Clinical Infectious Diseases

Landmark studies on the dynamics of HIV-1 infection, conducted nearly a decade ago, provided the theoretical framework on which the modern approach to combination antiretroviral therapy is based [1]. It is now accepted dogma that the high turnover rate of the virus, coupled with a high mutation rate—a consequence of the low fidelity of reverse transcriptase—leads to the accumulation of mutations in the viral quasispecies over time. According to this model, individual drug-resistance mutations are represented many times in the quasispecies; doublemutants are less common, and specific triple mutants are relatively rare [2]. Antiretroviral regimens consisting of several drugs with nonoverlapping resistance patterns erect a genetic barrier to resistance, because multiple mutations—which are unlikely to be preexisting in any single viral genome—are needed to reduce activity of the regimen. Because the level of plasma HIV-1 RNA at steady state is a function of the replication rate and because the replication rate is a determinant of the mutation rate, it is reasonable to assume that patients with high plasma HIV-1 RNA levels are more likely to harbor preexisting drug-resistant variants than are patients with lower virus loads. Likewise, patients with advanced HIV-1 disease may be at greater risk for the development of drug-resistant virus. In such patients, the genetic barrier of triple combination therapy might not suffice to prevent emergence of resistance and ensure durable suppression of virus replication. Indeed, for certain 3-drug combination regimens, high virus load and low CD4 cell count are associated with a greater risk of treatment failure [3].

A multicenter prospective, randomized, controlled trial, with 0.5% tincture of chlorhexidene versus 10% povidone-iodine as cutaneous antisepsis for central venous catheter (CVC) insertion, was conducted for patients in intensive care units. Of 374 patients, 242 had a CVC inserted for >3 days and were used for the primary analysis. Outcomes included catheter-related bacteremia, significant catheter colonization (⩾15 colony-forming units [cfu]), exit-site infection, serial quantitative exit-site culture (every 72 h), and molecular subtyping of all isolates. Patients in both study groups were comparable with respect to age, sex, underlying disease, length of hospitalization, reason for line insertion, and baseline APACHE II score. Documented catheter-related bacteremia rates were 4.6 cases per 1000 catheter-days in the chlorhexidine group (n = 125) and 4.1 cases per 1000 catheter-days in the povidone-iodine group (n = 117; not significant [NS]). Significant catheter-tip colonization occurred in 24 (27%) of 88 patients in the povidone-iodine group and in 31 (34%) of 92 patients in the chlorhexidine group (NS). A mean exit-site colony count of 5.9 × 105 cfu/mL per 25 cm2 of the surface area of skin in the povidone-iodine group versus 3.1 × 105 cfu/mL per 25 cm2 in the chlorhexidine group (NS) was found. There was a trend toward fewer exit-site infections in the chlorhexidine group (0 of 125 patients) versus those in the povidone-iodine group (4 of 117 patients; P = .053). Results of an intention-to-treat analysis were unchanged from the primary analysis. No difference was demonstrable between 0.5% tincture of chlorhexidine and 10% povidone-iodine when used for cutaneous antisepsis for CVC insertion in patients in the intensive care unit.

Although drug-induced rash is frequent in human immunodeficiency virus (HIV)-infected patients, rash due to pyrimethamine has not been described previously. In a randomized, double-blind, placebo-controlled study of pyrimethamine as primary prophylaxis for toxoplasmic encephalitis, the incidence of rash (per hundred patient-years) was 8.1 in the pyrimethamine group versus 1.5 in the placebo group (P < .0002). The 1-year incidence of toxoplasmic encephalitis after occurrence of rash was 37%, as compared with 9.6% in the pyrimethamine group without rash, with a 3.7 times higher risk for patients with pyrimethamine-induced rash (P = .001); the incidence was 13% in the placebo group. At the time of toxoplasmic encephalitis, pyrimethamine was successfully readministered to 80% of patients who discontinued it because of rash. Thus, pyrimethamine, when used for prophylaxis, does induce rash in HIV-infected patients. These patients are at higher risk for toxoplasmic encephalitis and should be carefully monitored for it.

Background. Invasive candidiasis is the third most common bloodstream infection in the intensive care unit (ICU) and is associated with morbidity and mortality. Prophylaxis and preemptive therapy are attractive strategies for this setting. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of caspofungin as antifungal prophylaxis in 222 adults who were in the ICU for at least 3 days, were ventilated, received antibiotics, had a central line, and had 1 additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants). Subjects’ (1,3)-β-d-glucan levels were monitored twice weekly. The primary endpoint was the incidence of proven or probable invasive candidiasis by EORTC/MSG criteria in patients who did not have disease at baseline. Patients who had invasive candidiasis were allowed to break the blind and receive preemptive therapy with caspofungin. The preemptive approach analysis included patients all patients who received study drug, including those positive at baseline. Results. The incidence of proven/probable invasive candidiasis in the placebo and caspofungin arms was 16.7% (14/84) and 9.8% (10/102), respectively, for prophylaxis (P = .14), and 30.4% (31/102) and 18.8% (22/117), respectively, for the preemptive approach (P = .04); however, this analysis included patients with baseline disease. There were no significant differences in the secondary endpoints of mortality, antifungal use, or length of stay. There were no safety differences. Conclusions. Caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant. A preemptive therapy approach deserves further study. Clinical Trials Registration. NCT00520234.

Sindbis virus (SINV) is a mosquito-borne alphavirus found in Eurasia, Africa, and Oceania. Clinical SINV infection, characterized by arthropathic disease that may persist for years, is primarily reported in Northern Europe where the disease has considerable public health importance in endemic areas. The aim of this study was to investigate the role of genetic factors in the susceptibility and outcome of SINV infection and to elucidate the association between SINV infection and autoimmunity. The study included 49 patients with serologically confirmed symptomatic SINV infection who were followed for 3 years after acute infection. Human leukocyte antigen (HLA) genes known to be associated with rheumatic and infectious diseases and complement C4 genes were determined in 35 patients. Furthermore, a set of autoantibodies was measured at the acute phase and 3 years after infection in 44 patients. The frequency of DRB1*01 was significantly higher among patients with SINV infection than in the reference population (odds ratio, 3.3; 95% confidence interval, 1.7-6.5; P = .003). The DRB1*01 allele was particularly frequent in patients who at 3 years postinfection experienced joint manifestations. The frequency of rheumatoid factor at 3 years postinfection was 29.5% and had increased significantly (P = .02) during the 3-year period. In addition, antinuclear and antimitochondrial antibodies were present in serum 3 years postinfection with frequencies of 15.9% and 6.8%, respectively. Our data show that symptomatic SINV infection is associated with the HLA system and that autoantibody titers are elevated in patients 3 years postinfection. These findings indicate that SINV-induced arthritis shares features with autoimmune diseases.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

E. coli O157:H7 is one of many E. coli organisms that contain genes encoding one or more toxins similar in structure and function to Shiga toxin. E. coli O157:H7 is the most frequently isolated diarrheagenic type of E. coli isolated in North America today; this pathogen can cause serious, even fatal disease. Syndromes caused by E. coli O157:H7 include diarrhea, hemorrhagic colitis, and HUS. Poorly cooked ground beef has been the most frequently implicated vehicle of transmission, but additional vehicles are being identified. Treatment consists of rehydration during hemorrhagic colitis and support of the patient during the multiple systemic complications of HUS. A policy of routine screening for E. coli O157:H7 in clinical microbiology laboratories, without reliance on the physician to request that this organism be sought or the technician to notice blood in the stool, is the most effective way to find cases. Timely and accurate diagnosis can prevent secondary transmission, avert unnecessary and possibly dangerous procedures and/or therapies, and detect continuing outbreaks. SLTEC strains other than E. coli O157:H7 may cause diseases similar to or less severe than those caused by E. coli O157:H7. At present, however, screening for such pathogens in clinical laboratories is too labor-intensive to be practical. Education and legislation should promote safe food-preparation and food-handling practices. Research should be directed at reducing the carriage of E. coli O157:H7 at its bovine source, minimizing the microbial content of food and water, and averting systemic microangiopathic hemolytic anemia after infection with this pathogen.

During a study of the nutritional requirements of clinical isolates of Escherichia coli, we found that 21 (7.0%) of 301 strains required nicotinamide to grow in minimal medium. The nicotinamide-requiring strains were present in 16 (15.8%) of 101 cultures of urine from young women with acute cystitis, in 5 (5.0%) of 100 stool specimens from healthy adults, and in none of 100 blood samples from adult patients with bacteremia. Most of the strains belonged to serogroup 018:K1:H7, were hemolytic, possessed type 1 fimbriae, and exhibited similar patterns of antibiotic susceptibility. Two of the urinary isolates expressed S fimbriae, and all 16 urinary isolates contained the sfaS homologue gene on their chromosomes. One of the stool isolates contained the sfaS gene. The urinary isolates closely resembled a large clone of E. coli that is reportedly associated with neonatal meningitis and sepsis. It may be possible to detect this and related clones by their requirement for nicotinamide and to screen strains for S fimbriae by relatively inexpensive hemagglutination methods, including the use of avian P1 antigens to detect mannose-resistant, non-P-fimbriated E. coli; the agglutination of bovine erythrocytes; and the use of bovine mucin to detect sialyl galactosides in S fimbriae.

The goal of this study was to determine the nature and prevalence of abnormalities in lipids, glucose metabolism, and body composition in behaviorally human immunodeficiency virus (HIV)-infected young women and the relationship of these abnormalities to different classes of antiretroviral therapy regimens. We conducted a cross-sectional, multicenter study involving 173 behaviorally HIV-infected women aged 14-24 years and 61 HIV-seronegative control subjects. HIV-infected women were categorized as follows: antiretroviral therapy naive (n=85), receiving a regimen containing a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n=33), receiving a regimen containing a protease inhibitor (PI; n=36), or receiving a regimen not containing an NNRTI or a PI (n=19). Measurements included fasting lipid levels, glucose and insulin levels before and 2 hours after an oral glucose challenge, high-sensitivity C-reactive protein (hsCRP) levels, anthropometry, fat distribution (measured by dual energy X-ray absorptiometry), and antiretroviral therapy and medical histories. Race-adjusted results were compared across groups and within HIV-infected groups. The median age of participants was 20 years. Of HIV-infected subjects, 77% were African American, 35% smoked cigarettes, and 32% reported exercising regularly. More than 40% had a body mass index > or =25. Triglycerides; total, high-density lipoprotein (HDL), and non-HDL cholesterol; and hsCRP levels differed significantly among groups, with higher levels being most common among those receiving antiretroviral therapy. Indices of glucose metabolism did not differ among groups. In general, cholesterol levels, hsCRP levels, and indices of glucose metabolism worsened as body mass index increased. Obesity, dyslipidemia, and inflammation were prominent among HIV-infected adolescent women and, coupled with other risk factors, may accelerate the lifetime risk of cardiovascular disease and other adverse events. These results underscore the need for a multifaceted approach to addressing risk reduction in this population.

Peak bone mass is achieved in adolescence/early adulthood and is the key determinant of bone mass in adulthood. We evaluated the association of bone mass with human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) during this critical period among behaviorally HIV-infected young men and seronegative controls. HIV-positive men (N = 199) and HIV-negative controls (N = 53), ages 14-25 years, were studied at 15 Adolescent Trials Network for HIV/AIDS Interventions sites. HIV-positive participants were recruited on the basis of ART status: ART-naive (N = 105) or on a regimen containing a nonnucleoside reverse transcriptase inhibitor (NNRTI; N = 52) or protease inhibitor (PI; N = 42). Bone mineral density (BMD) and content (BMC) and body composition were measured by dual-energy X-ray absorptiometry (DXA). Results were compared across groups by linear modeling. Bone results were adjusted for race, body mass index (BMI), and type of DXA (Hologic/Lunar). The HIV-positive and HIV-negative groups had comparable median age (21 years) and racial/ethnic distribution. Median times since HIV diagnosis were 1.3, 1.9, and 2.2 years in the ART-naive, NNRTI, and PI groups, respectively (P = .01). Total and regional fat were significantly lower in the ART-naive group compared with seronegative controls. Mean BMD and Z scores were generally lower among HIV-positive participants on ART, particularly in the PI group. Average Z scores for the spine were below zero in all 4 groups, including controls. Young men on ART with a relatively recent diagnosis of HIV infection have lower bone mass than controls. Longitudinal studies are required to determine the impact of impaired accrual or actual loss of bone during adolescence on subsequent fracture risk.

A series of measures were implemented, in a secondary/tertiary-care hospital in Quebec, to control an epidemic of nosocomial Clostridium difficile-associated disease (n-CDAD) caused by a virulent strain; these measures included the development of a nonrestrictive antimicrobial stewardship program. Interrupted time-series analysis was used to evaluate the impact of these measures on n-CDAD incidence. From 2003–2004 to 2005–2006, total and targeted antibiotic consumption, respectively, decreased by 23% and 54%, and the incidence of n-CDAD decreased by 60%. No change in n-CDAD incidence was noted after strengthening of infection control procedures (P = .63), but implementation of the antimicrobial stewardship program was followed by a marked reduction in incidence (P = .007). This suggests that nonrestrictive measures to optimize antibiotic usage can yield exceptional results when physicians are motivated and that such measures should be a mandatory component of n-CDAD control. The inefficacy of infection control measures targeting transmission through hospital personnel might be a result of their implementation late in the epidemic, when the environment was heavily contaminated with spores.

Background. We identified 12 patients with Clostridium difficile infection between July 2011 and March 2012 from whom an unusual C. difficile strain was isolated. This strain had a single-nucleotide deletion of the tcdC gene at position 117 and binary toxin genes, which are characteristic of the hypervirulent ribotype (RT) 027 strain. Methods. A retrospective cohort study of 12 patients infected with C. difficile RT244 and 24 patients infected with non-RT244/non-RT027 strains matched for place of diagnosis and time of collection of specimen was performed. We performed whole-genome sequencing to understand the relationship of the RT244 strain to other C. difficile strains and further understand its virulence potential. Results. Clostridium difficile RT244 was associated with more severe disease and a higher mortality rate. Phylogenomic analysis using core genome single-nucleotide polymorphisms showed that RT244 is in the same genetic clade (clade 2) as RT027 but is distinct from all RT027 strains. The pathogenicity locus of the RT244 strain encodes a variant toxin B, and this was confirmed by demonstration of Clostridium sordellii–like cytopathic effect on Vero cells. Toxin B production in culture supernatants was lower than that seen with a RT027 strain. Conclusions. Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains.

Background: Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. Methods: Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. Results: In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). Conclusions: Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

We conducted a randomized, open-label trial in 42 French hospitals to compare the clinical and bacteriologic efficacy of combination therapy with clarithromycin/clofazimine (Clm/Clof) with that of combination therapy with clarithromycin/rifabutin/ethambutol (Clm/Rib/Eth) as treatment for Mycobacterium avium bacteremia. One hundred forty-four human immunodeficiency virus-seropositive patients older than 18 years of age who had CD4 lymphocyte counts of <100/mm3 and a blood culture positive for M. avium were enrolled in the study. The main measures of outcome were blood cultures, abatement of clinical symptoms (fever), and survival. Treatment success (defined as patient living, either no fever or a reduction of > or = 1 degrees C in initial body temperature, and a blood culture negative for M. avium) was similar in both treatment groups at months 2 and 6. However, following initial resolution of infection, relapse of M. avium bacteremia occurred in more patients in the Clm/Clof group than in the Clm/Rib/Eth group (22 vs. six, respectively; P < .001); these relapses were accompanied by emergence of strains resistant to clarithromycin in 21 and two patients, respectively. In conclusion, combination therapy with Clm/Rib/Eth prevented relapse of mycobacterial disease and, compared with combination therapy with Clm/Clof, was associated with a significant decrease in the emergence of resistant M. avium strains in HIV-infected patients treated for at least 28 weeks.

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

The objective of this prospective, noncomparative study was to assess the safety and efficacy of clindamycin and primaquine therapy for mild-to-moderate pneumocystis pneumonia (defined as a difference of <40 mm Hg between the alveolar and the arterial oxygen determinations) in patients with AIDS. In the first part of the study, 22 patients were treated with iv clindamycin (900 mg every 8 hours) for the first 10 days, and then their therapy was switched to oral clindamycin (450 mg every 6 hours) for an additional 11 days. In the second part of the study, 38 patients were treated entirely with oral clindamycin (600 mg every 8 hours). All patients were treated with oral primaquine base (30 mg once daily). Fifty-five (92%) of 60 patients responded to the study treatment. Forty-six (77%) of 60 patients completed a full course of therapy. Of the nine patients with treatment-limiting toxic effects, four had only a mild rash. This study indicates that the combination of clindamycin and primaquine is an effective and well-tolerated therapy for mild-to-moderate pneumocystis pneumonia in patients with AIDS. Entirely oral therapy appears to be as effective as initial therapy with iv clindamycin.

Background: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. Methods: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. Results: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. Conclusions: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Since 2005, an increase in the prevalence of Clostridium difficile infection (CDI) due to polymerase chain reaction ribotype 078 has been noticed in The Netherlands. This strain has also been identified as the predominant strain in pigs and calves. CDI caused by type 078 was studied in relation to CDI caused by the hypervirulent type 027 and by types other than 027 and 078. Human and porcine isolates were further investigated and characterized by multilocus variable number tandem repeat analysis. From February 2005 through February 2008, the incidence of type 078 among isolates obtained from 1687 patients increased from 3% to 13%. Compared with patients infected with type 027, patients infected with type 078 were younger (67.4 vs. 73.5 years; P < .01) and more frequently had community-associated disease (17.5% vs. 6.7%; odds ratio, 2.98; 95% confidence interval, 2.11-8.02); rates of severe diarrhea (38.9% vs. 40.0%) and attributable mortality (3.8% vs. 4.0%) were similar in both groups. Compared with patients infected with other types, patients infected with type 078 more frequently received fluoroquinolone therapy (29.4% vs. 19.8%; odds ratio, 2.17; 95% confidence interval, 1.06-4.44). Type 078 isolates contained genes for toxin A, toxin B, binary toxin, and a 39-base pair deletion in toxin regulator gene (tcdC), as well as a point mutation at position 184, resulting in a stop codon. Multilocus variable number tandem repeat analysis of 54 human and 11 porcine isolates revealed 4 clonal complexes containing both porcine and human isolates. CDI due to type 078 and CDI due to type 027 present with similar severity, but CDI due to type 078 affects a younger population and is more frequently community associated. C. difficile type 078 isolates from humans and pigs are highly genetically related.

Few data are available regarding the immunogenicity and safety of the pandemic influenza vaccine in immunocompromised patients. We evaluated the humoral response to the influenza A H1N1/09 vaccine in solid-organ transplant (SOT) recipients, in patients with human immunodeficiency virus (HIV) infection, and in healthy individuals. Patients scheduled to receive the pandemic influenza vaccine were invited to participate. All participants received the influenza A H1N1/09 AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin. SOT recipients and HIV-infected patients received 2 doses at 3-week intervals, whereas control subjects received 1 dose. Blood samples were taken at day 0, day 21, and day 49 after vaccination. Antibody responses were measured with the hemagglutination inhibition assay (HIA) and a microneutralization assay. Twenty-nine SOT recipients, 30 HIV-infected patients, and 30 healthy individuals were included in the study. Seroconversion measured by HIA was observed in 15 (52%) of 29 SOT recipients both at day 21 and day 49; in 23 (77%) of 30 at day 21 and 26 (87%) of 30 at day 49 in HIV-infected patients, and in 20 (67%) of 30 at day 21 and in 23 (77%) of 30 at day 49 in control subjects (P = .12 at day 21 and P = .009 at day 49, between groups). Geometric means of antibody titers were not significantly different between groups at day 21 or at day 49. Influenza A H1N1/09 vaccine elicited a similar antibody response in HIV-infected individuals and in control subjects, whereas SOT recipients had an overall lower response. A second dose of the vaccine only moderately improved vaccine immunogenicity in HIV-infected patients.

Gliadel wafers (1,3-bis [2-chloroethyl]-1-nitrosourea; Guilford Pharmaceuticals) are approved for the treatment of malignant gliomas; however, the incidence of and risk factors associated with infection with respect to this new technology are unknown. We identified 32 patients who received Gliadel wafers from December 1996 through October 1999. Nine patients (28%) developed ∼1 surgical site infection (SSI), which included 4 cases of brain abscess. All 3 patients who received vancomycin for surgical prophylaxis developed an SSI. In addition, multivariable analysis revealed an association between infection and a clinical diagnosis of depression. The National Nosocomial Infection Surveillance Surgical Site Index did not predict the onset of SSI after Gliadel wafer implantation. Patients who received a Gliadel wafer had a higher incidence of infection than previously has been reported, and additional studies are required to better quantify this risk and describe the epidemiology of such infections.

(1,3)-β-D-glucan (BG) is a biomarker for invasive candidiasis (IC). The usefulness of BG level as a prognostic marker of treatment outcome is not well characterized. Two hundred fifty-seven patients with proven IC were enrolled in an anidulafungin study. Clinical and microbiological responses at the end of therapy were evaluated. Serial serum BG was measured. Correlation of initial and final BG levels with overall outcome was assessed in each patient. Two hundred three patients had at least 2 BG levels and outcomes assessed. The majority of IC was caused by non-Candida albicans (53%) and found in the blood (84%). Overall, treatment success was 85%. In successfully treated patients, the mean ± SD initial and final BG were 573 ± 681 pg/mL and 499 ± 635 pg/mL (P = .03), respectively; while in treatment-failure patients, the levels were 1224 ± 1585 pg/mL and 1293 ± 1283 pg/mL (P = .29), respectively. A negative slope in BG levels correlated with a successful treatment outcome with a positive predictive value (PPV) of 90%, and a positive slope in BG levels correlated with treatment failure with a negative predictive value (NPV) of 90%. The cutoff value for initial BG <416 pg/mL has potential to predict treatment success with a PPV of 89%. A decrease in BG levels during therapy is associated with treatment success. An initial BG of <416 pg/mL has potential to predict successful treatment outcomes. Baseline and consecutive serum BG measurements may be useful as prognostic markers of treatment outcome in patients with IC receiving primarily echinocandin therapy.

To study the difference between the sexes with regard to chronic hepatitis B virus infection, we surveyed levels of serum hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) among 10,431 asymptomatic Chinese carriers of hepatitis B surface antigen (HBsAg) in Taiwan. There were 7,095 men and 3,336 women in this study; ages ranged from 15 to 70 years. HBeAg was detected in 19.6% of HBsAg carriers. The prevalence of HBeAg decreased significantly with increasing age. HBeAg was detected in 17.7% of men and 23.6% of women. After correction for the confounding effect of age, it was found that the prevalence of HBeAg was significantly higher among women than among men. The level of serum ALT was abnormal in 20.8% of HBsAg carriers. Abnormal ALT levels were significantly more frequent among HBsAg carriers who tested positive for HBeAg (39.7%) than among those who did not (16.2%; P < .001). Among the HBeAg-positive carriers, 43.2% of men and 34.2% of women had abnormal ALT levels, and men were 1.45 times more likely to have abnormal ALT levels than women (P < .001). Among the carriers who were negative for HBeAg, 20.6% of men and only 6.0% of women had abnormal ALT levels, and men were 3.98 times more likely to have abnormal ALT levels than women (P < .001). Overall, 24.6% of men and only 12.6% of women had abnormal ALT levels, and men were 2.33 times more likely to have abnormal ALT levels than were women (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Linezolid, the first oxazolidinone, is active against gram-positive bacteria, including multidrug-resistant strains. This multinational, randomized, double-blind, controlled trial compared the efficacy, safety, and tolerability of linezolid with vancomycin in the treatment of nosocomial pneumonia. A total of 203 patients received intravenous linezolid, 600 mg twice daily, plus aztreonam, and 193 patients received vancomycin, 1 g intravenously twice daily, plus aztreonam for 7–21 days. Clinical and microbiological outcomes were evaluated at test of cure 12–28 days after treatment. Clinical cure rates (71 [66.4%] of 107 for linezolid vs. 62 [68.1%] of 91 for vancomycin) and microbiological success rates (36 [67.9%] of 53 vs. 28 [71.8%] of 39, respectively) for evaluable patients were equivalent between treatment groups. Eradication rates of methicillin-resistant Staphylococcus aureus and safety evaluations were similar between treatment groups. Resistance to either treatment was not detected. Linezolid is a well-tolerated, effective treatment for adults with gram-positive nosocomial pneumonia.

The current West Africa Ebola virus disease (EVD) outbreak has resulted in multiple individuals being medically evacuated to other countries for clinical management. We report two patients who were transported from West Africa to the United States for treatment of EVD. Both patients received aggressive supportive care measures, as well as an investigational therapeutic (TKM-100802) and convalescent plasma. While one patient experienced critical illness with multi-organ failure requiring mechanical ventilation and renal replacement therapy, both patients recovered without serious long-term sequelae to date. It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Phaeohyphomycosis refers to infections caused by darkly pigmented fungi. These fungi rarely cause life-threatening disease. We reviewed 101 cases of culture-proven primary central nervous system phaeohyphomycosis reported in the English-language literature from 1966 to 2002. The most frequently isolated species was Cladophialophora bantiana. The next most frequent isolate was Ramichloridium mackenziei, seen exclusively in patients from the Middle East. More than one-half of the cases occurred in patients with no known underlying immunodeficiency. Mortality rates were high regardless of immune status. Therapy is not standardized, although the combination of amphotericin B, flucytosine, and itraconazole may improve survival rates. Newer azoles, such as voriconazole, also have a broad spectrum of activity against these fungi, although clinical experience is limited. Complete excision of brain lesions may provide better results than simple aspiration. An aggressive medical and surgical approach is warranted in treating these infections to optimize outcomes.

Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1:<10 were defined as nonreactive, which was considered to be nonprotective. The results were compared with data for HIV-uninfected individuals. Serious adverse events were defined as hospitalization or death within 6 weeks after receipt of 17DV. At the time of 17DV administration, the median CD4 cell count was 537 cells/mm(3) (range, 11-1730 cells/mm(3)), and the HIV RNA level was undetectable in 41 of 102 HIV-infected patients. During the first year after vaccination, fewer HIV-infected patients (65 [83%] of 78; P = .01) than HIV-uninfected patients revealed reactive NTs, and their NTs were significantly lower (P < .001) than in HIV-uninfected individuals. Eleven patients with initially reactive NTs lost these reactive NTs <or= 5 years after vaccination. Higher NTs during the first year after vaccination were associated with undetectable HIV RNA levels, increasing CD4 cell count, and female sex. We found no serious adverse events after 17DV administration among HIV-infected patients. Compared with HIV-uninfected individuals, HIV-infected patients respond to 17DV with lower reactive NTs, more often demonstrate nonprotective NTs, and may experience a more rapid decline in NTs during follow-up. Vaccination with 17DV appears to be safe in HIV-infected individuals who have high CD4 cell counts, although rate of serious adverse events of up to 3% cannot be excluded.

Objective. ACTG A5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure on first-line regimens in Africa and Asia. Methods. Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200,000copies/mL. All subjects received LPV/r 400/100mg twice daily. Virologic failure (VF) was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200mg/tenofovir 300mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r-monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. Results. 123 subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 /123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39/41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400copies/mL over 104 weeks on LPV/r-monotherapy was 60% [95% CI 50%, 68%]; 80-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level<400 copies/mL at weeks 24, 48 and 104 revealed that 61%, 62% and 65% were suppressed to <40 copies/mL, respectively. Conclusion. LPV/r monotherapy after first-line virologic failure with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.

We identified the incidence and primary clinical characteristics of histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS) in our hospital. Disseminated histoplasmosis is a common and severe disease among patients with AIDS in Panama and should be suspected for patients with a CD4 cell count of <100 cells/µL, fever, respiratory symptoms, weight loss, and diarrhea.

Multidrug-resistant Salmonella enterica serotype Typhimurium Definitive Type 104 (DT104) emerged in the 1990s and is associated with greater clinical severity than pansusceptible S. Typhimurium. Although infection with DT104 is common in the United States, it is rarely associated with outbreaks. From October to December 2003, a cluster of DT104 infections with indistinguishable pulsed-field gel electrophoresis patterns was identified in the northeastern United States. A case-control study that assessed exposures compared case patients to age- and geography-matched control subjects. Information on consumer purchasing and grocery store suppliers was used to trace the implicated food to its source. We identified 58 case patients in 9 states by pulsed-field gel electrophoresis. Representative isolates were phage type DT104 and were resistant to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (R-type ACSSuT). Of 27 patients interviewed for the case-control study, 41% were hospitalized (median duration of hospitalization, 4 days). Compared with 71 healthy control subjects, case patients had more medical comorbidities (matched odds ratio, 4.3; 95% confidence interval, 1.5-12.7). Illness was associated with consuming store-bought ground beef prepared as hamburgers at home (matched odds ratio, 5.3; 95% confidence interval, 1.9-15.3) and with eating raw ground beef (P< or =.001). Seven case patients (27%), but no control subjects, ate raw ground beef. Product traceback linked cases to a single large ground beef manufacturer previously implicated in a multistate outbreak of highly drug-resistant Salmonella enterica Newport infections in 2002. This first multistate outbreak of highly drug-resistant S. Typhimurium DT104 infection associated with ground beef highlights the need for enhanced animal health surveillance and infection control, prudent use of antimicrobials for animals, improved pathogen reduction during processing, and better product tracking and consumer education.

Multidrug-resistant Salmonella enterica serotype Typhimurium definitive type 104 (MRDT104), with resistance to at least ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (R-type ACSSuT), was first detected in the United States in 1985, and the prevalence increased to account for nearly 7% of Salmonella infections in 1998. A retrospective study of S. Typhimurium infections in an urban health care system assessed whether infection with an antibiotic-resistant strain--and specifically MRDT104--was associated with invasive disease or HIV infection. Sixty cases of S. Typhimurium infection were identified. Of the 50 isolates available for analysis, 30 (60%) were MRDT104. Pathogens were isolated from blood in 25 (83%) of 30 patients infected with MRDT104, compared with 10 (50%) of 20 patients who were infected with non-MRDT104 strains (P = .01). Among isolates obtained from 32 HIV-infected patients, 19 (95%) of 20 MRDT104 isolates were from blood specimens, compared with 8 (66%) of 12 non-MRDT104 isolates (P = .05). MRDT104 accounted for the majority of S. Typhimurium infections in this patient population, and MRDT104 infections were more invasive than non-MRDT104 infections, particularly in HIV-infected persons.

Cases of nontuberculous mycobacterial lymphadenitis were analyzed in a prospective study spanning 32 years, from 1958 to 1990. The results are based on personal observations and long-term follow-up. There were 105 cases, all of which occurred in children aged 9 1/2 months to 12 years (median age, 2.92 years). The patients were predominantly female, and the cases occurred more often in the winter and spring. The cervical or facial nodes were involved in 96 cases. An abrupt change in the predominant etiologic agent (from Mycobacterium scrofulaceum to Mycobacterium avium complex) was noted in the 1970s. Positive tuberculin skin tests were the rule, and reactivity was long lasting. Complications included a prolonged initial phase of infection (n = 6) and recurrences 3 1/2 months to 7 years later (n = 5). Resection during the early stage of infection produced the most satisfactory healing.

The etiologic and clinical features of cholecystitis in infection due to human immunodeficiency virus (HIV) were studied retrospectively. The charts and histopathologic specimens of 136 HIV-infected patients who underwent cholecystectomy between February 1987 and May 1993 at a large tertiary care center were reviewed. Opportunistic pathogens infecting the 107 patients with AIDS included microsporidia (eight cases—Enterocytozoon bieneusi in six and Septata intestinalis in two); cytomegalovirus alone (six cases); Cryptosporidium alone (eight cases); cytomegalovirus plus Cryptosporidium (15 cases); and Pneumocystis carinii and Isospora belli (one case each). In addition, histopathologic changes characteristic of Kaposi's sarcoma were seen in one case. Thirty-eight patients with AIDS had acalculous cholecystitis for which no etiologic agent was found. Twenty-eight AIDS patients had cholelithiasis, six with coexistent opportunistic gallbladder infection. In the 107 AIDS patients, no specific symptom was found to be predictive of opportunistic infection of the gallbladder, but such infection was significantly associated with an abnormal abdominal ultrasound (P = .017) and with nonvisualization of the gallbladder by radionucleotide biliary scan (P < .001).

Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression. JCV establishes latency mainly in the kidney, and its reactivation results in the development of progressive multifocal leukoencephalopathy. BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis. Recent studies have reported SV40 in the allografts of children who received renal transplants and in the urine, blood, and kidneys of adults with focal segmental glomerulosclerosis, which is a cause of end-stage renal disease and an indication for kidney transplantation. Clinical syndromes related to polyomavirus infection are summarized in the present review, and strategies for the management of patients who receive transplants are discussed.

We report the clinical and microbiological characteristics of 11 cases of Aeromonas hydrophila infection of skin and soft tissue, and we review the English-language literature on such infections. Of our 11 patients, seven (64%) presented to the hospital between the months of May and September (inclusive). Three patients (27%) had an underlying systemic illness, and two (18%) had nosocomially acquired infection. The nine patients with community-acquired infection had all experienced antecedent trauma, and seven (78%) of these nine reported recent exposure to freshwater. All patients had clinical evidence of soft-tissue inflammation, and nine (82%) had fever. Four wounds were characterized by a foul odor. The infection was polymicrobial in nine cases (82%). Treatment included the administration of antibiotics in nine instances, but empirical antimicrobial therapy provided coverage against Aeromonas in only two cases. Ten patients required surgical management of their wounds. Posttraumatic wound infections with a history of freshwater exposure should alert the clinician to the possible presence of A. hydrophila. Prompt surgical evaluation of wounds in combination with appropriate antibiotic therapy is recommended for the management of these infections.

We report the clinical and biological course of infection with human immunodeficiency virus (HIV) type 1 in 11 liver transplant recipients who acquired this infection between 1985 and 1987. Eight patients were infected by blood or blood products from graft-related transfusions and one by the graft itself; the remaining two patients were infected after transplantation and had independent risk factors. All patients received a triple-drug immunosuppressive regimen including cyclosporine. The mean duration of follow-up after liver transplantation was 52 months (standard error, ±32 months). Chronic graft rejection was documented in four cases. The cumulative incidences of HIV-related complications and HIV-related deaths were 82% and 27%, respectively. Three patients died rapidly of HIV disease. The survival rate 7 years after transplantation was 36% among the 11 HIV-infected patients, whereas it was ∼70% among HIV-negative liver transplant recipients during the same period. The course of HIV infection in the four survivors did not appear to differ from that in other patients infected by blood transfusion.

Hemorrhagic cystitis that occurs late after bone marrow transplantation (BMT) in BMT recipients is often associated with adenovirus or polyomavirus BK infections. Intravesical instillation of cidofovir in a BMT recipient with intractable hemorrhagic cystitis resulted in clinical improvement. Local cidofovir therapy for viral hemorrhagic cystitis could be an alternative to intravenous administration of cidofovir.