The impact of antibiotic stewardship interventions and patient related factors on antibiotic prescribing in a vascular surgical department.

PURPOSE: The development of guidelines tailored to the departments' needs and counselling during ward rounds are important antibiotic stewardship (AS) strategies. The aim was to analyse the impact of AS ward rounds and institutional guidelines as well as patient-related factors on antibiotic use in vascular surgical patients. METHODS: A retrospective prescribing-analysis of 3 months (P1, P2) before and after implementing weekly AS ward rounds and antimicrobial treatment guidelines was performed. Choice of systemic antibiotics, days of antibiotic therapy and clinical data were obtained from electronic patient records. RESULTS: During P2, the overall antibiotic consumption as well as the use of last-resort compounds like linezolid and fluoroquinolones decreased distinctly (overall: 47.0 days of therapy (DOT)/100 patient days (PD) vs. 35.3 DOT/100PD, linezolid: 3.7 DOT/100PD vs. 1.0 DOT/100PD, fluoroquinolones: 7.0 DOT/100PD vs. 3.2 DOT/100PD) while narrow-spectrum beta-lactams increased by 48.4%. Courses of antibiotics were de-escalated more often during P2 (30.5% vs. 12.1%, p = 0.011). Only in P2, an antibiotic therapy was initiated in patients suffering from more comorbidities (i.e. higher Charlson Comorbidity Index) more frequently. Other patient factors had no distinct impact on antibiotic prescribing. CONCLUSION: Weekly AS ward rounds improved adherence to institutional antibiotic treatment guidelines and antibiotic prescribing in vascular surgical patients. Clear patient-related determinants affecting choice of antibiotic therapies could not be identified.

Measles, mumps, rubella and VZV: importance of serological testing of vaccine-preventable diseases in young adults living with HIV in Germany.

Measles, mumps, rubella (MMR) and varicella zoster virus (VZV) infection can cause serious diseases and complications in the HIV-positive population. Due to successful vaccination programmes measles, mumps and congenital rubella syndrome has become neglected in Germany. However, recent outbreaks of measles have occurred from import-associated cases. In this cross-sectional study the serostatus for MMR and VZV in 2013 HIV-positive adults from three different university outpatient clinics in Bonn (n = 544), Cologne (n = 995) and Munich (n = 474) was analysed. Sera were tested for MMR- and VZV-specific immunglobulin G antibodies using commercial immunoassays. Seronegativity was found in 3% for measles, 26% for mumps, 11% for rubella and 2% for VZV. Regarding MMR, 35% of patients lacked seropositivity against at least one infectious agent. In multivariable analysis younger age was strongly associated with seronegativity against all four viruses, measles, mumps, rubella (P < 0·001, P < 0·001 and P = 0·001, respectively) and VZV (P = 0·001). In conclusion, there is high need for MMR and VZV vaccination in people living with HIV in Germany born in 1970 or later. Thus, systematic MMR and VZV antibody screening and vaccination should be implemented in the HIV-positive population to prevent serious disease and complications of vaccine-preventable diseases.

Novel antibiotics: are we still in the pre-post-antibiotic era?

PURPOSE: Therapeutic efficacy and safety in infections due to multidrug-resistant bacteria can be improved by the clinical development of new compounds and devising new derivatives of already useful antibiotics. Due to a striking global increase in multidrug-resistant Gram-positive but even more Gram-negative organisms, new antibiotics are urgently needed. METHODS: This paper provides a review of novel antibiotic compounds which are already in clinical development, mainly in phase III clinical trials. CONCLUSION: Each of these new trials increases the possibility of new antibiotics receiving approval.

Sexual and reproductive health services for people living with HIV/AIDS in Germany: are we up to the challenge?

PURPOSE: Germany is witnessing an increase in the number of new infections with human immunodeficiency virus (HIV). Enabling persons living with HIV (PLHIV) to adopt safer sex practices might contribute towards reducing the incidence of HIV infections. The aim of this study was to identify gaps in the sexual and reproductive health (SRH) services provided to PLHIV in Germany. METHODS: Within the framework of the European public health project Eurosupport 5, self-reported questionnaires were distributed to PLHIV and a survey of SRH-service providers was carried out. The completed questionnaires and survey results were analysed. RESULTS: Of the questionnaires distributed, 218 PLHIV (90 % men, 10 % women) returned a completed questionnaire. Of these, 74 % self-identified as men having sex with men (MSM) and 13 % as heterosexual men. MSM reported a median number of ten casual partners in the previous 6 months and unprotected sex in one-third of anal intercourses with casual partners, demonstrating that this group adopted more risky sexual behaviours than heterosexual PLHIV. Even though all PLHIV stated they would appreciate more support and service providers indicated that they provided a wide range of SRH services, SRH-relevant topics were rarely discussed between PLHIV and service providers. According to the patients' perception, shortage of time, lack of initiative by service providers and their own difficulty to address SRH-related topics were the most relevant obstacles to receiving satisfactory support. CONCLUSION: Many PLHIV consult their HIV-physician regularly for medical follow-up and also indicate that HIV-physicians should be the source of information concerning SRH counselling. HIV-physicians should take advantage of their key role in HIV care and strengthen their efforts to integrate SRH services in routine HIV care.

A new cytokine release assay: a simple approach to monitor the immune status of HIV-infected patients.

PURPOSE: To test a new assay based on an ex vivo cytokine release from whole blood for the monitoring of immune changes in human immunodeficiency virus (HIV)-infected patients. METHODS: A pilot study of outpatients with HIV infection (n = 9) at a large academic hospital who were divided into three groups: HIV-infected patients on highly active antiretroviral therapy (HAART) with a CD4(+) cell count >350/µL (group I) or a CD4(+) cell count <350/µL (group II) and HIV-infected HAART-naïve subjects with a CD4(+) cell count >350/µL (group III). All groups were compared with healthy volunteers (n = 3). The ex vivo cytokine release assay was performed in a three-step process: (1) blood collection, (2) whole-blood ex vivo incubation over 48 h without or with a standard set of well-defined recall antigens as comparable to those used formerly in the skin delayed-type hypersensitivity (DTH) test, (3) cytokine determination from the assay supernatant. RESULTS: Under stimulated conditions, untreated HIV-infected patients with a CD4(+) count >350/µL had similar interleukin-2 (IL-2) levels in the supernatant of the whole-blood incubation to HIV-infected patients on HAART with a low CD4(+) count. Both groups revealed lower IL-2 levels in the supernatant than HIV-infected patients on HAART and with a CD4(+) count >350/µL or healthy volunteers. The determination of interferon-γ and tumour necrosis factor-α in the supernatant showed a similar arrangement of cytokines between groups. CONCLUSIONS: Our results suggest that this cytokine release assay could be a suitable tool to mirror the immunological responsiveness of patients with HIV infection in a gradual manner; further studies are required in order to assess its value in HAART monitoring.

[New antibiotics: small or big advances?]. / Neue Antibiotika: Schritt- oder Sprunginnovationen?

This contribution summarizes the "state-of-the-art" in the field of new antibiotics. On the one hand interesting new substances are discussed, on the other hand areas of interest for more research are shown. Doripenem is a new broad-spectrum antibiotic which proved superior to other carbapenems as far as gram-negative bacilli were concerned and also showed less development of resistance. For the treatment of methicillin-resistant Staphylococcus aureus (MRSA), linezolid, tigecyclin and daptomycin reached drug approval within recent years. The new glycopeptides and iclaprim await approval. The majority of these substances are also effective against other resistant organisms like vancomycin-intermediate Staph. aureus and vancomycin-resistant entercoccus. Increasing virulence of some Clostridium difficile strains (particularly ribotype 027) within the past years has led to a growing need for new strategies concerning treatment and prophylaxis of Clostridium difficile associated diarrhea.

HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy.

Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes. HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy.

[Options in HIV therapy: present and future]. / Therapieoptionen bei HIV Realität und Zukunft.

Highly active antiretroviral therapy (HAART) has markedly decreased HIV-associated mortality. It consists of a combination of three antiretroviral drugs from four different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and inhibitors of virus-cell fusion. Increasing resistance against antiretroviral drugs calls for the development of new compounds and drug classes. The growing understanding of molecular mechanisms in HIV-replication led to the identification of further steps which might serve as novel antiretroviral targets. Uninfected cells could be protected from HIV by inhibiting extracellular binding mechanisms. Improvement of existing antiretroviral drugs and further development of novel therapeutic targets will enrich antiretroviral treatment.

What's new in HIV/AIDS. Protective immunity in HIV infection: where do we stand?

In the face of a global epidemic of HIV/AIDS with the majority of individuals living in the developing countries, a protective vaccine seem the foremost goal. As this is not within imminent reach, the other option would be immunotherapy that prolongs the asymptomatic phase of infection. The basis for such a therapy is to understand the correlates of protective immunity against HIV. Here we present the most recent advances regarding selected parts of the immune response towards HIV.

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities.

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection.

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/ micro l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

[Adverse effects of antiretroviral therapy. Aspects of pathogenesis]. / Nebenwirkungen der antiretroviralen Therapie. Aspekte der Pathogenese.

Highly active antiretroviral therapy has resulted in remarkable reduction of morbidity and mortality of HIV infection. With increasing duration of therapy metabolic alterations such as hyperlipidemia, diabetes mellitus type 2 and lipodystrophy are encountered which considerably reduced quality of life for the patients. These adverse events are most likely due to protease inhibitors and nucleoside analogues with synergistic effects. The pathogenesis is related to metabolic alterations of the adipocytes with cellular insulin resistance and enhanced apoptosis of these cells caused by adipocytic cytokines such as adiponectin, leptin, TNF-alpha and interleukin 2. Switch of therapy regimens with elimination of the most suspicious substances and certain protease inhibitors can lead to improvement of deranged metabolism. Also symptomatic therapy is possible to cope with hyperlipidemia and diabetes, although no effective treatment is available to reverse already existing lipodystrophy. Our knowledge about the pathogenesis of these alterations might lead to new concepts and causal therapy in the future.

Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load.

Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/10(6) PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.