observed in the idelalisib groups of three trials . The manufacturer has suggested that patients taking idelalisib receive Pneumocystis prophylaxis. They have also suggested that patients taking idelalisib be monitored for CMV reactivation and that idelalisib be discontinued in patients with evidence of infection or viremia. Changes to the prescribing information are expected, pending review by the US Food and Drug Administration. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Idelalisib' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib and idelalisib'.)
Nonmedical vaccine exemptions and risk of measles and pertussis (March 2016)
Despite universal childhood vaccination programs in the United States, the incidence of measles and pertussis has increased since the early 2000s. A systematic review evaluated the association between vaccine refusal and measles or pertussis infection in the United States between 2000 and 2015 . Nearly 60 percent of 1416 measles cases occurred in people who were not vaccinated against measles. Among the 574 unvaccinated cases who were old enough to have received measles vaccine, 71 percent refused it for nonmedical reasons (eg, religious or philosophic beliefs). Nonmedical exemptions also were prevalent among unvaccinated cases of pertussis (ranging from 59 to 93 percent in eight outbreaks). These findings confirm that nonmedical exemptions increase the risk of vaccine-preventable illness in the unvaccinated individual and, by reducing overall community immunity, increase the risk of illness in children too young to be vaccinated, people with medical contraindications to vaccination, and vaccinated people with waning immunity . (See "Standard childhood vaccines: Parental hesitancy or refusal", section on 'For the individual'.)
Duration of protection after hepatitis B vaccination (February 2016)
After completion of the hepatitis B vaccination series, levels of protective antibody decline over time. Protection against clinical disease is provided by memory cells, which elicit an anamnestic antibody response. However, the duration of protection is unknown. In a long-term follow-up study, 51 percent of 243 Alaska Native adults and children maintained protective antibody levels 30 years after completion of the hepatitis B vaccine series and 88 percent of those without protective levels mounted an anamnestic response . These findings suggest that protection persists for up to 30 years and support the current hepatitis B immunization schedule, which does not include a booster dose for patients with normal immune status. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Duration of immunity' and "Hepatitis B virus vaccination", section on 'Duration of protection'.)
Updated adult immunization schedule in the United States (February 2016)
Updates to the adult immunization schedule for 2016 have been issued by the United States Advisory Committee on Immunization Practices (ACIP) (figure 1 and figure 2) . Changes from the 2015 schedule include updates to the recommendations for pneumococcal vaccine, serogroup B meningococcal (MenB) vaccine, and human papillomavirus (HPV) vaccine. The interval between administration of the 23-valent pneumococcal polysaccharide (PPSV23) and the 13-valent pneumococcal conjugate (PCV13) vaccines has been changed from '6 to 12 months' to 'at least one year' for immunocompetent adults aged ≥65 years. In addition, the MenB vaccine series should be administered to individuals age ≥10 years who are at increased risk for serogroup B meningococcal disease. Finally, the nine-valent HPV vaccine has been added to the schedule as an option for routine HPV vaccination for females and males. (See "Approach to immunizations in healthy adults", section on 'Immunization schedule for healthy adults'.)
Adjuvanted influenza vaccine approved for elderly adults in the United States (November 2015)
There has been interest in using adjuvants in influenza vaccines in elderly individuals, who have reduced immune responses to influenza vaccines; adjuvants are substances that amplify the immune response to an antigen. In November 2015, an adjuvanted trivalent inactivated influenza vaccine (Fluad) was approved for use in individuals ≥65 years of age in the United States . It is the first adjuvanted seasonal influenza vaccine to be approved in the United States, but it has been approved already in >35 other countries. The vaccine is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. Studies have shown that the MF59-adjuvanted vaccine has comparable  or higher immunogenicity compared with unadjuvanted vaccines [30-32]. Until further data are available, we continue to suggest the non-adjuvanted high-dose inactivated vaccine for individuals ≥65 years of age. (See "Seasonal influenza vaccination in adults", section on 'Adjuvanted vaccine' and "Seasonal influenza vaccination in adults", section on 'Vaccine formulations'.)
Statins and influenza vaccine immunogenicity and effectiveness (November 2015)
Statins are used commonly in older adults with hyperlipidemia and are known to have immunomodulatory effects, which could affect vaccine responses. In an observational study conducted in the context of a randomized trial that evaluated influenza vaccines in individuals >65 years of age, hemagglutination inhibition (HAI) geometric mean titers to various influenza strains were substantially lower in those receiving chronic statin therapy than in those not receiving it . In addition, in the adjusted analysis of a large retrospective cohort study, statin use was associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness . The observed associations between statin use and vaccine effectiveness could be due to confounding, as patients receiving statins are likely to be at differing baseline risk of influenza from those not receiving statins. Although these studies raise the possibility that older patients receiving statins are less likely to be protected by the influenza vaccine, such individuals should still receive statins, when indicated, as well as an influenza vaccine annually. (See "Seasonal influenza vaccination in adults", section on 'Efficacy'.)
Influenza vaccination and influenza-associated pneumonia (October 2015)
Many studies have demonstrated that influenza vaccination decreases the incidence of laboratory-confirmed influenza infection, but few have evaluated the effect on the serious complications of influenza. Recent data suggest that vaccination is associated with a reduced risk of influenza pneumonia. In a case-control study of adult and pediatric patients hospitalized for community-acquired pneumonia (CAP), those with laboratory-confirmed influenza-associated pneumonia had lower odds of having received an influenza vaccine during the same influenza season compared with those with CAP not associated with influenza . The estimated vaccine effectiveness for preventing influenza-associated pneumonia was 57 percent. (See "Seasonal influenza vaccination in adults", section on 'Trivalent inactivated vaccines' and "Seasonal influenza in children: Prevention with vaccines", section on 'Indications'.)
Urine mycobacterial antigen lipoarabinomannan (LAM) for TB testing (March 2016)
Urine-based detection of mycobacterial antigen lipoarabinomannan (LAM) is a bedside assay to diagnose hematogenously disseminated tuberculosis (TB). LAM plus routine diagnostic testing (smear microscopy, Xpert-MTB/RIF and culture) was compared with routine diagnostic testing alone in a randomized trial involving over 2500 HIV-infected hospitalized adults in four African countries with at least one symptom suggesting TB . All-cause mortality at eight weeks was decreased in the group that had LAM testing to guide initiation of antituberculosis treatment (relative risk reduction 17 percent). Neither patients nor health care workers were masked to group allocation or test results, presenting a risk of bias. Nonetheless, we are in agreement with the World Health Organization (WHO), which favors use of urine LAM testing for hospitalized HIV-infected patients with signs and symptoms of tuberculosis and CD4 ≤100 cells/microL, and HIV-infected patients who are seriously ill regardless of CD4 count. (See "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients", section on 'Urine antigen detection'.)
Nontuberculous mycobacteria in patients with cystic fibrosis (February 2016)
Nontuberculous mycobacteria (NTM) are in the sputum of up to 20 percent of patients with cystic fibrosis (CF), and some of these patients develop progressive NTM pulmonary disease (NTM-PD). New guidelines provide recommendations for the screening, diagnosis, and management of NTM in CF patients . Annual screening of sputum is recommended for all expectorating patients. Patients with persistently positive results or symptoms suggesting NTM-PD should have a full evaluation including high-resolution computed tomography (HRCT) and sometimes bronchoscopy to determine if they meet criteria for NTM pulmonary disease (table 2). For any patient on chronic azithromycin therapy suspected of NTM infection, azithromycin should be stopped temporarily pending further diagnostic evaluation, to reduce the risk of inducing resistance because of monotherapy. (See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Nontuberculous mycobacteria'.)
Artemisinin combination therapy for uncomplicated falciparum malaria in pregnancy (March 2016)
An artemisinin combination therapy (ACT) is the regimen of choice for treatment of pregnant women with uncomplicated chloroquine-resistant P. falciparum malaria during the second or third trimesters. This approach is supported by a recent large trial including 3428 pregnant women in four African countries (Burkina Faso, Ghana, Malawi and Zambia) randomly assigned to treatment with one of four ACT regimens (artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine) with cure rates of 95 to 99 percent . Dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile, with the benefit of a longer post-treatment prophylactic effect. Artemether-lumefantrine was associated with the fewest adverse effects and acceptable cure rates, but had the shortest post-treatment prophylactic effect; this may be particularly important in high-transmission settings where a prolonged post-treatment prophylactic effect can reduce morbidity by decreasing the frequency of new infections. (See "Prevention and treatment of malaria in pregnant women", section on 'Second and third trimesters'.)
Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy (March 2016, Modified March 2016)
For pregnant women who live in areas with medium and high malaria transmission, we agree with the World Health Organization (WHO) strategy to provide intermittent preventive treatment during pregnancy (IPTp). Sulfadoxine-pyrimethamine (SP) has been an effective drug for IPT, although its benefit may be limited given the emergence of drug resistance. Two trials in Kenya and Uganda (where SP resistance is widespread) have evaluated the efficacy of dihydroartemisinin-piperaquine (DP) for IPTp:
●In a trial including over 1500 Kenyan women randomly assigned to receive IPT with SP or DP, IPT with DP resulted in a lower prevalence of malaria infection at delivery (3 versus 10 percent) and fewer episodes of clinical malaria during pregnancy (38 versus 6 episodes) compared with IPT with SP . The trial was not powered to detect small differences in neonatal outcomes.
●In a trial including 300 pregnant adolescents and women in Uganda randomly assigned to receive IPT with SP (three doses), DP (three doses), or DP (monthly treatments starting as early as 16 weeks of gestation) , the prevalence of histopathologically confirmed placental malaria was lower among those who received monthly DP (27 percent) than among those who received three doses of DP (34 percent) or IPT with SP (50 percent). In addition, monthly DP treatment was superior to three-dose DP with regard to several outcomes, including adverse birth outcomes and the incidence of symptomatic malaria.
DP is a promising alternative agent for IPTp; further study of DP dosing in pregnancy is needed. (See "Prevention and treatment of malaria in pregnant women", section on 'Intermittent preventive treatment during pregnancy'.)
SEXUALLY TRANSMITTED DISEASES
Azithromycin versus doxycycline for uncomplicated chlamydia (January 2016)
The first-line regimens for uncomplicated urogenital chlamydial infection are azithromycin administered as a single dose or a seven-day course of doxycycline administered twice daily. There is emerging evidence that the efficacy of doxycycline may be marginally greater than that of azithromycin, although the reasons for this are unknown. In a trial of 310 adolescents and young adults who screened positive for urogenital Chlamydia trachomatis upon entrance into a correctional facility, microbial cure rates at 28 days were high for both doxycycline and azithromycin (each administered as directly-observed therapy), but were numerically higher for doxycycline (100 versus 97 percent) . Adherence is the main challenge with the doxycycline regimen, and direct observation of the full course is unrealistic in most situations; thus, it is uncertain that doxycycline would achieve a similarly superior cure rate in the community. Given the very high efficacy of azithromycin, we continue to favor directly-observed single-dose azithromycin for treatment of uncomplicated urogenital C. trachomatis infection. (See "Treatment of Chlamydia trachomatis infection", section on 'First-line agents'.)
VIRAL INFECTIONS, NON-HIV
Investigational laboratory test for Zika virus in donated blood (April 2016)
A laboratory test that detects Zika virus RNA is under investigation in the United States to screen donated blood for Zika . This test has been implemented under a US Food and Drug Administration (FDA)-approved investigational new drug application (IND) for all blood that is collected in Puerto Rico, a jurisdiction defined by the Centers for Disease Control (CDC) as an active Zika virus transmission area. In areas without active transmission, the donor medical and travel history is used to disqualify individuals who may be infected with Zika. (See "Blood donor screening: Laboratory testing", section on 'Zika virus'.)
Zika virus and tissue/gamete donation (March 2016)
Zika virus has been detected in a number of tissues and body fluids. To avoid possible transmission of Zika virus infection, the US Food and Drug Administration (FDA) has issued donor deferral recommendations for hematopoietic stem cells, tissues, and donor sperm or eggs; the recommendations do not apply to solid organs . Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for donation for six months. Deceased donors with Zika virus infection in the preceding six months should also be considered ineligible. The deferral period recommended by the FDA for blood donors with risk factors for Zika virus infection remains at four weeks. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)
Zika virus and Guillain-Barre syndrome (March 2016)
Zika virus has been associated with Guillain-Barre syndrome (GBS), although a direct causal relationship has not been definitively established. A case-control study in French Polynesia evaluated the association between GBS and Zika virus infection during the 2013 to 2014 outbreak . Cases included 42 patients diagnosed with GBS; one control group included 98 patients with nonfebrile illnesses and a second control group included 70 patients with Zika virus infection in the absence of neurological complications. Zika IgM was positive in 93 percent of GBS cases (versus 17 percent of patients in the first control group); serologic evidence of past dengue infection was similar among all three groups. Antiglycolipid IgG antibodies were detected in fewer than 50 percent of GBS cases, raising the possibility of direct viral neurotoxicity. Results of nerve conduction studies were consistent with the acute motor axonal neuropathy type of GBS; clinical improvement during follow-up suggested reversible conduction failure. Symptoms of Zika virus infection occurred in 88 percent of patients with GBS; the median interval between viral syndrome and onset of neurological symptoms was six days. All GBS cases received intravenous immune globulin, 38 percent required intensive care, and 29 percent needed respiratory care; all survived. The incidence of GBS during the outbreak was estimated to be 0.24 cases per 1000 Zika virus infections. (See "Zika virus infection: An overview", section on 'Guillain-Barré syndrome'.)
Elbasvir-grazoprevir for chronic HCV infection (February 2016)
Despite the proliferation of interferon-free regimens for the treatment of chronic hepatitis C (HCV) infection, safety concerns have limited options for patients with severe renal impairment, who have been excluded from trials of most available regimens. In January 2016, the US Food and Drug Administration approved the new combination regimen elbasvir-grazoprevir for the treatment of patients with genotypes 1 and 4 HCV infection, including those with any degree of renal impairment (including dialysis dependence) . In a randomized, placebo-controlled trial of genotype 1-infected patients with estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2, the sustained virologic response (SVR) rate was 94 percent among the 122 patients who received elbasvir-grazoprevir for 12 weeks, and adverse event rates were similar between treatment and placebo groups . These results were comparable to those among patients with normal renal function. Elbasvir-grazoprevir is given for 12 to 16 weeks with or without ribavirin, depending on the presence of pre-existing resistance-associated variants in the NS5A protein and prior exposure to HCV protease inhibitors. (See "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Regimens with direct-acting antivirals'.)
Hepatitis B virus reactivation in patients undergoing chemotherapy for solid tumors (January 2016)
Patients with serologic evidence of hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg]-positive or hepatitis B core antibody [anti-HBc]-positive) are at risk for HBV reactivation if they receive immunosuppressive therapy. However, the magnitude of risk for patients receiving chemotherapy for solid tumors has not been well established. In a systematic review of such patients, the risk of reactivation among those who were HBsAg-positive ranged from 4 to 68 percent, with most studies reporting a reactivation risk greater than 10 percent . Antiviral therapy administered during chemotherapy was associated with an approximately 90 percent reduction in HBV reactivation risk as well as reductions in HBV-related hepatitis and the need for chemotherapy interruption. Although some expert groups disagree, we check HBV serologies before initiating therapy with any potentially immunosuppressive chemotherapy. Our recommendations for prophylactic antiviral therapy depend upon the HBsAg status of the patient and the type of chemotherapy used. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Who is at risk for HBV reactivation'.)
Zika virus infection in the Americas (January 2016)
Zika virus is a member of the flavivirus family that is spread via mosquito bites. Outbreaks have occurred in Africa, Southeast Asia, and the Pacific Islands; more recently Zika virus has spread to the Americas. More than 20 countries in Latin America have confirmed circulation; cases of Zika virus infection in the United States have occurred among returning travelers. The illness is usually mild; typical symptoms include fever, rash, joint pain, and conjunctivitis. However, Zika virus infection has also been associated with perinatal complications (congenital microcephaly and fetal losses) and Guillain-Barre syndrome . In 2015-2016, more than 5000 cases of microcephaly were reported among newborns in Brazil; this represents a >20-fold increase in the number of cases compared with years prior to the circulation of Zika virus . A number of authorities have advised that pregnant women consider postponing travel to areas below 6500 feet (2000 meters) where mosquito transmission of Zika virus is ongoing . Sexual transmission have been described . It is prudent for individuals with Zika virus infection/exposure to abstain from sexual activity (vaginal, anal, and oral sex) or use barrier protection; men who have a pregnant partner should follow such guidance for the duration of the pregnancy. Zika virus is also transmissible via blood products; deferral of blood donors for one month following Zika virus infection/exposure is advised . (See "Zika virus infection: An overview", section on 'Geographic distribution'.)
Investigational combination of sofosbuvir plus velpatasvir for chronic HCV infection (November 2015)
The selection of all-oral antiviral regimens for patients with chronic hepatitis C virus (HCV) infection currently depends on the infecting genotype, treatment history, and the presence of cirrhosis. The investigational agent sofosbuvir-velpatasvir, a coformulated combination of an NS5B and an NS5A inhibitor, appears extremely effective across viral genotypes and patient characteristics, and thus offers the possibility of a streamlined approach to regimen selection. In a randomized, placebo-controlled trial of patients with genotypes 1, 2, 4, 5, and 6 infection, including those with cirrhosis and prior treatment failure with interferon-containing regimens, the sustained virologic response (SVR) rate among the 624 patients who were assigned to receive sofosbuvir-velpatasvir for 12 weeks was 99 percent . In another study, the regimen resulted in an SVR rate of 98 percent among 163 treatment-naïve genotype 3-infected patients without cirrhosis . SVR rates were somewhat lower, but still high (89 to 93 percent), in the setting of genotype 3 infection with cirrhosis and/or prior treatment failure. (See "Investigational therapies for hepatitis C virus infection", section on 'Sofosbuvir and velpatasvir'.)
Hepatic decompensation associated with ombitasvir-paritaprevir-ritonavir for chronic HCV infection (November 2015)
With more widespread use of ombitasvir-paritaprevir-ritonavir with or without dasabuvir for patients with chronic hepatitis C virus (HCV) genotypes 1 and 4 infection, reports of associated hepatic injury and decompensation have emerged . Most cases occurred in patients with existing cirrhosis and within one to four weeks of drug initiation; some cases resulted in death or need for liver transplantation. Patients with compensated cirrhosis who use this regimen should be monitored closely for signs of decompensation and undergo interval transaminase and bilirubin testing after initiation. The regimen is contraindicated in individuals with Child B and C class cirrhosis. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ombitasvir-paritaprevir-ritonavir with or without dasabuvir'.)
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