Impact of empiric antimicrobial therapy on outcomes in patients with Escherichia coli and Klebsiella pneumoniae bacteremia: a cohort study.

BACKGROUND: It is unclear whether appropriate empiric antimicrobial therapy improves outcomes in patients with bacteremia due to Escherichia coli or Klebsiella. The objective of this study is to assess the impact of appropriate empiric antimicrobial therapy on in-hospital mortality and post-infection length of stay in patients with Escherichia coli or Klebsiella bacteremia while adjusting for important confounding variables. METHODS: We performed a retrospective cohort study of adult patients with a positive blood culture for E. coli or Klebsiella between January 1, 2001 and June 8, 2005 and compared in-hospital mortality and post-infection length of stay between subjects who received appropriate and inappropriate empiric antimicrobial therapy. Empiric therapy was defined as the receipt of an antimicrobial agent between 8 hours before and 24 hours after the index blood culture was drawn and was considered appropriate if it included antimicrobials to which the specific isolate displayed in vitro susceptibility. Data were collected electronically and through chart review. Survival analysis was used to statistically assess the association between empiric antimicrobial therapy and outcome (mortality or length of stay). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Among 416 episodes of bacteremia, 305 (73.3%) patients received appropriate empiric antimicrobial therapy. Seventy-one (17%) patients died before discharge from the hospital. The receipt of appropriate antimicrobial agents was more common in hospital survivors than in those who died (p = 0.04). After controlling for confounding variables, there was no association between the receipt of appropriate empiric antimicrobial therapy and in-hospital mortality (HR, 1.03; 95% CI, 0.60 to 1.78). The median post-infection length of stay was 7 days. The receipt of appropriate antimicrobial agents was not associated with shortened post-infection length of stay, even after controlling for confounding (HR, 1.11; 95% CI 0.86 to 1.44). CONCLUSION: Appropriate empiric antimicrobial therapy for E. coli and Klebsiella bacteremia is not associated with lower in-hospital mortality or shortened post-infection length of stay. This suggests that the choice of empiric antimicrobial agents may not improve outcomes and also provides data to support a randomized trial to test the hypothesis that use (and overuse) of broad-spectrum antibiotics prior to the availability of culture results is not warranted.

A systematic review of the methods used to assess the association between appropriate antibiotic therapy and mortality in bacteremic patients.

Studies of the association between inappropriate antibiotic therapy and mortality among bacteremic patients have generated conflicting findings. We systematically reviewed these studies to identify methodological heterogeneity that may explain the lack of agreement. We identified 51 articles that met the inclusion criteria, and we extracted the following data: study design, definition and measurement of variables, and statistical methods. Only 8 studies (16%) defined inappropriate antibiotic therapy as that which was inactive in vitro against the isolated organism(s) and not consistent with current clinical practice recommendations and distinguished between empiric and definitive treatment. Thirty-four studies (67%) measured the severity of illness, but only 6 (12%) specified the time at which it was measured. The methodological recommendations suggested in this article are intended to improve the validity and generalizability of future research. In brief, future studies should define "inappropriate" therapy on the basis of in vitro susceptibility data, should separately evaluate empiric and definitive therapy, and should control for the baseline severity of illness.

Multifocal herpes simplex virus type 2 encephalitis in a patient with AIDS.

Herpes simplex virus type 2 (HSV-2) infection commonly causes meningitis and genital herpes. We describe a rare case of brain stem encephalitis with cutaneous manifestations attributable to HSV-2 infection in a patient with HIV infection.

Multidisciplinary Point-of-Care Testing in South African Primary Health Care Clinics Accelerates HIV ART Initiation but Does Not Alter Retention in Care.

BACKGROUND: Lack of accessible laboratory infrastructure limits HIV antiretroviral therapy (ART) initiation, monitoring, and retention in many resource-limited settings. Point-of-care testing (POCT) is advocated as a mechanism to overcome these limitations. We executed a pragmatic, prospective, randomized, controlled trial comparing the impact of POCT vs. standard of care (SOC) on treatment initiation and retention in care. METHODS: Selected POC technologies were embedded at 3 primary health clinics in South Africa. Confirmed HIV-positive participants were randomized to either SOC or POC: SOC participants were venesected and specimens referred to the laboratory with patient follow-up as per algorithm (∼3 visits); POC participants had phlebotomy and POCT immediately on-site using Pima CD4 to assess ART eligibility followed by hematology, chemistry, and tuberculosis screening with the goal of receiving same-day adherence counseling and treatment initiation. Participant outcomes measured at recruitment 6 and 12 months after initiation. RESULTS: Four hundred thirty-two of 717 treatment eligible participants enrolled between May 2012 and September 2013: 198 (56.7%) SOC; 234 (63.6%) POC. Mean age was 37.4 years; 60.5% were female. Significantly more participants were initiated using POC [adjusted prevalence ratio (aPR) 0.83; 95% confidence interval (CI): 0.74 to 0.93; P < 0.0001], the median time to initiation was 1 day for POC and 26.5 days for SOC. The proportion of patients in care and on ART was similar for both arms at 6 months (47 vs. 50%) (aPR 0.96; 95% CI: 0.79 to 1.16) and 12 months (32 vs. 32%) (aPR 1.05; 95% CI: 0.80 to 1.38), with similar mortality rates. Loss to follow-up at 12 months was higher for POC (36% vs. 51%) (aPR 0.82; 95% CI: 0.65 to 1.04). CONCLUSIONS: Adoption of POCT accelerated ART initiation but once on treatment, there was unexpectedly higher loss to follow-up on POC and no improvement in outcomes at 12 months over SOC.

Nosocomial enterobacter meningitis: risk factors, management, and treatment outcomes.

Enterobacter species are increasingly a cause of nosocomial meningitis among neurosurgery patients, but risk factors for these infections are not well defined. A review of all adult patients hospitalized at the University of California-Los Angeles (UCLA) Medical Center during an 8-year period identified 15 postneurosurgical cases of Enterobacter meningitis (EM). Cure was achieved in 14 cases (93%), and efficacy was similar for carbapenem- and cephalosporin-based treatment. A matched case-control study comparing 26 controls with 13 case patients hospitalized exclusively at the UCLA Medical Center found that external cerebrospinal fluid (CSF) drainage devices (odds ratio [OR], 21.8; P=.001), isolation of Enterobacter species from a non-CSF culture (OR, 24.6; P=.002), and prolonged administration of antimicrobial drugs before the diagnosis of meningitis that were inactive in vitro against Enterobacter species (OR, 13.3; P=.008) were independent risk factors for EM. Despite favorable treatment outcomes, EM is a serious infection associated with Enterobacter species colonization or infection at other surgical sites, with selective antimicrobial pressure, and with invasive CNS devices.

Impact of recommendation updates in well-controlled patients on nonrecommended antiretroviral therapies: the Swiss HIV cohort study.

BACKGROUND: HIV treatment recommendations are updated as clinical trials are published. Whether recommendations drive clinicians to change antiretroviral therapy in well-controlled patients is unexplored. METHODS: We selected patients with undetectable viral loads (VLs) on nonrecommended regimens containing double-boosted protease inhibitors (DBPIs), triple-nucleoside reverse transcriptase inhibitors (NRTIs), or didanosine (ddI) plus stavudine (d4T) at publication of the 2006 International AIDS Society recommendations. We compared demographic and clinical characteristics with those of control patients with undetectable VL not on these regimens and examined clinical outcome and reasons for treatment modification. RESULTS: At inclusion, 104 patients were in the DBPI group, 436 in the triple-NRTI group, and 19 in the ddI/d4T group. By 2010, 28 (29%), 204 (52%), and 1 (5%) patient were still on DBPIs, triple-NRTIs, and ddI plus d4T, respectively. 'Physician decision,' excluding toxicity/virological failure, drove 30% of treatment changes. Predictors of recommendation nonobservance included female sex [adjusted odds ratio (aOR) 2.69, 95% confidence interval (CI) 1 to 7.26; P = 0.01] for DPBIs, and undetectable VL (aOR 3.53, 95% CI 1.6 to 7.8; P = 0.002) and lack of cardiovascular events (aOR 2.93, 95% CI 1.23 to 6.97; P = 0.02) for triple-NRTIs. All patients on DBPIs with documented diabetes or a cardiovascular event changed treatment. Recommendation observance resulted in lower cholesterol values in the DBPI group (P = 0.06), and more patients having undetectable VL (P = 0.02) in the triple-NRTI group. CONCLUSION: The physician's decision is the main factor driving change from nonrecommended to recommended regimens, whereas virological suppression is associated with not switching. Positive clinical outcomes observed postswitch underline the importance of observing recommendations, even in well-controlled patients.

Performance evaluation of the Pima™ point-of-care CD4 analyser using capillary blood sampling in field tests in South Africa.

BACKGROUND: Point-of-care CD4 testing can provide immediate CD4 reporting at HIV-testing sites. This study evaluated performance of capillary blood sampling using the point-of-care Pima™ CD4 device in representative primary health care clinics doing HIV testing. METHODS: Prior to testing, prescribed capillary-sampling and instrument training was undertaken by suppliers across all sites. Matching venous EDTA samples were drawn throughout for comparison to laboratory predicate methodology (PLG/CD4). In Phase I, Pima™ cartridges were pipette-filled with EDTA venous blood in the laboratory (N = 100). In Phase II (N = 77), Pima™ CD4 with capillary sampling was performed by a single operator in a hospital-based antenatal clinic. During subsequent field testing, Pima™ CD4 with capillary sampling was performed in primary health care clinics on HIV-positive patients by multiple attending nursing personnel in a rural clinic (Phase-IIIA, N = 96) and an inner-city clinic (Phase-IIIB, N = 139). RESULTS: Pima™ CD4 compared favourably to predicate/CD4 when cartridges were pipette-filled with venous blood (bias -17.3 ± STDev = 36.7 cells/mm3; precision-to-predicate %CV < 6%). Decreased precision of Pima™ CD4 to predicate/CD4 (varying from 17.6 to 28.8%SIM CV; mean bias = 37.9 ± STDev = 179.5 cells/mm3) was noted during field testing in the hospital antenatal clinic. In the rural clinic field-studies, unacceptable precision-to-predicate and positive bias was noted (mean 28.4%SIM CV; mean bias = +105.7 ± STDev = 225.4 cells/mm3). With additional proactive manufacturer support, reliable performance was noted in the subsequent inner-city clinic field study where acceptable precision-to-predicate (11%SIM CV) and less bias of Pima™ to predicate was shown (BA bias ~11 ± STDev = 69 cells/mm3). CONCLUSIONS: Variable precision of Pima™ to predicate CD4 across study sites was attributable to variable capillary sampling. Poor precision was noted in the outlying primary health care clinic where the system is most likely to be used. Stringent attention to capillary blood collection technique is therefore imperative if technologies like Pima™ are used with capillary sampling at the POC. Pima™ CD4 analysis with venous blood was shown to be reproducible, but testing at the point of care exposes operators to biohazard risk related to uncapping vacutainer samples and pipetting of blood, and is best placed in smaller laboratories using established principles of Good Clinical Laboratory Practice. The development of capillary sampling quality control methods that assure reliable CD4 counts at the point of care are awaited.

Causes of death on antiretroviral therapy: a post-mortem study from South Africa.

BACKGROUND: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. METHODS: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. RESULTS: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. CONCLUSIONS: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Loss to follow-up of stable antiretroviral therapy patients in a decentralized down-referral model of care in Johannesburg, South Africa.

A retrospective record review was conducted for patients down referred to primary health care facilities between 2007 and 2009 to assess the rate and reported reasons for loss to follow-up among stable antiretroviral patients in a down-referral model of care in Johannesburg, South Africa. Missing patients were traced telephonically. Of 3361 patients down referred, 4.11% were lost to follow-up. Most patients who were lost to follow-up were lost at the transfer stage between initiation and maintenance sites. Decentralization and nurse management of ART should be prioritized to increase access to and retention in HIV/AIDS care.

Providing immediate CD4 count results at HIV testing improves ART initiation.

BACKGROUND: In South Africa, CD4 count results are typically available within a week of testing. However, 35%-55% of newly diagnosed HIV-positive patients do not return for their CD4 results and therefore, do not access further care. We evaluated the impact of a CD4 count result and patient written information provided immediately after diagnosis on retention in care. METHODS: HIV-infected subjects were randomized to 3 arms; receipt of a CD4 result at time of HIV diagnosis, receipt of written information, and standard of care (CD4 collection after 1 week) or standard of care alone. The outcome of interest was enrollment for further care within 1 month for pre-antiretroviral therapy (ART) care or within 3 months for ART initiation. Secondary outcome was time taken from diagnosis to each stage of care pathway. Independent predictors of retention were assessed with multivariate analysis. RESULTS: Three hundred forty-four patients recruited, of which 64.5% were females with a median age of 30 years (interquartile range: 27-35). Subjects were similar in age, gender, CD4 count, education, and employment status. Providing CD4 results at HIV diagnosis increases the likelihood of reporting for ART initiation (risk ratio = 2.1; 95% confidence interval = 1.39 to 3.17) compared with standard of care. Written information only reduced the time to presentation for pre-ART care although increasing age was associated with retention. There was 49% attrition in the standard of care arms. CONCLUSIONS: Receipt of a CD4 count at the time of HIV testing increases ART initiation rates. Point-of-care diagnostics can be used to improve retention, but losses to pre-ART care remain high.

Achieving the HIV and AIDS National Strategic Plan: A practical calculator for local target setting in district health facilities.

The South African HIV National Strategic Plan (NSP) aims to provide access to appropriate treatment, care and support to 80% of the HIV-infected population by 2011. By mid-2008, highly active antiretroviral treatment (HAART) was being dispensed to about half the HIV-infected population in need. Reaching the NSP targets will require full mobilisation of all of South Africa's health facilities. While the NSP has broad political and programmatic support from the Department of Health and civil society, and managers are able to recite the national targets, it has been difficult for these managers to relate the targets to their own geographical areas of responsibility. National, regional and district targets for HIV care have been set from South Africa's relatively good census, modelling and epidemiological data. However, few practical tools are available to help clinicians and managers understand their facility's actual contribution to the district regional and national NSP targets for each step of the HIV care pathway (HIV testing, CD4 testing, HAART referral and initiation). The calculation of HAART initiation targets is complicated by the anticipated additional demand for treatment that will be generated by a change in the recommended CD4-count threshold for initiation of treatment.4 Accordingly, we provide a data-based tool that is readily available, and that district and facility managers can use to calculate their annual steady-state HIV testing, CD4 testing and HAART initiation requirements. These calculated values can be used for local and regional planning and to assess and improve current performance at facility level.

Outcomes of patients on dual-boosted PI regimens: experience of the Swiss HIV cohort study.

Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV-1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400 copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available.

Controlling for severity of illness in outcome studies involving infectious diseases: impact of measurement at different time points.

BACKGROUND: Severity of illness is an important confounder in outcome studies involving infectious diseases. However, it is unclear whether the time at which severity of illness is measured is important. METHODS: We performed a retrospective study of 328 episodes of gram-negative bacteremia in adult patients to assess the impact of the time of measurement of severity of illness on the association between empirical antimicrobial therapy received and in-hospital mortality. Using a modified Acute Physiology Score (APS), severity of illness was measured at 2 time points: (1) hospital admission and (2) 24 hours before the first culture-positive blood sample was collected. Multivariate logistic regression was used to estimate the impact of adjusting for the APS on the relationship between empirical therapy received (ie, the exposure) and in-hospital mortality (ie, the outcome). RESULTS: The mean APS (+/- standard deviation) of patients with bacteremia increased during their hospital stay (from 19.2 +/- 11.6 at admission to 24.2 +/- 13.6 at the second time point; P < .01). When examining the association between empirical antimicrobial therapy received and in-hospital mortality, and controlling for the APS, there was a trend toward a decreased impact of appropriate therapy received on in-hospital mortality. The unadjusted odds ratio (OR) for the association between appropriate therapy received and in-hospital mortality was 0.83 (95% confidence interval [CI], 0.51-1.34). After controlling for the APS at admission, this association was attenuated (OR, 0.94 [95% CI, 0.57-1.55]), and when a change in the APS was also included in the multivariate logistic regression model, the association was further attenuated (OR, 0.99 [95% CI, 0.58-1.69]). CONCLUSIONS: The magnitude of the association between appropriate antimicrobial therapy received and in-hospital mortality among patients with gram-negative bacteremia was sensitive to the timing of adjustment for severity of illness.

Impact of empiric antibiotic therapy on outcomes in patients with Pseudomonas aeruginosa bacteremia.

The impact of appropriate empirical antimicrobial therapy for Pseudomonas aeruginosa bacteremia on patient outcomes has not been clearly established. We assessed the effect of appropriate empirical therapy on in-hospital mortality and length of stay (LOS) among patients with P. aeruginosa bacteremia. This was a retrospective cohort study of inpatients with a positive blood culture for P. aeruginosa between January 2001 and June 2005. Empirical therapy was defined as appropriate if the patient received an antibiotic the organism was susceptible to between 8 h before culture collection and the time the susceptibility results were available. The severity of the illness was measured 24 h before culture collection. The data were analyzed using logistic regression (in-hospital mortality) and linear regression (LOS). Overall, there were 167 episodes of P. aeruginosa bacteremia, 123 (86%) of which received appropriate empirical antibiotics. Sixty-one patients died (36.5%). The median time from culture collection to susceptibility results was 3.4 days. After we adjusted for age, severity of illness, and time at risk, we found that the appropriate empirical therapy was not significantly associated with mortality (odds ratio = 0.96; 95% confidence interval = 0.31 to 2.93). There was a 7% reduction in the mean LOS for patients who had received appropriate therapy at the time susceptibility results were available compared to those who did not (P = 0.74). These data suggest that the use of appropriate empirical therapy, i.e., before susceptibility results are known may not be as critical to patient outcomes as other studies have suggested.