Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Diabetes IN hospital - Glucose and Outcomes in the COVID-19 pandemic (DINGO COVID-19): the 2020 Melbourne hospital experience prior to novel variants and vaccinations.

BACKGROUND AND AIMS: A relationship between diabetes, glucose and COVID-19 outcomes has been reported in international cohorts. This study aimed to assess the relationship between diabetes, hyperglycaemia and patient outcomes in those hospitalised with COVID-19 during the first year of the Victorian pandemic prior to novel variants and vaccinations. DESIGN, SETTING: Retrospective cohort study from March to November 2020 across five public health services in Melbourne, Australia. PARTICIPANTS: All consecutive adult patients admitted to acute wards of participating institutions during the study period with a diagnosis of COVID-19, comprising a large proportion of patients from residential care facilities and following dexamethasone becoming standard-of-care. Admissions in patients without known diabetes and without inpatient glucose testing were excluded. RESULTS: The DINGO COVID-19 cohort comprised 840 admissions. In 438 admissions (52%), there was no known diabetes or in-hospital hyperglycaemia, in 298 (35%) patients had known diabetes, and in 104 (12%) patients had hyperglycaemia without known diabetes. ICU admission was more common in those with diabetes (20%) and hyperglycaemia without diabetes (49%) than those with neither (11%, P < 0.001 for all comparisons). Mortality was higher in those with diabetes (24%) than those without diabetes or hyperglycaemia (16%, P = 0.02) but no difference between those with in-hospital hyperglycaemia and either of the other groups. On multivariable analysis, hyperglycaemia was associated with increased ICU admission (adjusted odds ratio (aOR) 6.7, 95% confidence interval (95% CI) 4.0-12, P < 0.001) and longer length of stay (aOR 173, 95% CI 11-2793, P < 0.001), while diabetes was associated with reduced ICU admission (aOR 0.55, 95% CI 0.33-0.94, P = 0.03). Neither diabetes nor hyperglycaemia was independently associated with in-hospital mortality. CONCLUSIONS: During the first year of the COVID-19 pandemic, in-hospital hyperglycaemia and known diabetes were not associated with in-hospital mortality, contrasting with published international experiences. This likely mainly relates to hyperglycaemia indicating receipt of mortality-reducing dexamethasone therapy. These differences in published experiences underscore the importance of understanding population and clinical treatment factors affecting glycaemia and COVID-19 morbidity within both local and global contexts.

Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin-Piperaquine.

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.

Impact of weekend admission and changes in treating team on patient flow and outcomes in adults admitted to hospital with community-acquired pneumonia.

BACKGROUND: The effect of workflow factors, such as timing of admission and changes in treating team, on patient outcomes remains inconclusive. AIMS: To investigate the impact of weekend admission and changes in treating team on four pre-defined outcomes in patients admitted to hospital with community-acquired pneumonia (CAP). METHODS: We performed an observational cohort study by utilising prospective longitudinal data collected during the IMPROVE-GAP trial, a stepped-wedge randomised study investigating an evidence-based bundle of care in the management of CAP. We assessed the effect of two exposure variables, day of admission and change of treating team, on four pre-specified outcomes: (i) length of stay; (ii) time to clinical stability; (iii) readmission within 30 days; and (iv) mortality at 30 days. Our analysis was restricted to patients with a primary diagnosis of CAP and employed multivariable Cox regression and logistic regression to adjust for potential measured confounders. RESULTS: Of 753 participants, 224 (29.7%) were admitted on the weekend and 71 (9.4%) changed treating team during admission. Weekend admissions had significantly longer hospital stays than weekday admissions (hazard ratio (95% confidence interval; P-value) 0.82 (0.70-0.98; 0.03)) and took longer to reach clinical stability (0.80 (0.68-0.95; 0.01)). Change of treating team doubled the odds of readmission at 30 days (odds ratio 1.95 (1.08-3.58; 0.03)). CONCLUSIONS: These results suggest workflow factors can negatively impact both health service and patient outcomes. Systems interventions aimed at improving out of hours service and reducing changes in treating team should be considered.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

Lead poisoning associated with illicit opium use.

Lead poisoning is an uncommon and challenging diagnosis to make. In 2018, The Victorian Department of Health issued a health warning following four cases of lead poisoning associated with illicit opium use in Melbourne, Australia. We present these cases to highlight clinical features and the relevant investigations leading to diagnosis. All cases occurred in recent immigrants to Australia, who had access to non-traditional sources of opioids. Health care professionals should consider lead poisoning in patients with appropriate symptoms and a history of illicit opium use.

The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis.

BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. METHODS AND FINDINGS: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. CONCLUSIONS: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration.

Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered for use as a tool for malaria elimination. As an effective and long-acting antimalarial, dihydroartemisinin-piperaquine (DHA-PQP) appears to be suitable as a candidate for MDA. However, the absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA. We conducted an interventional study in Lihir Island, Papua New Guinea, using healthy individuals age 3 to 60 years who received a standard 3-day course of DHA-PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted predose and 4 h after the final dose of each month. The primary safety endpoint was QT interval correction (QTc using Fridericia's correction [QTcF]) prolongation from baseline to 4 h postdosing. We compared the difference in prolongations between the third course postdose and the first course postdose. Of 84 enrolled participants, 69 (82%) participants completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (standard deviation [SD], 17.8 ms) and 17.1 ms (SD, 17.1 ms) for the first-course and third-course postdosing ECGs risk difference, -2.4 (95% confidence interval [95% CI], -6.9 to 2.1; P = 0.285), respectively. We recorded a QTcF prolongation of >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course (P = 1.00), respectively. No participants had QTcF intervals of >500 ms at any time point. Three consecutive monthly courses of DHA-PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing supports the use of monthly DHA-PQP as part of malaria elimination strategies.

Quantifying the hidden healthcare cost of diabetes mellitus in Australian hospital patients.

BACKGROUND: Diabetes mellitus in hospital inpatients is most commonly present as a comorbidity rather than as the primary diagnosis. In some hospitals, the prevalence of comorbid diabetes mellitus across all inpatients exceeds 30%, which could add to complexity of care and resource utilisation. However, whether and to what extent comorbid diabetes mellitus contributes indirectly to greater hospitalisation costs is ill-defined. AIM: To determine the attributable effect of comorbid diabetes mellitus on hospital resource utilisation in a General Internal Medical service in Melbourne, Australia. METHODS: We extracted data from a database of all General Internal Medical discharge episodes from July 2012 to June 2013. We fitted multivariable regression models to compare patients with diabetes mellitus to those without diabetes mellitus with respect to hospitalisation cost, length of stay, admissions per year and inpatient mortality. RESULTS: Of 4657 patients 1519 (33%) had diabetes mellitus, for whom average hospitalisation cost (AUD9910) was higher than those without diabetes mellitus (AUD7805). In multivariable analysis, this corresponded to a 1.22-fold (95% confidence interval (CI) 1.12-1.33, P < 0.001) higher cost. Mean length of stay for those with diabetes was 8.2 days versus 6.8 days for those without diabetes, with an adjusted 1.19-fold greater odds (95% CI 1.06-1.33, P = 0.001) of staying an additional day. Number of admissions and mortality were similar. CONCLUSION: Comorbid diabetes mellitus adds significantly to hospitalisation duration and costs in medical inpatients. Moreover, diabetes mellitus patients with chronic complications had a greater-still cost and hospitalisation duration compared to those without diabetes mellitus.

Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling.

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n = 15 in each group) and SP-chloroquine (n = 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.

How important is gametocyte clearance after malaria therapy?

There has been increasing interest in the role of malaria drugs in preventing malaria transmission from humans to mosquitoes, which would help augment malaria control and elimination strategies. Nevertheless, only one stage in the malaria parasite life cycle, the gametocyte, is infectious to mosquitoes. The Worldwide Antimalarial Resistance Network (WWARN) have analyzed data from 48,840 patients from 141 clinical trials in order to define the nature and determinants of gametocyte clearance following artemisinin combination treatment (ACT) for symptomatic malaria infections. However, the presence of gametocytes does not always predict their infectivity, meaning that the microscopy-based methods used by the WWARN investigators represent an imperfect surrogate marker of transmissibility. Their findings, that some ACTs clear gametocytes faster than others, should be interpreted in light of these limitations and important gaps in our understanding of the biology and epidemiology of malaria transmission.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0621-7.

False economies in home-based parenteral antibiotic treatment: a health-economic case study of management of lower-limb cellulitis in Australia.

OBJECTIVES: The majority of healthcare costs accrued managing cellulitis can be attributed to the small proportion of patients treated with parenteral antibiotics. Hospital in the home (HITH) instead of or following initial inpatient treatment is a safe and effective alternative, but there are few data evaluating its cost-effectiveness for cellulitis. PATIENTS AND METHODS: Our retrospective cohort study included all treatment episodes (by either HITH or an inpatient service for >24 h) with an ICD-10 primary diagnosis code of lower-leg cellulitis at a tertiary-level health service in Melbourne, Australia over 12 months (2012-13). Data included demography, social factors and ICD-10 codes mapped to major comorbidities constituting the Charlson comorbidity index (CCI). Differences in length of stay (LOS) and individual clinical costing (ICC) between HITH- and non-HITH-treated patients were tested with univariable and multivariable (generalized linear model) analyses. RESULTS: For 328 admissions in 294 patients, the average per-day costs were AU$431 for HITH and AU$761 for inpatient care. For 124 patients (38%) treated in HITH, both LOS [mean (95% CI) 7.48 days (6.76-8.20 days) versus 5.82 days (3.45-8.18 days)] and ICC [mean (95% CI) AU$5873 (AU$5212-AU$6534) versus AU$5196 (AU$4567- AU$5824)] were higher than those for patients with solely inpatient care. In multivariable analysis controlling for age, comorbidity, carer support and language, HITH remained associated with significantly longer LOS [1.63-fold (95% CI: 1.24- to 2.13-fold): P < 0.001] and non-significantly with higher cost [1.14-fold (95% CI: 0.97- to 1.34-fold): P = 0.11]. CONCLUSIONS: Management of cellulitis represents a substantial cost burden for hospital services. Modest per-day cost savings from HITH can be offset by much longer HITH LOS.

A Retrospective Review: Significance of Vegetation Size in Injection Drug Users with Right-Sided Infective Endocarditis.

BACKGROUND: Previously described prognostic markers in right-sided infective endocarditis (RSIE) include vegetation size ≥1cm, fever for more than three weeks, cardiac failure and severe sepsis. This study aimed to evaluate effectiveness of medical therapy for vegetations ≥1cm and explore determinants of outcome in a representative population of intravenous drug users (IDUs) at a metropolitan Australian health service. METHODS: Retrospective review of consecutive IDUs presenting to our institution with native-valve RSIE (by modified Duke criteria) over seven years (2005-2011). Data recorded included echocardiographic estimation of maximal vegetation diameter (classified as < or ≥1cm). Relationships between vegetation size and specified outcomes of death, septic shock, recurrence and relapse were examined by Chi-squared testing. RESULTS: Of 49 episodes five (10%) were managed surgically and a further four (8%) were lost to follow-up and excluded from the analysis. Of the remaining 40 evaluable medically treated patients (median age 28, range 20-55), 37 (93%) cultured methicillin-sensitive S. aureus and all had tricuspid valve involvement. Of 24 with vegetations ≥1cm, three died (mortality 13%) compared with one (6%) in 16 medically treated patients with vegetations <1cm (p=0.63). A Pittsburgh (PITT) bacteraemia score of ≥4 at presentation was associated with a mortality of 24% (four of 17 patients died) compared with 0 in 23 patients with PITT scores <4 (p=0.026). CONCLUSION: Medical therapy alone can be effective for RSIE when large vegetations are present. However a high sepsis score at presentation may increase risk of death. Larger studies are required to determine optimal indications for early surgical intervention.

Parasite clearance after malaria therapy: staying a step ahead of drug resistance.

The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health. However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment. If this were also to occur in Africa, it would have disastrous implications for the continent subject to the world's greatest burden of Plasmodium falciparum. The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment. The Worldwide Antimalarial Resistance Network have analysed data from 29,493 patients from 84 clinical trials in order to define the nature and determinants of early parasite clearance following artemisinin-based treatment in African populations. In doing so, they lay the foundation for systems intended to enable the earliest possible detection of emerging artemisinin resistance in Africa. Please see related article: http://www.biomedcentral.com/1741-7015/13/212.

Significant geographical differences in prevalence of mutations associated with Plasmodium falciparum and Plasmodium vivax drug resistance in two regions from Papua New Guinea.

BACKGROUND: Drug resistance remains a major obstacle to malaria treatment and control. It can arise and spread rapidly, and vary substantially even at sub-national level. National malaria programmes require cost-effective and timely ways of characterizing drug-resistance at multiple sites within their countries. METHODS: An improved multiplexed post-PCR ligase detection reaction-fluorescent microsphere assay (LDR-FMA) was used to simultaneously determine the presence of mutations in chloroquine resistance transporter (crt), multidrug resistance 1 (mdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes in Plasmodium falciparum (n = 727) and Plasmodium vivax (n = 574) isolates collected in 2006 from cross-sectional community population surveys in two geographically distinct regions (Madang and East Sepik) of Papua New Guinea (PNG) where strong regional differences in in vivo aminoquinoline and antifolate therapeutic efficacy had previously been observed. Data were compared to those of a follow-up survey conducted in 2010. RESULTS: Despite some very low parasite densities, the assay successfully amplified all P. falciparum and P. vivax loci in 77 and 69 % of samples, respectively. In 2006, prevalences of pfdhfr (59R-108 N) double mutation/wild type pfdhps haplotype, pfcrt SVMNT haplotype (72S-76T double mutation), and 86Y pfmdr1 mutation all exceeded 90 %. For P. vivax, 65 % carried at least two pvdhfr mutations, 97 % the 647P pvdhps mutation and 54 % the 976F pvmdr1 mutation. Prevalence of mutant haplotypes was higher in Madang than East Sepik for pfcrt SVMNT (97.4 vs 83.3 %, p = 0.001), pfdhfr (59R-108 N) (100 vs 90.6 %, p = 0.001), pvdhfr haplotypes (75.8 vs 47.6 %, p = 0.001) and pvmdr1 976F (71.2 vs 26.2 %, p < 0.001). Data from a subsequent Madang survey in 2010 showed that the prevalence of pfdhps mutations increased significantly from <5 % to >30 % (p < 0.001) as did the prevalence of pvdhfr mutant haplotypes (from 75.8 to 97.4 %, p = 0.012). CONCLUSIONS: This LDR-FMA multiplex platform shows feasibility for low-cost, high-throughput, rapid characterization of a broad range of drug-resistance markers in low parasitaemia infections. Significant geographical differences in mutation prevalence correlate with previous genotyping surveys and in vivo trials and may reflect variable drug pressure and differences in health-care access in these two PNG populations.

Plasmodium falciparum and Plasmodium vivax genotypes and efficacy of intermittent preventive treatment in Papua New Guinea.

Intermittent preventive treatment of infants (IPTi) reduces early childhood malaria-related morbidity. While genotypic drug resistance markers have proven useful in predicting the efficacy of antimalarial drugs in case management, there are few equivalent data relating to their protective efficacy when used as IPTi. The present data from an IPTi trial in Papua New Guinea demonstrate how these markers can predict protective efficacy of IPTi for both Plasmodium falciparum and Plasmodium vivax.