The following represent additions to UpToDate since the last version of What’s New that were considered by the authors and editors to be of particular interest.
BACTERIAL INFECTIONS
Treatment of acute bacterial rhinosinusitis — Guidelines for the treatment of acute bacterial rhinosinusitis (ABRS) have been released from the Infectious Diseases Society of America (IDSA) [1]. Although it is difficult to distinguish viral from bacterial acute rhinosinusitis (ARS), three features suggest the diagnosis of ABRS: 1) persistent symptoms or signs of ARS lasting 10 or more days with no clinical improvement; 2) onset with severe symptoms (fever >39°C or 102°F and purulent nasal discharge or facial pain) lasting at least three consecutive days at the beginning of illness; or 3) onset with worsening symptoms following a viral upper respiratory infection that lasted five to six days and was initially improving. Patients who meet criteria for ABRS should be treated with an antibiotic. The guidelines recommend an empiric course of amoxicillin-clavulanate (500 mg/125 mg orally three times daily or 875 mg/125 mg orally twice daily) for five to seven days for most patients; doxycycline is a reasonable alternative. Doxycycline or a respiratory fluoroquinolone may be used in patients with penicillin allergy. Because of high rates of microbial resistance, macrolides (clarithromycin or azithromycin), trimethoprim-sulfamethoxazole, or oral second- or third-generation cephalosporins should not be used for empiric treatment. (See "Acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Community-acquired acute bacterial rhinosinusitis'.)
Fluoroquinolones and retinal detachment — A nested case-control study of patients who had visited an ophthalmologist found an increased rate of retinal detachment in patients who were currently receiving an oral fluoroquinolone [2]. Past fluoroquinolone use (even if recent) was not associated with retinal detachment, suggesting that retinal detachment may be an acute adverse effect. A possible reason for the increased risk of retinal detachment in patients taking a fluoroquinolone is the destructive effect of this class of agents on collagen and connective tissue. This adverse effect requires confirmation in an additional study. (See "Fluoroquinolones", section on 'Retinal detachment'.)
Nocardia susceptibility patterns — Reported antimicrobial susceptibility patterns of Nocardia isolates vary among different studies, countries, and species. Unexpectedly high rates of resistance to trimethoprim-sulfamethoxazole (TMP-SMX) and sulfamethoxazole were reported in a study of Nocardia isolates collected between 1995 and 2004 that were sent voluntarily to the US Centers for Disease Control and Prevention (CDC) [3]. These results prompted another study in which only 2 percent of 552 clinical Nocardia isolates collected between 2005 and 2011 from six referral centers were resistant to TMP-SMX and/or sulfamethoxazole [4]. Possible differences in the preparation of samples and/or the interpretation of results of in vitro susceptibility testing may explain some of the discordance in the findings [5]. In addition, the earlier study may have been less representative because isolates collected from patients who were not responding to treatment may be more likely to be sent to the CDC than isolates from patients who were responding to treatment. (See "Treatment of nocardiosis", section on 'Antibiotic susceptibility'.)
C. difficile and proton pump inhibitors — Proton pump inhibitors (PPIs) may be associated with an increased risk of C. difficile-associated diarrhea (CDAD). The US Food and Drug Administration (FDA) issued a drug safety communication in February 2012 following a review of published literature [6]. Most studies reviewed found that the risk of C. difficile infection or disease, including CDAD, ranged from 1.4 to 2.75 times higher among patients with PPI exposure compared with those without PPI exposure. The relationship between the risk of C. difficile infection and PPI dose and duration of use is uncertain. Given the potential risk of CDAD, the FDA has also recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. (See "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults", section on 'Gastric acid suppression' and "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Clostridium difficile and other enteric infections'.)
Recurrent C. difficile infection — Recurrent C. difficile infection often represents relapse rather than reinfection, regardless of the interval between episodes. Among 134 paired stool isolates from 102 patients with recurrent C. difficile infections, isolates obtained two to eight weeks apart were identical in 88 percent of cases; isolates obtained 8 weeks to 11 months apart were identical in 65 percent of cases [7]. (See "Clinical manifestations and diagnosis of Clostridium difficile infection in adults", section on 'Recurrent disease: relapse vs reinfection'.)
FUNGAL INFECTIONS
Candida glabrata resistance to azoles and echinocandins — There is increasing concern that some Candida glabrata bloodstream isolates with resistance to fluconazole and voriconazole are also resistant to the echinocandins (caspofungin, micafungin, and anidulafungin). This is important because echinocandins are used commonly for bloodstream infections caused by C. glabrata. In a surveillance study of the in vitro susceptibility of 1669 C. glabrata bloodstream isolates collected in the United States between 2006 and 2010, 9.7 percent were resistant to fluconazole, of which 98.8 percent were also not susceptible to voriconazole [8]. Among the fluconazole-resistant isolates, 9.3, 9.3, and 8 percent were resistant to anidulafungin, caspofungin, and micafungin, respectively, and 11.1 percent were resistant to one or more of the echinocandins. In comparison, there were no echinocandin-resistant strains detected among 110 fluconazole-resistant C. glabrata isolates tested between 2001 and 2004, years during which only one echinocandin, caspofungin, was available, and echinocandins were used sparingly. At this point, it is not clear what impact these findings will have on treatment regimens for candidemia. (See "Antifungal susceptibility testing", section on 'Echinocandins'.)
PARASITIC INFECTIONS
Empiric treatment for malaria species coinfection — In areas where both P. vivax and P. falciparum are endemic and species diagnosis is unreliable, some advocate treatment with dihydroartemisinin-piperaquine combination therapy. This combination of drugs was shown to be an effective alternative to chloroquine in a randomized trial including 500 patients with acute vivax malaria on the northwestern border of Thailand [9]. The high risk of morbidity and mortality associated with inadequate treatment of improperly diagnosed P. falciparum may justify this approach, particularly in areas where chloroquine-resistant P. vivax exists. (See "Overview of non-falciparum malaria", section on 'Chloroquine resistance'.)
PNEUMONIA
Linezolid versus vancomycin — In a randomized double-blind trial that compared linezolid to vancomycin for the treatment of hospital-acquired pneumonia or healthcare-associated pneumonia due to proven MRSA, the end of study success rate was 58 percent for linezolid and 47 percent for vancomycin [10]. Linezolid was noninferior and statistically superior to vancomycin in end of treatment clinical outcome, and microbiologic outcome at end of treatment and end of study, but there were no differences in all-cause 60-day mortality or overall adverse events. Nephrotoxicity occurred more commonly with vancomycin than linezolid (18 versus 8 percent). (See "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Linezolid and vancomycin'.)
SEXUALLY TRANSMITTED DISEASES
Genital herpes vaccine — A large clinical trial evaluated the efficacy of herpes simplex virus (HSV) vaccine compared with placebo in over 8000 women who were seronegative for HSV-1 and HSV-2 infection [11]. Over 20 months of follow-up after immunization, the HSV vaccine was not efficacious in preventing either HSV-2-related infection or genital ulcerative disease. (See "Prevention of genital herpes virus infections", section on 'Clinical trials of HSV vaccines'.)
Human papillomavirus and oral cancer — Despite the decrease in tobacco use, the incidence of oropharyngeal cancer has been increasing due to human papillomavirus (HPV)-related cancers arising in the base of the tongue and the tonsillar region. A cross-sectional study of men and women aged 14 to 69 years found that the overall prevalence of HPV DNA in oral exfoliated cells was 6.9 percent, and the prevalence of HPV16 was 1 percent [12]. HPV prevalence was approximately threefold more common in men compared with women (10.1 versus 3.6 percent), consistent with the observed sex distribution for HPV associated oropharyngeal cancer. (See "Human papillomavirus associated head and neck cancer", section on 'Epidemiology'.)
IMMUNIZATIONS
Prevention of varicella-zoster infection after exposure — In the past, passive immunization with VariZIG was recommended within four days of exposure to varicella for nonimmune children and adults who are not candidates for varicella vaccine (eg, persons with malignancy, immunocompromise, or pregnant women). However, limited data suggest that the incidence of varicella is comparable among persons who receive passive immunization within four days of varicella exposure or within 5 to 10 days of exposure [13,14]. Based on these data, the United States Food and Drug Administration (FDA) has extended the window of passive immunization after varicella exposure from 4 to 10 days [15]. When postexposure prophylaxis is indicated and active immunization is contraindicated, passive immunization with VariZIG should be offered as soon as possible. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'VariZIG'.)
Norovirus vaccine — No effective norovirus vaccine is available for clinical use, but results from an efficacy trial appear promising [16]. The study included 98 healthy adults with functional fucosyltransferase 2 gene (required for the susceptibility to infection with the prototype norovirus, Norwalk virus). Participants were given two intranasal doses of vaccine or placebo three weeks apart and then challenged orally with a norovirus homologous to that in the vaccine. The proportion of individuals who experienced acute Norwalk virus gastroenteritis was significantly lower in the vaccine group than in the placebo group (37 versus 69 percent), as was the proportion infected with the virus (61 versus 82 percent). Among those who became infected, the vaccine delayed the onset of illness and reduced overall disease severity. No serious adverse events were associated with the experimental vaccine. (See "Prevention and treatment of viral gastroenteritis in adults", section on 'Norovirus'.)
Pneumococcal conjugate vaccine in adults — In December 2011, the 13-valent conjugate pneumococcal vaccine (PCV13) that is used routinely in children was approved by the US Food and Drug Administration (FDA) for use in adults ≥50 years of age based upon safety and immunogenicity data [17]. These data showed that PCV13 induced antibody responses that were either comparable to or higher than the responses induced by the pneumococcal polysaccharide vaccine (PPSV23) [17,18]. It appears to have a similar safety profile as PPSV23. PCV13 has not yet been recommended by the United States Advisory Committee on Immunization Practices. (See "Pneumococcal vaccination in adults", section on 'Conjugate vaccines'.)
Group B meningococcal vaccine in adolescents — Although group B meningococcus is one of the most common serotypes causing infection, no broadly effective vaccine preparation is licensed for use to prevent infection with this serogroup. An investigational vaccine against group B meningococcus, which includes three recombinant proteins (neisserial adhesin A, factor H binding protein, and neisserial heparin binding antigen) with outer membrane vesicles from the strain that caused an epidemic in New Zealand (NZ98/254), was found to be highly immunogenic in a randomized trial of adolescents [19]. These data suggest that a broadly cross-reactive meningococcal B vaccine may soon be available pending further studies showing similar effectiveness against a worldwide bank of meningococcal B strains. (See "Meningococcal vaccines", section on 'Group B meningococcus vaccines'.)
Group B meningococcal vaccine in infants — An investigational vaccine against group B meningococcus, including three recombinant proteins and outer membrane vesicles from the strain that caused an epidemic in New Zealand, was evaluated in a randomized trial of healthy infants [20]. Infants were given three doses of the group B meningococcal vaccine with or without the routine childhood vaccines. After three doses of the group B meningococcal vaccine, 99 percent or more of infants developed substantial titers (serum bactericidal activity titers ≥5) against two of the three reference strains of meningococcus evaluated. Responses to the routine vaccines given concurrently with the group B meningococcal vaccine were non-inferior to the responses to the routine vaccines given alone, except for the responses to pertactin (a correlate of immunity to pertussis) and serotype 6B pneumococcal polysaccharide. These results in infants suggest that this candidate vaccine is promising for use in infants at increased risk of group B meningococcus. (See "Meningococcal vaccines", section on 'Group B meningococcus vaccines'.)
Human papillomavirus vaccine for prevention of anal intraepithelial neoplasia — A quadrivalent vaccine has been shown to be effective in preventing infection with human papillomavirus vaccine (HPV) types 6, 11, 16, and 18 and to prevent the development of external genital lesions [21]. A planned substudy of that trial analyzed the impact of the vaccine on the development of anal intraepithelial neoplasia in 602 men who have sex with men [22]. Study subjects were aged 16 to 26 years, had no history or evidence of anal lesions, had five or fewer lifetime sexual partners, and were HIV-negative. Administration of the HPV vaccine was associated with a significant decrease in the incidence of anal intraepithelial neoplasia. (See "Anal intraepithelial neoplasia: Diagnosis, screening, prevention, and treatment", section on 'Prevention'.)
Vaccination of patients with diabetes mellitus — The Advisory Committee on Immunization Practices recommends that hepatitis B virus (HBV) vaccination be given to unvaccinated adults with diabetes mellitus who are ages 19 to 59 [23]. For older patients with diabetes, vaccination can be administered at the discretion of the treating clinician based on the risk of acquiring HBV and the likelihood of an adequate immune response to vaccination. (See "Hepatitis B virus vaccination", section on 'Other high-risk groups'.)
Influenza vaccination in patients receiving rituximab — The anti-CD20 monoclonal antibody, rituximab, has become a standard part of the treatment of CD20-positive B cell lymphomas. Since this agent depletes normal B cells, there is concern that it will attenuate the response to vaccines. In a study of lymphoma patients who had received a rituximab-containing treatment regimen within the previous six months, none of 67 patients developed seroprotective titers following administration of an adjuvanted inactivated pandemic H1N1 influenza A vaccine [24]. In contrast, 82 percent of healthy controls developed seroprotective titers following vaccination. This study suggests that, when feasible, the influenza vaccine (and other indicated vaccines) should be given to lymphoma patients before initiation of rituximab. (See "Immunizations in patients with cancer", section on 'Influenza vaccine' and "Immunizations in patients with cancer", section on 'General approach'.)
MYCOBACTERIA
Diagnosis of extrapulmonary tuberculosis — The GeneXpert MTB/RIF assay is an automated nucleic acid amplification test that can simultaneously identify M. tuberculosis and rifampin resistance. The assay is known to have excellent sensitivity and specificity for detection of pulmonary tuberculosis. Recently the test was also shown to have excellent sensitivity and specificity for diagnosis of extrapulmonary tuberculosis for the majority of specimen types, with the exception of cerebrospinal fluid [25]. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Xpert MTB/RIF'.)
Treatment of latent tuberculosis — Rifapentine is a rifamycin derivative with a long half-life and greater potency against M. tuberculosis than rifampin. A three-month regimen of weekly isoniazid (INH) and rifapentine (RPT) given as directly observed therapy (DOT) has been shown to be noninferior to a nine-month self-administered regimen of daily INH in a randomized, open label international trial in predominantly HIV-negative individuals at high risk for progression from latent tuberculosis infection (LTBI) to active infection [26]. Hepatoxicity occurred more frequently in the INH group while hypersensitivity was more frequent in the combination therapy group. The completion rate was higher for the combination therapy, partially attributable to the administration of combination therapy via DOT. Higher completion rates with DOT may also explain some of the difference in efficacy of the two regimens.
The Centers for Disease Control and Prevention recommends either the three-month regimen of INH and RPT (directly observed therapy) or the nine-month regimen of INH as equal alternatives for treatment of LTBI in otherwise healthy patients aged ≥12 years with risk for TB reactivation [27]. We favor the three-month regimen of INH-RPT for treatment of LTBI in adults when directly observed therapy is feasible, given its noninferiority to INH and the higher treatment completion rate (table 1). (See "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Treatment regimens' and "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Selecting a regimen'.)
HIV
When to initiate HIV treatment — In 2012, the expert panel of the United States Department of Health and Human Services (DHHS) issued a major change in the previously-issued HIV treatment guidelines; antiretroviral therapy (ART) is now recommended in all HIV-infected patients, regardless of CD4 cell counts [28]. Supportive arguments for this significant shift in treatment recommendations include the availability of more potent agents with less toxicity and recognition that untreated HIV infection has been associated with increased morbidity and mortality related to various comorbidities, including cardiovascular, kidney and liver disease and malignancy. (See "When to initiate antiretroviral therapy in HIV-infected patients".)
Drug interactions with boceprevir in patients with HIV — Boceprevir is a protease inhibitor used in the treatment of patients with hepatitis C virus (HCV) genotype 1 infection. If boceprevir is used in combination with certain ritonavir-boosted HIV protease inhibitors (eg, atazanavir, lopinavir, darunavir), the effectiveness of boceprevir as well as the ritonavir-boosted medications may be decreased. The US Food and Drug Administration recommends that patients taking boceprevir along with one of the listed ritonavir-boosted protease inhibitors should be closely monitored for potential HCV and HIV virologic rebound [29]. (See "Treatment of hepatitis C virus infection in the HIV-infected patient", section on 'ART and HCV protease inhibitors'.)
Prevention of HIV transmission in breastfeeding infants — Nevirapine is effective in preventing HIV perinatal transmission during the first six weeks of life. In a clinical trial in Africa, nevirapine was administered from birth to six weeks as standard of care to 1527 breastfeeding infants born to HIV-infected mothers [30]. Subsequently the infants were randomly assigned to either extended nevirapine prophylaxis or placebo until six months of follow-up or until breastfeeding cessation, whichever came first. Compared with placebo, extended nevirapine prophylaxis reduced mother-to-child transmission of HIV by 54 percent (ie, 18 of 699 infants versus 8 of 700 infants, respectively). (See "Prevention of HIV transmission through breastfeeding in resource-limited settings", section on 'Infant antiretroviral prophylaxis to prevent HIV acquisition'.)
Treatment of latent tuberculosis in HIV-infected patients — In the large randomized clinical trial discussed in detail above, a three-month regimen of weekly isoniazid (INH) and rifapentine (RPT), given as directly observed therapy, was noninferior to a nine-month self-administered regimen of daily isoniazid for the treatment of latent tuberculosis [26]. (See 'Treatment of latent tuberculosis' above.)
This trial included 161 HIV-infected patients who were not taking antiretroviral therapy, representing approximately 3 percent of the total number of study participants. Patients were not randomly assigned to treatment arm by HIV status; thus, 87 received dual therapy and 74 received monotherapy. The Centers for Disease Control suggests that isoniazid plus rifapentine given once weekly for 12 weeks is a therapeutic alternative to nine months of daily isoniazid for the HIV-infected patient who does not have an indication for antiretroviral therapy [27]. This three-month-course of directly-observed dual therapy may be an attractive option for patients living in areas with low to moderate risk of tuberculosis who may not be able to adhere to nine months of daily isoniazid. (See "Treatment of latent tuberculosis infection in HIV-infected patients", section on 'North America'.)
Treatment of the pregnant HIV-infected patient — The US Department of Health and Human Services has published new guidelines for the treatment of the pregnant HIV-infected female [31]. Three-drug combination antiretroviral therapy is recommended during the antepartum and intrapartum periods to prevent perinatal transmission. Women who do not need treatment for their own health should still be offered antiretroviral prophylaxis to prevent mother-to-child transmission of HIV infection. (See "Antiretroviral therapy for the pregnant HIV-infected patient in resource-rich settings", section on 'General principles'.)
VIRAL INFECTIONS, NON-HIV
Subclinical and mild avian influenza — Sporadic transmission of H5N1 avian influenza to more than 590 humans since 2003 has prompted concerns that conditions are suitable for emergence of a severe influenza pandemic [32]. The case-fatality rate of H5N1 avian influenza has been reported to be approximately 60 percent, which is much higher than the case-fatality rate of seasonal influenza. An important question is whether cases of H5N1 avian influenza have gone undetected, given the fact that most known cases have occurred in rural areas with limited access to healthcare providers. In a meta-analysis of published studies that evaluated serologic evidence of H5N1 influenza infection in humans, 1.2 percent of individuals without a history of documented infection had H5N1 avian influenza antibodies [33]. Most participants reported no recent respiratory and/or febrile illnesses. These results indicate that subclinical and/or mild infections occur, albeit infrequently, suggesting that the high case-fatality rate that has been reported with H5N1 influenza may be an overestimate. (See "Epidemiology, transmission, and pathogenesis of avian influenza", section on 'Subclinical and mild infections'.)
H3N2 variant influenza — Between August and December 2011, the United States Centers for Diseases Control and Prevention (CDC) reported 12 cases in five states of infection with H3N2 influenza A viruses caused by reassortment of swine-origin H3N2 influenza A viruses and pandemic H1N1 influenza A viruses [34]. Six of the 12 patients had no recent exposure to swine. Surveillance of swine herds suggests that the same strain is circulating concurrently in swine. Based on cases that have occurred in clusters and cases that have occurred following swine exposure, it is likely that limited human-to-human and swine-to-human transmission has occurred. (See "Epidemiology of influenza", section on 'H3N2 variant influenza'.)
Transmissible experimental avian influenza — Researchers in the United States and the Netherlands have reported creating recombinant H5N1 avian influenza viruses that are transmissible in ferrets, which are considered an excellent model for human influenza infections [35]. In the fall of 2011, a United States government advisory panel, the National Science Advisory Board for Biosecurity, asked the journals considering these manuscripts, Science and Nature, to withhold details that would allow replication of the experiments because of concerns about this information being used for bioterrorism. This intervention has spurred much debate [36-47]. A group of experts that met at the World Health Organization in February 2012 recommended that the full results of these studies be published [48].
The first of the two studies was published in May 2012 [49,50]. In this study, researchers randomly mutated the hemagglutinin (HA) gene in an H5N1 avian influenza virus and detected an isolate that possessed two mutations that enabled the HA protein to preferentially bind to alpha 2-6 galactose receptors; these receptors are found on epithelial cells of the human upper respiratory tract. After introducing additional HA mutations, the resulting virus had improved transmission among ferrets. However, this virus spread more slowly and caused less damage in the lungs than the 2009-2010 pandemic H1N1 influenza virus, and did not result in any fatal infections. (See "Epidemiology, transmission, and pathogenesis of avian influenza", section on 'Transmissible experimental avian influenza'.)
CHRONIC FATIGUE SYNDROME
Lack of association with retroviruses — A study that reported the detection of DNA from the retrovirus xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome [51] was later partially retracted by the authors [52] and subsequently fully retracted by the editor of the journal in which it was published due to concerns about the validity of the results [53]. Soon after this full retraction occurred, the authors of a similar study [54] retracted their results as well [55]. (See "Clinical features and diagnosis of chronic fatigue syndrome", section on 'XMRV and MLV'.)
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