Journal of Infection

The HIV-1/HAART associated metabolic syndrome – Novel adipokines, molecular associations and therapeutic implications

S. Tsiodras, A. Perelas, C. Wanke, C.S. Mantzoros — 2010-07-09

Summary: The use of highly active anti-retroviral therapy has been associated with effects on various metabolic and morphological parameters that are underlied by significant hormonal and cytokine changes. Novel adipokines may have a role in the pathogenesis of these changes. In fact, leptin deficiency and hypoadiponectinemia correlate with lipoatrophy and central fat accumulation respectively whereas hypoadiponectinemia also appears to be associated with insulin resistance and lipid disorders. Preliminary evidence from proof-of-concept studies suggests that administration of recombinant leptin in replacement doses and/or administration of medications that increase adiponectin levels may improve the HIV-1/HAART associated metabolic syndrome (HAMS). Immune effects of hypoleptinemia and hypoadiponectinemia might have a role in the evolution of the HAMS that need to be further elucidated. The role for resistin in relation to HAMS is controversial and further investigation is necessary. A potential role of other novel cytokines like visfatin, retinol-binding protein-4, apelin, acylation stimulating protein, omentin and vaspin needs to be further elucidated.

The risk of sequelae due to pneumococcal meningitis in high-income countries: A systematic review and meta-analysis

Mark Jit — 2010-05-18

Summary: Objectives: To determine the risk of various kinds of sequelae in survivors of meningitis due to Streptococcus pneumoniae, as well as the influence of co-factors such as study design, study population and treatment on this risk.Methods: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1 September 1991 to 18 June 2009 for original articles on pneumococcal meningitis sequelae. Prevalence of sequelae was pooled using random effects meta-analysis. Studies were appraised for the influence of referral bias, external validity of study populations, testing procedure and publication bias.Results: Data were extracted from 63 studies involving 3408 pneumococcal meningitis survivors. The pooled prevalence of any reported sequelae from 48 studies was 31.7% (95% confidence interval 27.2–36.3%) using a random effects model (Cochran-Q = 277, p < 0.01). Differences in studies due to design, study population and treatment were not significant. The pooled prevalence of hearing loss, seizures, hydrocephalus, spasticity/paresis, cranial nerve palsies and visual impairment was 20.9% (17.1–24.7%), 6.5% (3.3–9.7%), 6.8% (3.3–10.2%), 8.7% (6.4–11.0%), 12.2% (5.3–19.1%) and 2.4% (0–5.7%) respectively.Conclusions: The burden of sequelae due to pneumococcal meningitis remains high in the reviewed studies.

Six weeks of antibiotic treatment is sufficient following surgery for septic arthroplasty

2010-07-02

Summary: Objectives: In the treatment of prosthetic joint infections (PJI), the benefit of antibiotic therapy for more than 6 weeks after surgery is uncertain. We compared PJI cure rates according to the duration of antibiotics, 6 versus 12 weeks.Methods: A prospective observational non-randomized study in Geneva University Hospitals 1996–2007.Results: A total of 144 PJI (62 hip arthroplasties, 62 knee arthroplasties, and 20 hip hemiarthroplasties) were included with a prolonged follow-up ranging from 26 to 65 months. Surgical treatment included 60 débridements with implant retention, 10 one-stage exchanges of the prosthesis, 57 two-stage exchanges, and 17 Girdlestone procedures or knee arthrodeses. Seventy episodes (49%) received 6 weeks antibiotic therapy and 74 episodes, 12 weeks. Cure was achieved in 115 episodes (80%). Cure rate did not change according to the duration of intravenous antibiotics (>8 days, 8–21 days, >21 days) (Kruskal–Wallis-test; p = 0.37). In multivariate analysis, none of the following parameters was statistically significantly associated with cure: two-stage exchange (odds ratio 1.1,95%CI 0.2–4.8); number of débridements (0.9, 0.4–1.9); six weeks antibiotherapy (2.7, 0.96–8.3); duration of intravenous course (1.0, 0.96–1.03); sinus tract (0.6, 0.2–1.7); or MRSA infection (0.5, 0.2–1.5), although implant retention showed a tendency for less cure (0.3, 0.1–1.1).Conclusions: Following surgery for treatment of PJI, antibiotic therapy appears able to be limited to a 6-week course, with one week of intravenous administration. This approach needs confirmation in randomized trials.

IFN-γ, but not IP-10, MCP-2 or IL-2 response to RD1 selected peptides associates to active tuberculosis

2010-06-18

Summary: Objectives: To evaluate whether in vitro response to Mycobacterium tuberculosis RD1 peptides selected by computational analysis, measured by IFN-γ, IP-10, MCP-2 or IL-2 production, is associated with active tuberculosis (TB) in a country with a high incidence of TB.Methods: 129 individuals were prospectively enrolled, 41 with active-pulmonary TB and 88 without (household contacts and community controls). A whole blood assay based on RD1 selected peptides was performed. Soluble factors were evaluated by ELISA in plasma harvested at day1-post-culture. Enrolled individuals were also tested by QuantiFERON TB-Gold In tube (QFT-IT) and tuberculin skin tests (TST).Results: IFN-γ response to RD1 selected peptides was significantly higher in active TB patients than in household contacts and community controls. IP-10 and MCP-2 response did not differ between active TB patients and household contacts, although it was higher in these groups compared to community controls; conversely IL-2 response did not differ among the three groups. When IFN-γ response to RD1 selected peptides was scored based on receiver-operator-characteristic analysis, active TB was predicted with 68% sensitivity and 86% specificity. QFT-IT and TST showed a sensitivity for active TB of 90% and 68% and a specificity of 58% and 59%, respectively.Conclusions: IFN-γ (but not IP-10, MCP-2 and IL-2) response to RD1 selected peptides is associated with active TB with a higher specificity than QFT-IT and TST.

Serial testing of interferon-γ-release assays for the diagnosis of latent tuberculosis in hemodialysis patients

2010-05-26

Summary: Introduction: The performance of serial interferon-γ-release assays (IGRAs) for the diagnosis of latent tuberculosis has not been studied in hemodialysis patients.Method: The QuantiFERON-TB-Gold In-Tube test (QFT) and T-SPOT-TB test (TSPOT) were performed 1 year after initial testing at a hemodialysis center.Results: Ninety-eight patients were included in the final analysis. Positive rates for the initial tuberculin skin test (TST), QFT and TSPOT were 26.5%, 43.9% and 58.2%, respectively. The follow-up QFT and TSPOT showed positive responses in 52.0% and 53.1%. Conversion rates of the QFT and TSPOT were 20.0% and 26.8%. Reversion rates of the QFT and TSPOT were 16.3% and 29.8%; however, they decreased to 0.0% and 4.8% in patients with a concordantly positive response at the initial TST. A group at high risk for latent tuberculosis increased the risk for the TSPOT conversion [odds ratio (95% confidence interval), 7.76 (1.27–47.40)] and showed a trend of increasing the risk for the QFT conversion [1.97 (0.45–8.71)]. Reversion of both the QFT [18.92 (2.01–178.65)] and TSPOT [6.16 (1.57–24.19)] occurred more frequently in the group at low risk.Conclusions: Both conversion and reversion of the IGRAs were associated with the risk for latent tuberculosis in hemodialysis patients. However, serial IGRAs results should be interpreted cautiously due to their high variability.

Mutation characterization of gyrA and gyrB genes in levofloxacin-resistant Mycobacterium tuberculosis clinical isolates from Guangdong Province in China

Xiaomao Yin, Zhaoxian Yu — 2010-05-26

Summary: Objective: Fluoroquinolone (FQ)-resistant Mycobacterium tuberculosis (MTB) clinical isolates have emerged in many areas of the world. The aim of this study was to observe the molecular characterization of gyrA and gyrB genes in FQ-resistant MTB clinical isolates from Guangdong Province in China.Materials and methods: A total of 62 MTB clinical strains were originally isolated from patients with pulmonary tuberculosis. The phenotype of susceptibility of each strain was determined by the absolute concentration method and the sequences of the QRDR in gyrA and gyrB genes were detected with DNA direct sequencing technique.Results: 44 of 60 (73.3%) levofloxacin-resistant MTB clinical isolates, including 17 of 18 (94.4%) high-level resistant strains and 27 of 42 (64.3%) low-level resistant strains, had mutation in QRDR of gyrA gene. The mutation patterns involved six patterns of single codon mutation (H70R, A90V, S91A, D94G, D94A or D94N) and one pattern of double codons mutation (A90V with D94A). Of 60 levofloxacin-resistant MTB clinical isolates, only one (1.6%) mutated in gyrB gene (T511N).Conclusions: These findings confirm that mutations of gyrA codons 90, 91 and 94 constitute the primary mechanism of FQ resistance in MTB. Furthermore, our findings indicate that the regional investigations are necessary for the comprehensive understanding of FQ resistance of MTB.

Favourable one-year ART outcomes in adult Malawians with hepatitis B and C co-infection

2010-05-31

Summary: Background: Few studies have investigated the impact of chronic hepatitis B and C infection on antiretroviral therapy (ART) outcomes in sub-Saharan Africa. Hepatotoxicity may be a particular concern in co-infected patients taking nevirapine–stavudine–lamivudine.Methods: We conducted a prospective cohort study of 300 Malawian adults starting ART and describe one-year ART outcomes according to viral hepatitis status.Results: At baseline, patients had advanced HIV disease (29.3% were in WHO stage 4; mean CD4 = 157 cells/μL; mean log10HIV-1 RNA = 5.24 copies/ml). Co-infection with hepatitis B, C and B + C were present in 6.7%, 5.7% and 1.7% respectively. At 50 weeks, all-cause mortality was 43 (14.3%). Sixteen (5.3%) had transferred to another unit. Eight (2.7%) were lost to follow up. Sixteen (5.3%) had stopped ART. 217 (72.3%) were alive on ART, of whom 82.5% had an HIV-1 RNA <400 copies/ml at week 50. During the first 50 weeks of ART, severe hepatotoxicity (liver enzyme values >5 times upper level of normal) occurred in 9%, but did not result in any ART discontinuations. Clinical hepatitis or jaundice was not observed. There were no significant differences in occurrence of hepatotoxicity, other side effects, mortality, severe morbidity, immune reconstitution or virological failure between hepatitis B and/or C co-infected patients and those who were not. Viral hepatitis co-infection was not associated with severe hepatotoxicity, mortality, severe morbidity or virological failure in multivariate analyses.Conclusion: Our data suggest that screening for viral hepatitis B and C and liver enzyme monitoring may not require high priority in ART programmes in sub-Saharan Africa.

High genetic diversity of HIV-1 viruses in Macao, China

2010-06-07

Summary: Objective: To investigate the molecular epidemiology of recently diagnosed HIV-1 infection in Macao for better understanding the epidemiology in this Chinese city, in context of its relationship with other countries in Asia and the rest of the world.Methods: Serum samples of HIV positive cases reported between 2005 and 2007 were collected from the Macao Public Health Laboratory. HIV genotype was determined by phylogenetic analysis of sequences from gag, RT, and env regions.Results: A total of 30 HIV positive samples were genotyped. The HIV-1 viruses circulating in Macao were characterized by their relatively high genetic diversity. CRF01_AE was predominant (56%), followed by subtype B (13%), CRF12_BF (10%), G/CRF12_BF, A1/CRF10_AD and CRF07_BC, of which CRF12_BF and G/CRF12_BF were first reported in Southeast Asia. Phylogenetic analysis showed that there was no clear clustering of CRF01_AE strains but a distinct CRF12_BF cluster associated with injection drug use could be delineated.Conclusion: The results suggested that there were multiple introductions of HIV strains in Macao that have been circulating for an extended period of time, superimposed by an outbreak in injection drug users.

Amphotericin B regulates the host immune response in visceral leishmaniasis: Reciprocal regulation of protein kinase C isoforms

2010-06-11

Summary: Objectives: Treatment of visceral leishmaniasis (VL) is marked by the failure of pentavalent antimonials which has brought amphotericin B (AmpB) to the forefront. In this study we have focused on signaling pathway regulating AmpB triggered effector response.Methods: AmpB triggered effector response in the form of free radicals and proinflammatory cytokines was determined by FACS, colorimetric estimation or Real-Time PCR (RT-PCR). Specific peptide inhibitors for classical and atypical protein kinase C (PKC) were used to investigate the role of PKC isoforms in the functioning of AmpB during VL.Results: In vitro studies with THP1 cells showed that 2 μg/ml dose of AmpB could mediate effective parasite clearance due to strong induction of free radicals and proinflammatory cytokines. This induction of proinflammatory response paralleled with antagonistic regulation of classical and atypical PKC. Further confirmation was provided by RT-PCR of (peripheral blood mononuclear cells) PBMC isolated from VL infected patients undergoing AmpB treatment.Conclusions: Overall, our results suggest that classical and atypical PKC signaling pathways are involved in the modulation of proinflammatory response triggered by AmpB against Leishmania donovani. These observations may contribute to the understanding of the mechanism responsible for the initiation of protective response induced by AmpB during VL.

Fetal death as a result of placental immune reconstitution inflammatory syndrome

2010-04-30

Summary: A 26-year-old woman was HIV-1 diagnosed at 11 weeks of pregnancy (CD4 = 7/mm3, HIV-1 RNA = 108,000 copies/mL) with immunity against toxoplasmosis (Toxoplasma IgG = 1800 UI/mL). A fetal death was diagnosed 7 weeks after starting HAART (CD4 = 185/mm3, HIV-1 RNA = 391 copies/mL) with a positive Toxoplasma PCR on fetal tissues and amniotic fluid. The absence of severe toxoplasmic foetopathy, the very exaggerated and atypical placental inflammation and the immune restoration context led to the diagnosis of placental IRIS associated with Toxoplasma gondii reactivation. This outcome remains undescribed and could represent an issue in resource-limited settings where HIV-pregnant patients are often severely immunodeficient and infected with opportunistic pathogens.

Severe acute renal failure associated with rhabdomyolysis during treatment with raltegravir. A call for caution

Mar Masiá, Ricardo Enríquez, Ana Sirvent, Félix Gutiérrez — 2010-05-24

Hughes and colleagues reviewed new treatment options for HIV infection including the integrase inhibitors. Raltegravir, the first approved HIV-1 integrase inhibitor, has demonstrated a potent antiretroviral effect in both treatment-naïve and–experienced patients. Raltegravir is usually well tolerated. In phase II and III clinical trials, the safety event profile was similar or even better than that of comparators, including placebo. Grade 2–4 creatine kinase (CK) elevations were reported in patients treated with raltegravir, which did not lead in any case to treatment discontinuation In view of these data, the latest updated US Food and Drug Administration-released drug label includes the recommendation of using raltegravir with caution in patients at increased risk of myopathy or rhabdomyolysis, such as those receiving concomitant medications known to cause these conditions. Renal adverse events are also uncommon. Data analysis from the controlled clinical trials including more than 1000 treatment-experienced patients provided three cases of renal failure, all of them in association with other triggering/contributing factors, such as congestive heart failure, sepsis, or pre-existing renal insufficiency.

Natural killer cells during primary varicella zoster virus infection

2010-07-01

We read with interest the paper by Turnbridge et al. in the journal, on the clinical management of chickenpox in adults. Chickenpox is a significant cause of morbidity and mortality in Sri Lanka as it predominantly affects adults. We previously described the association of clinical disease severity with viral loads and cellular immune responses in Sri Lankan adults with chickenpox. We wish to highlight the possible role of natural killer cells in the control of virus replication in patients with acute infection.

Clindamycin-resistant Staphylococcus aureus in foot ulcers of patients with diabetes

2010-06-28

We read with interest the article of Woodford and Livermore about the increasing numbers of Gram-positive resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). These numbers are impressive and at the same time ominous. The MRSA levels in The Netherlands are still low, however, recently we observed a rise in the number of clindamycin-resistant S. aureus (CRSA) at the diabetic foot outpatient clinic of the Academic Medical Center (AMC) in Amsterdam, The Netherlands. These strains were also ciprofloxacin-resistant. Since the first line of treatment for clinically infected deep diabetic foot ulcers consists of clindamycin and ciprofloxacin in our center, as well as in many others, we aimed to identify the prevalence and risk factors of CRSA infected foot ulcers in our foot clinic.

Antimicrobial activity of daptomycin against Staphylococcus aureus isolates from skin and skin structure infections of trauma patients

Bijayini Behera, Neetu Jain, Satyapriya Sharma, Purva Mathur, Mahesh C. Misra — 2010-07-05

The new modalities for treatment of skin and soft tissue and surgical site infections due to MDR Gram- positive bacteria, particularly Methicillin resistant Staphylococcus aureus (MRSA) has been addressed in your journal by StevensDL and Eliopoulos GM. MRSAskin and skin structure infections (SSTIs) in the trauma patients is a growing and difficult clinical problem.Availability of limited number of antimicrobials effective against MRSA as well as their side effects further limits therapeutic options in the critically ill trauma patients. Daptomycin is a cyclic lipopeptide, which has been recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated skin and skin structure infections (cSSTIs). We aimed to evaluate the in vitro activity of this drug against a contemporary collection of consecutive S. aureus isolates from clinically documented SSTIs of admitted trauma patients at level I trauma centre of India.