Choosing Wisely internationally - helpful recommendations for antimicrobial stewardship!

PURPOSE: Antimicrobial resistance poses a major threat to human health globally and antibiotic overuse is a main driver of resistance. Antimicrobial stewardship (AMS) was developed to improve the rationale use of antibiotics. The Choosing Wisely campaign was initiated to ameliorate medical practice through avoidance of unnecessary diagnostic and therapeutic procedures. Our objective was to give an overview on the Choosing Wisely recommendations related to AMS practices from a selection of different countries in order to define future needs. METHODS: We evaluated the seven countries already analyzed for Choosing Wisely recommendations related to topics of infectious medicine before. Finally, we included five of the former countries (Australia/New Zealand, Canada, Italy, Switzerland, and USA) and Germany with easily accessible recommendations and selected those related to six categories of AMS as following: diagnostics, indication, choice of antiinfective drugs, dosing, application and duration of therapy. RESULTS: In total, 213 recommendations could be extracted related to AMS for the six countries and were matched to the chosen categories. Interestingly, no recommendations were found for the category "dosing." Topics related to indication and diagnostics were most frequently found with 85 and 78 recommendations, respectively. Perioperative prophylaxis was a frequently addressed issue - both related to application, indication and duration. Avoiding antibiotic treatment of asymptomatic bacteriuria and upper respiratory tract infections were central topics of all countries. CONCLUSION: AMS is an important strategy to fight increasing resistance and is frequently addressed by Choosing Wisely recommendations of different countries. Similar issues are considered important in the selected countries.

Update on the "Choosing Wisely" initiative in infectious diseases in Germany.

PURPOSE: The Choosing Wisely® initiative is an international campaign addressing over- and underuse of diagnostic and therapeutic measures in infectious diseases among others. Since 2016, the German Society for Infectious Diseases (DGI) has constantly designed new items in this regard. Here we report the most recent recommendations. METHODS: The recommendations of the DGI are part of the "Klug entscheiden" initiative of the German Society of Internal Medicine (DGIM). Topics for the new items were suggested by members of the DGI, checked for scientific evidence and consented within the DGI and the DGIM before publication. RESULTS: The new recommendations are: (1) individuals with immune-suppression, advanced liver cirrhosis or renal insufficiency should receive a dual pneumococcal vaccination. (2) In case of positive blood cultures with Candida spp. thorough diagnostics and treatment should be initiated. (3) In case of suspected meningitis, adult patients should receive dexamethasone and antibiotics immediately after venipuncture for blood cultures and before potential imaging. (4) In case of suspected meningitis a CT scan before lumbar puncture should not be ordered-except for symptoms indicating high CSF pressure or focal brain pathology or in cases of severe immune-suppression. (5) In patients with suspected severe infections, a minimum of two pairs of blood cultures should be drawn using separate venipunctures prior to antibiotic therapy-regardless of body temperature. There is no need of a minimum time interval in between the blood draws. CONCLUSION: Applying these new Choosing Wisely® recommendations will increase patient safety and the value of health care.

Comparison of Self-report to Biomarkers of Recent HIV Infection: Findings from the START Trial.

Identifying individuals with recent HIV infection is critical to research related to viral reservoirs, outbreak investigations and intervention applications. A multi-assay algorithm (MAA) for recency of infection was used in conjunction with self-reported date of infection and documented date of diagnosis to estimate the number of participants recently infected in the Strategic Timing of AntiRetroviral Treatment (START) trial. We tested samples for three groups of participants from START using a MAA: (1) 167 individuals who reported being infected ≤ 6 months before randomization; (2) 771 individuals who did not know their date of infection but were diagnosed within 6 months before randomization; and (3) as controls for the MAA, 199 individuals diagnosed with HIV ≥ 2 years before randomization. Participants with low titer and avidity and a baseline viral load > 400 copies/mL were classified as recently infected. A significantly higher percentage of participants who self-reported being infected ≤ 6 months were classified as recently infected compared to participants diagnosed ≥ 2 years (65% [109/167] vs. 2.5% [5/199], p < 0.001). Among the 771 individuals who did not know their duration of infection at randomization, 206 (26.7%) were classified as recently infected. Among those diagnosed with HIV in the 6 months prior to enrollment, the 373 participants who reported recent infection (n = 167) or who had confirmed recent infection by the MAA (n = 206) differed significantly on a number of baseline characteristics from those who had an unknown date of infection and were not confirmed by the MAA (n = 565). Participants recently infected by self-report and/or MAA were younger, more likely to be Asian, less likely to be black, less likely to be heterosexual, more likely to be enrolled at sites in the U.S., Europe or Australia, and have higher HIV RNA levels. There was good agreement between self-report of recency of infection and the MAA. We estimate that 373 participants enrolled in START were infected within 6 months of randomization. Compared to those not recently infected, these participants were younger, had higher HIV RNA levels and were more likely to come from high income countries and from populations such as MSM with more regular HIV testing.

Selective inhibitors of the FK506-binding protein 51 by induced fit.

The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.

Kinetics of human myeloid-derived suppressor cells after blood draw.

BACKGROUND: Human myeloid-derived suppressor cells (MDSC) have been described as a group of immature myeloid cells which exert immunosuppressive action by inhibiting function of T lymphocytes. While there is a huge scientific interest to study these cells in multiple human diseases, the methodological approach varies substantially between published studies. This is problematic as human MDSC seem to be a sensible cell type concerning not only cryopreservation but also time point after blood draw. To date data on delayed blood processing influencing cell numbers and phenotype is missing. We therefore evaluated the kinetics of granulocytic MDSC (gMDSC) and monocytic MDSC (mMDSC) frequencies after blood draw in order to determine the best time point for analysis of this recently defined cell type. METHODS: In this study, we isolated peripheral blood mononuclear cells (PBMC) of patients with HIV infection or solid tumors directly after blood draw. We then analyzed the frequencies of gMDSC and mMDSC 2, 4 and 6 h after blood draw and after an overnight rest by FACS analysis using the standard phenotypic markers. In addition, part of the cells was frozen directly after PBMC preparation and was measured after thawing. RESULTS: gMDSC levels showed no significant difference using fresh PBMC over time with a limitation for the overnight sample. However they were massively diminished after freezing (p = 0.0001 for all subjects). In contrast, frequencies of fresh mMDSC varied over time with no difference between time point 2 and 4 h but a significantly reduction after 6 h and overnight rest (p = 0.0005 and p = 0.005 respectively). Freezing of PBMC decreased the yield of mMDSC reaching statistical significance (p = 0.04). For both MDSC subgroups, FACS analysis became more difficult over time due to less sharp divisions between populations. CONCLUSIONS: According to our data human MDSC need to be studied on fresh PBMC. gMDSC can be studied with delay, mMDSC however should be studied no later than 4 h after blood draw. These results are crucial as an increasing number of clinical trials aim at analyzing MDSC nowadays and the logistics of blood processing implies delayed sample processing in some cases.

Lack of significant elevation of myeloid-derived suppressor cells in peripheral blood of chronically hepatitis C virus-infected individuals.

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive function. Compared to the level in healthy controls (HC), no elevation of MDSC in chronic hepatitis C (cHEP-C) patients was found, and there was no difference in MDSC based on genotype or viral load (P > 0.25). Moreover, MDSC of cHEP-C patients inhibited CD8 T cell function as efficiently as MDSC of HC did. Since we detected neither quantitative nor qualitative differences in MDSC of cHEP-C patients relative to those of HC, we postulate that MDSC in peripheral blood are most likely not significant regarding immune dysfunction in cHEP-C.

Comparison of experimental fine-mapping to in silico prediction results of HIV-1 epitopes reveals ongoing need for mapping experiments.

Methods for identifying physiologically relevant CD8 T-cell epitopes are critically important not only for the development of T-cell-based vaccines but also for understanding host-pathogen interactions. As experimentally mapping an optimal CD8 T-cell epitope is a tedious procedure, many bioinformatic tools have been developed that predict which peptides bind to a given MHC molecule. We assessed the ability of the CD8 T-cell epitope prediction tools syfpeithi, ctlpred and iedb to foretell nine experimentally mapped optimal HIV-specific epitopes. Randomly - for any of the subjects' HLA type and with any matching score - the optimal epitope was predicted in seven of nine epitopes using syfpeithi, in three of nine epitopes using ctlpred and in all nine of nine epitopes using iedb. The optimal epitope within the three highest ranks was given in four of nine epitopes applying syfpeithi, in two of nine epitopes applying ctlpred and in seven of nine epitopes applying iedb when screening for all of the subjects' HLA types. Knowing the HLA restriction of the peptide of interest improved the ranking of the optimal epitope within the predicted results. Epitopes restricted by common HLA alleles were more likely to be predicted than those restricted by uncommon HLA alleles. Epitopes with aberrant lengths compared with the usual HLA-class I nonamers were most likely not predicted. Application of epitope prediction tools together with literature searches for already described optimal epitopes narrows down the possibilities of optimal epitopes within a screening peptide of interest. However, in our opinion, the actual fine-mapping of a CD8 T-cell epitope cannot yet be replaced.

Effect and sustainability of a stepwise implemented multidisciplinary antimicrobial stewardship programme in a university hospital emergency department.

Objectives: To explore effectiveness and sustainability of guideline adherence and antibiotic consumption after establishing treatment guidelines and initiating antimicrobial stewardship (AMS) ward rounds in a university hospital emergency department (ED). Methods: Data were gathered retrospectively from 2017 to 2021 in the LMU University Hospital in Munich, Germany. Four time periods were compared: P1 (pre-intervention period); P2 (distribution of guideline pocket cards); P3 (reassessment after 3 years); and P4 (refresher of guideline pocket cards and additional daily AMS ward rounds for different medical disciplines). Primary outcome was adherence to guideline pocket cards for community-acquired pneumonia, cystitis, pyelonephritis and COVID-19-associated bacterial pneumonia. Secondary outcomes were reduction in antibiotic consumption and adherence to AMS specialist recommendations. Results: The study included 1324 patients. Guideline adherence increased in P2 for each of the infectious diseases entities. After 3 years (P3), guideline adherence decreased again, but was mostly on a higher level than in P1. AMS ward rounds resulted in an additional increase in guideline adherence (P1/P2: 47% versus 58.6%, P = 0.005; P2/P3: 58.6% versus 57.3%, P = 0.750; P3/P4: 57.3% versus 72.5%, P < 0.001). Adherence increased significantly, not only during workdays but also on weekends/nightshifts. Adherence to AMS specialist recommendations was excellent (91.3%). We observed an increase in use of narrow-spectrum antibiotics and a decrease in the application of fluoroquinolones and cephalosporins. Conclusions: Establishing treatment guidelines in the ED is effective. However, positive effects can be diminished over time. Daily AMS ward rounds are useful, not only to restore but to further increase guideline adherence significantly.

Spinal Tuberculosis within the Vertebral Arch Mimicking a Malignant Tumor: Case Report.

BACKGROUND: Spinal tuberculosis is a manifestation of extrapulmonary tuberculosis. The incidence of tuberculosis is low in high-income countries; however, globally, it still remains one of the most frequent fatal infectious diseases. Because of its rarity in developed countries, spinal tuberculosis can be mistaken for malignant tumors of the spine, especially in case of an atypical radiologic manifestation and without pulmonary affection. METHODS: We present the case of a 39-year-old man from South India with quickly progressing gait disturbance and hypesthesia below the Th10 level. Magnetic resonance imaging revealed an osteolytic lesion of the vertebral arch Th2 with central necrosis and compression of the spinal cord altogether highly suspicious for spinal metastasis. RESULTS: After surgical removal of the mass by laminectomy, the patient regained normal neurologic function. Histology revealed a severe granulomatous inflammation and DNAhybridization of polymerase chain reaction (PCR) products detected Mycobacterium tuberculosis-specific DNA in the sample. Biopsy of an enlarged hilar lymphnode allowed us to obtain material to successfully perform a drug resistance test to start specific antimicrobial therapy. CONCLUSION: Spinal tuberculosis, even with atypical radiologic appearance, has to be considered a differential diagnosis in patients with provenance from endemic countries. A multidisciplinary diagnostic approach helps perform antimicrobial susceptibility testing to avoid delaying the start of antibiotic therapy.

Constraints on HIV-1 evolution and immunodominance revealed in monozygotic adult twins infected with the same virus.

The predictability of virus-host interactions and disease progression in rapidly evolving human viral infections has been difficult to assess because of host and genetic viral diversity. Here we examined adaptive HIV-specific cellular and humoral immune responses and viral evolution in adult monozygotic twins simultaneously infected with the same virus. CD4 T cell counts and viral loads followed similar trajectories over three years of follow up. The initial CD8 T cell response targeted 17 epitopes, 15 of which were identical in each twin, including two immunodominant responses. By 36 months after infection, 14 of 15 initial responses were still detectable in both, whereas all new responses were subdominant and remained so. Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin's virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.

Control of M184V HIV-1 mutants by CD8 T-cell responses.

Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug-resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A*02:01-YQYVDDLYV and A*02:01-VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies.

No association of natural killer cell number and function in peripheral blood with overweight/obesity and metabolic syndrome in a cohort of young women.

AIM: To reexamine the associations of NK cell number and function in the peripheral blood with overweight/obesity and the metabolic syndrome in a large, well-phenotyped human cohort. METHODS: Cross-sectional analysis of 273 women in the PPSDiab Study; measurement of absolute and relative number of NK cells in peripheral blood, and of functional parameters CD69 positivity and cytotoxicity against K562 cells; group comparison of NK cell characteristics between lean, overweight, and obese participants, as well as metabolic syndrome scores of 0, 1, 2, and ≥3; Spearman correlation analyses to clinical parameters related to the metabolic syndrome. RESULTS: We found no differences in NK cell number and function between lean, overweight, and obese women (relative NK cell number (median (Q1-Q3), [%]) 5.1(2.6-9.4) vs. 4.8 (2.9-8.4) vs. 3.8 (1.7-7.8), p = 0.187; absolute NK cell number [106 /L]: 86.9 (44.6-188.8) vs. 92.6 (52.5-154.6) vs. 85.9 (44-153.8), p = 0.632; CD69+ [%]: 27.2 (12.9-44.3) vs. 37.6 (13.2-52.8) vs. 33.6 (16.3-45), p = 0.136; cytotoxicity [%]: 11.0 (7.1-14.5) vs. 8.5 (6.4-13.2) vs. 11.3 (8.7-14.2), p = 0.094), as well as between different metabolic syndrome scores. Nonesterified fatty acids correlated with absolute and relative NK cell number and cytotoxicity (ρ [p-value]: 0.142 [0.021], 0.119 [0.049], and 0.131 [0.035], respectively). Relative NK cell number further correlated with high-density lipoprotein cholesterol (0.144 [0.018]) and cytotoxicity with 2 h glucose in oral glucose tolerance testing (0.132 [0.034]). CD69 positivity correlated with body fat (0.141 [0.021]), triglycerides (0.129 [0.033]), and plasma leptin (0.155 [0.010]). After correction for multiple testing, none of the associations remained significant. CONCLUSION: In the present study, we observed no associations of NK cell number and function in the peripheral blood with overweight/obesity and the metabolic syndrome. Extreme phenotypes of obesity and the metabolic syndrome might have caused differing results in previous studies. Further analyses with a focus on compartments other than peripheral blood may help to clarify the relation between NK cells and metabolic diseases.

Ecological effects of selective oral decontamination on multidrug-resistance bacteria acquired in the intensive care unit: a case-control study over 5 years.

PURPOSE: This case-control study investigated the long-term evolution of multidrug-resistant bacteria (MDRB) over a 5-year period associated with the use of selective oropharyngeal decontamination (SOD) in the intensive care unit (ICU). In addition, effects on health care-associated infections and ICU mortality were analysed. METHODS: We investigated patients undergoing mechanical ventilation > 48 h in 11 adult ICUs located at 3 campuses of a university hospital. Administrative, clinical, and microbiological data which were routinely recorded electronically served as the basis. We analysed differences in the rates and incidence densities (ID, cases per 1000 patient-days) of MDRB associated with SOD use in all patients and stratified by patient origin (outpatient or inpatient). After propensity score matching, health-care infections and ICU mortality were compared. RESULTS: 5034 patients were eligible for the study. 1694 patients were not given SOD. There were no differences in the incidence density of MDRB when SOD was used, except for more vancomycin-resistant Enterococcus faecium (0.72/1000 days vs. 0.31/1000 days, p < 0.01), and fewer ESBL-producing Klebsiella pneumoniae (0.22/1000 days vs. 0.56/1000 days, p < 0.01). After propensity score matching, SOD was associated with lower incidence rates of ventilator-associated pneumonia and death in the ICU but not with ICU-acquired bacteremia or urinary tract infection. CONCLUSIONS: Comparisons of the ICU-acquired MDRB over a 5-year period revealed no differences in incidence density, except for lower rate of ESBL-producing Klebsiella pneumoniae and higher rate of vancomycin-resistant Enterococcus faecium with SOD. Incidence rates of ventilator-associated pneumonia and death in the ICU were lower in patients receiving SOD.

Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA.

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

Impact and Sustainability of Antibiotic Stewardship on Antibiotic Prescribing in Visceral Surgery.

BACKGROUND: Antibiotic stewardship (AS) ward rounds are a core element in clinical care for surgical patients. Therefore, we aimed to analyze the impact of surgical AS ward rounds on antibiotic prescribing, and the sustainability of the effect after the AS interventions are no longer provided. METHODS: On four wards of the department of visceral surgery, we conducted two independent retrospective prescribing analyses (P1, P2) over three months each. During the study periods, the level of AS intervention differed for two of the four wards (ward rounds/no ward rounds). RESULTS: AS ward rounds were associated with a decrease in overall antibiotic consumption (91.1 days of therapy (DOT)/100 patient days (PD) (P1), 70.4 DOT/100PD (P2)), and improved de-escalation rates of antibiotic therapy (W1/2: 25.7% (P1), 40.0% (P2), p = 0.030; W3: 15.4 (P1), 24.2 (P2), p = 0.081). On the ward where AS measures were no longer provided, overall antibiotic usage remained stable (71.3 DOT/100PD (P1), 74.4 DOT/100PD (P2)), showing the sustainability of AS measures. However, the application of last-resort compounds increased from 6.4 DOT/100PD to 12.1 DOT/100PD (oxazolidinones) and from 10.8 DOT/100PD to 13.2 DOT/100PD (carbapenems). CONCLUSIONS: Antibiotic consumption can be reduced without negatively affecting patient outcomes. However, achieving lasting positive changes in antibiotic prescribing habits remains a challenge.

Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.

Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.

Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection.

Excessive immune activation is a hallmark of chronic uncontrolled HIV infection. During the past years, growing evidence suggests that immune inhibitory signals also play an important role in progressive disease. However, the relationship between positive and negative immune signals on HIV-specific CD8 T cells has not been studied in detail so far in chronic HIV-1 infection. In this study, the expression of markers of positive (CD38) and negative (PD-1) immune signals on virus-specific CD8 T cells in chronic, untreated HIV-1 infection was evaluated using intracellular cytokine staining. Viral escape mutations were assessed by autologous virus sequence analysis and subsequent peptide titration assays. Single-epitope CD8 T-cell responses toward Gag, Pol, and Nef were compared in 12 HIV-1 controllers (viral load <5,000 cp/ml) and 12 HIV-1 progressors (viral load >50,000 cp/ml) and a highly significant increase of CD38/PD-1 co-expression on virus-specific CD8 T cells in progressors was found (P < 0.0001). The level of CD38/PD-1 co-expression was independent of epitope specificity. Longitudinal follow-up revealed a clear drop in CD38/PD-1 co-expression on virus-specific CD8 T cells after the suppression of antigen following either viral escape mutation or the initiation of HAART (P = 0.004). Antigen persistence with a fluctuating viral load revealed stable levels of CD38/PD-1 co-expression whereas significant rises in viral load were accompanied or even preceded by substantial increases in CD38/PD-1 co-expression. The CD38/PD-1 phenotype clearly distinguishes HIV-specific CD8 T-cell responses between controllers and progressors. Whether it plays a causative role in disease progression remains debatable. J. Med. Virol. 82:358-370, 2010. (c) 2010 Wiley-Liss, Inc.

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection.

BACKGROUND: Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease. RESULTS: We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease. CONCLUSION: The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness-Experience and Recommendations from One Year in Routine Clinical Practice.

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.