Failure Of Prophylaxis Research Articles

Management of variceal hemorrhage: current concepts.

IntroductionThe treatment of portal hypertension is complex and the the best strategy depends on the underlying disease (cirrhosis vs. schistosomiasis), patient's clinical condition and time on it is performed (during an acute episode of variceal bleeding or electively, as pre-primary, primary or secondary prophylaxis). With the advent of new pharmacological options and technical development of endoscopy and interventional radiology treatment of portal hypertension has changed in recent decades.AimTo review the strategies employed in elective and emergency treatment of variceal bleeding in cirrhotic and schistosomotic patients.MethodsSurvey of publications in PubMed, Embase, Lilacs, SciELO and Cochrane databases through June 2013, using the headings: portal hypertension, esophageal and gastric varices, variceal bleeding, liver cirrhosis, schistosomiasis mansoni, surgical treatment, pharmacological treatment, secondary prophylaxis, primary prophylaxis, pre-primary prophylaxis.ConclusionPre-primary prophylaxis doesn't have specific treatment strategies; the best recommendation is treatment of the underlying disease. Primary prophylaxis should be performed in cirrhotic patients with beta-blockers or endoscopic variceal ligation. There is controversy regarding the effectiveness of primary prophylaxis in patients with schistosomiasis; when indicated, it is done with beta-blockers or endoscopic therapy in high-risk varices. Treatment of acute variceal bleeding is systematized in the literature, combination of vasoconstrictor drugs and endoscopic therapy, provided significant decline in mortality over the last decades. TIPS and surgical treatment are options as rescue therapy. Secondary prophylaxis plays a fundamental role in the reduction of recurrent bleeding, the best option in cirrhotic patients is the combination of pharmacological therapy with beta-blockers and endoscopic band ligation. TIPS or surgical treatment, are options for controlling rebleeding on failure of secondary prophylaxis. Despite the increasing evidence of the effectiveness of pharmacological and endoscopic treatment in schistosomotic patients, surgical therapy still plays an important role in secondary prophylaxis.

Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation

BackgroundCytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance.MethodsIn this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection.ResultsThe reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan–Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.ConclusionsLetermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.)

Comparison of fluconazole and posaconazole for fungal prophylaxis in high- risk patients with hematological malignity

Objective: To compare the frequency of fungal infection and mortality rates in patients with hematological malignity and receiving either flucanazole (FLU) or posaconazole (POS) prophylaxis. Methods: This retrospective, observational study investigated fungal prophylaxis in patients with a high risk of invasive fungal infections (IFIs) and diagnosed with hematological malignity at our hospital hematology clinic between 01.01.2011 and 01.01.2013. FLU (n=70) was the prophylactic regimen between 2011 and 2012 which was replaced by POS (n=35) in the following period. The incidence and mortality rates of IFIs developing in the two periods were compared. Results: The incidence of IFI in patients administered FLU prophylaxis was 22/70 (31%), compared to 13/35 (37%) in the patients receiving POS. Incidence of invasive pulmonary aspergillosis (IPA) in the FLU group was 21/70 (31%), compared to 9/35 (26%) in the POS group. The mortality rate in the group receiving FLU prophylaxis was 17 (24%), compared to 4 (11%) in the POS group. The difference was attributed to causes other than fungal infection. Results of subgroup analysis performed for AML were similar to the general findings in terms of both incidences of fungal infection and of mortality levels. In multivariate analysis, mean duration of neutropenia was correlated with prophylaxis failure. Conclusion: We conclude that both agents can be successfully used in fungal infection prophylaxis for patients at high risk for IFI.

First-Trimester Risk Factors for Preeclampsia Development in Women Initiating Aspirin by 16 Weeks of Gestation

The residual risk of preeclampsia in high-risk women on aspirin prophylaxis exceeds that of low-risk populations, and this study aimed to identify first-trimester maternal characteristics associated with aspirin prophylaxis failure. This is a nested cohort study of prospectively enrolled women with verified initiation of risk-indicated aspirin prophylaxis by 16 weeks of gestation. First-trimester maternal history, demographics, anthropometry, ultrasound parameters, and serum analytes were compared between women who developed preeclampsia and those who did not. Blood pressure measurements were classified as prehypertension or hypertension according to the Joint National Committee on Hypertension guidelines. Chi square, nonparametric, and logistic regression analyses were used to determine the contributors to preeclampsia development. Six hundred fourteen women prospectively enrolled at 9-14 weeks of gestation initiated aspirin by 16 weeks of gestation. The 59 (9.6%) women who developed preeclampsia were more likely to have chronic hypertension, diabetes, and obesity and had higher first-trimester blood pressure and lower serum pregnancy-associated plasma protein-A concentrations (all P<.05). Having first-trimester Joint National Committee on Hypertension prehypertension or hypertension was associated with a 2.18-fold increased risk of developing preeclampsia, whereas normotension was associated with a reduction of risk of 56%. Women who develop preeclampsia while taking aspirin prophylaxis are more likely to have elevated first-trimester blood pressures. Conversely, first-trimester normotension is associated with a reduced risk of preeclampsia.

Effectiveness of Short Prophylactic Course of Atovaquone‐Proguanil in Travelers to Sub‐Saharan Africa: Table 1

Current guidelines recommend continuation of atovaquone-proguanil (AP) malaria prophylaxis for 7 days after leaving Plasmodium falciparum endemic areas. Evidence from clinical studies suggests that discontinuation of AP 1 day after exposure ends may be safe and effective. Our objective was to assess the effectiveness of short-course AP prophylaxis among travelers to sub-Saharan Africa. To detect prophylactic failures associated with short-course AP prophylaxis discontinued 1 day after return, we conducted active surveillance during the years 2010 and 2011, by a retrospective telephone survey 1 to 6 months after travelers' return. Passive surveillance data were obtained from the Israel Ministry of Health (MOH) malaria registry. Among 485 travelers to sub-Saharan Africa (cumulative exposure of 4,979 days), 421 (87%) discontinued AP 1 day after leaving the endemic region (cumulative exposure of 4,337 days). None of the 485 travelers reported malaria infection. The MOH malaria registry survey included 363 P. falciparum-infected patients during the years 2003 to 2011. The majority (n = 305; 84%) did not use any malaria prophylaxis. None of the patients had used AP (neither regular nor short course AP) for malaria prophylaxis. We did not detect prophylaxis failures among a group of travelers who discontinued AP prophylaxis 1 day after leaving malaria-endemic areas. Passive surveillance in Israel did not detect any P. falciparum cases among AP users. We recommend further validation of our findings by clinical trials, prospective studies, and active surveillance in larger cohorts to assess the effectiveness of short-course AP prophylaxis in travelers.

Failure of secondary prophylaxis with erythromycin in rheumatic heart disease

Erythromycin is recommended for secondary prophylaxis in children with rheumatic heart disease, who are allergic to penicillin. A 9-year-old girl, with rheumatic heart disease, on secondary prophylaxis with erythromycin 250 mg BD, presented with acute rheumatic fever. Responded to steroids and started on a higher dose (250 mg TDS) of erythromycin for secondary prophylaxis. There is need to document the resistance of group A streptococci to erythromycin.

Rebleeding prophylaxis improves outcomes in patients with hepatocellular carcinoma. A multicenter case-control study

Outcome of variceal bleeding (VB) in patients with hepatocellular carcinoma (HCC) is unknown. We compared outcomes after VB in patients with and without HCC. All patients with HCC and esophageal VB admitted between 2007 and 2010 were included. Follow-up was prolonged until death, transplantation, or June 2011. For each patient with HCC, a patient without HCC matched by age and Child-Pugh class was selected. A total of 292 patients were included, 146 with HCC (Barcelona Classification of Liver Cancer class 0-3 patients, A [in 25], B [in 29], C [in 45], and D [in 41]) and 146 without HCC. No differences were observed regarding previous use of prophylaxis, clinical presentation, endoscopic findings, and initial endoscopic treatment. Five-day failure was similar (25% in HCC versus 18% in non-HCC; P = 0.257). HCC patients had greater 6-week rebleeding rate (16 versus 7%, respectively; P = 0.025) and 6-week mortality (30% versus 15%; P = 0.003). Fewer patients with HCC received secondary prophylaxis after bleeding (77% versus 89%; P = 0.009), and standard combination therapy was used less frequently (58% versus 70%; P = 0.079). Secondary prophylaxis failure was more frequent (50% versus 31%; P = 0.001) and survival significantly shorter in patients with HCC (median survival: 5 months versus greater than 38 months in patients without HCC; P < 0.001). Lack of prophylaxis increased rebleeding and mortality. On multivariate analysis Child-Pugh score, presence of HCC, portal vein thrombosis, and lack of secondary prophylaxis were predictors of death. Patients with HCC and VB have worse prognosis than patients with VB without HCC. Secondary prophylaxis offers survival benefit in HCC patients.

Molecular Mechanisms of HIV Type 1 Prophylaxis Failure Revealed by Single-Genome Sequencing

Trials of human immunodeficiency virus type 1 (HIV) pre- and postexposure prophylaxis show promise. Here, we describe a novel strategy for deciphering mechanisms of prophylaxis failure that could improve therapeutic outcomes. A healthcare worker began antiretroviral prophylaxis immediately after a high-risk needlestick injury but nonetheless became viremic 11 weeks later. Single-genome sequencing of plasma viral RNA identified 15 drug susceptible transmitted/founder HIV genomes responsible for productive infection. Sequences emanating from these genomes exhibited extremely low diversity, suggesting virus sequestration as opposed to low-level replication as the cause of breakthrough infection. Identification of transmitted/founder viruses allows for genome-wide assessment of molecular mechanisms of prophylaxis failure.

Trimethoprim Resistance of Dihydrofolate Reductase Variants from Clinical Isolates of Pneumocystis jirovecii

Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased Km values for dihydrofolic acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino acid substitutions (S106P and E127G) showed a doubling of kcat, as well as a Km for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.

Evaluation of the efficacy of chloroquine chemoprophylaxis for vivax malaria among Republic of Korea military personnel

Chloroquine has been used massively for vivax malaria prophylaxis and treatment in the Republic of Korea (ROK) military personnel from 1997. Although prophylaxis is generally regarded as successful among ROK military, prophylaxis failure has been repeatedly reported. Before the prophylaxis program was started on July 4th 2011, which was completed on October 16th 2011, by the ROK military, more than 60% of malaria cases were attributed to new infection or long-latency relapse. During the prophylaxis program, the authors re-examined the efficiency of chloroquine chemoprophylaxis in ROK military during the last 6months of 2011 by measuring compliance and whole blood chloroquine levels in 41 malaria patients immediately before instituting antimalarial therapy between July and December. Three patients (7.3%) showed good compliance, and had whole blood total chloroquine levels above the minimally inhibitory concentration (100ng/mL). However, 28 (69.3%) of these 41 patients when admitted to hospital showed poor or no compliance with prophylaxis; 4 of the 28 (14.3%) were stationed outside the mass prophylaxis region, and 5 (17.9%) subjects were infected after the prophylaxis program had finished. These findings indicate that the current malaria control program should be carefully reconsidered, in terms of, individual instruction, current chemoprophylaxis program regimens, and schedules to improve the efficacy of prophylaxis in the ROK military.

Oral antiretroviral drugs as public health tools for HIV prevention: global implications for adherence, drug resistance, and the success of HIV treatment programs.

Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally, further research involving the generalized epidemic is needed to determine when suboptimal drug use may occur and when regular testing and monitoring of the long-term consequences of ART use may not be routine.

Effects of Diagnostic Test Accuracy and Treatment Efficacy on the Occurrence of Suspected Failure of Heartworm Prophylaxis in Dogs

Food and Drug Administration Center for Veterinary Medicine (FDA/CVM) cited concern regarding failure of heartworm prophylaxis. The positive and negative predictive value of the heartworm antigen test is an estimate of the probability of adult heartworm infection. Assess the sensitivity, specificity, and predictive value of heartworm antigen tests. Explore the role of heartworm test accuracy and treatment with immiticide to generate reports of suspected failure of heartworm prophylaxis. Literature searches for published information on the accuracy of heartworm antigen tests and efficacy of immiticide for treatment of the adult heartworm. Weighted averages for heartworm antigen test sensitivity and specificity were 78.2 and 97.3%, respectively. Efficacy of immiticide by 2-injection or alternate dose protocols were 88.3 and 89.1%, respectively. Depending on prevalence, the positive predictive value of the heartworm antigen test ranged from 15 to 54% and negative predictive value from 99 to 99.9%. For a hospital testing 1,000 dogs per year, false-positive test results may vary from 24 to 27 dogs. If these dogs were on heartworm preventive, they may undergo treatment and be classified as prophylaxis failures. Ten percent of dogs who were treated and continued or placed on prophylaxis at the time of treatment may have adult heartworms when tested 1 year later and be presumed to represent failure of prophylaxis. When interpreting heartworm antigen test results, clinical signs, history, and regional prevalence of heartworm disease should be considered in estimating the predictive value of the test result. Limitations of test and treatment should be discussed with clients as part of the decision-making process.

Infection in Patients Undergoing Transrectal Ultrasound Guided Prostate Biopsy

With the widespread popularity of prostate specific antigen testing, transrectal ultrasound (TRUS)-guided prostate biopsy has become a common urological procedure. The most common risks and complications associated with TRUS-guided biopsy include hematuria, hematospermia, and hematochezia. In addition, some patients develop urinary tract infections, acute bacterial prostatitis, bacteremia, and, eventually, urosepsis. Although it is commonly accepted that use of a prophylactic antimicrobial agent will lower the incidence of post biopsy infection, there is little consensus regarding the most appropriate antimicrobial regimens. Fluoroquinolone (FQ) was the best analyzed class, with higher numbers of studies and patients. According to recent data, occurrence of infectious complications after prostate biopsy has increased in recent years. Several recent studies have highlighted an increasing trend of infectious complications due to FQ resistant organisms among men undergoing TRUS guided prostate biopsy. TRUS guided prostate biopsy can result in significant morbidity, which is occurring at an increasing rate due to the increasing prevalence of FQ resistant Escherichia coli in rectal flora. Risk factors for harboring FQ resistant E. coli should be considered before prostate biopsy, and rectal swab screening cultures may provide useful evidence for selection of appropriate antimicrobials for prophylaxis and treatment of prostate biopsy-associated infections. The estimate of the incidence of sepsis following TRUS-guided prostate biopsy is low; however, the initial treatment of patients with prophylaxis failure and identification of antibiotic-resistant bacterial strains might be the most important means for prevention of urosepsis.

Pneumocystis jiroveciiGenotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia

Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days.

Micafungin Versus Posaconazole Anti-Fungal Prophylaxis in Adult Patients with Acute Leukemia Undergoing Induction Chemotherapy

AbstractAbstract 3556 Introduction:Posaconazole has been shown to be effective in reducing the incidence of invasive fungal infections (IFI) in high-risk, neutropenic leukemia patients following induction chemotherapy. Its clinical utilization, however, may be limited by decreased oral absorption secondary to mucositis and other adverse events that occur during therapy. Micafungin is a broad spectrum antifungal agent approved for prophylaxis in stem cell transplant recipients. Nonetheless, its safety and efficacy in neutropenic leukemia patients has not been established. We therefore designed a prospective randomized study comparing micafungin to posaconazole as anti-fungal prophylaxis in patients with acute leukemia undergoing induction chemotherapy. The aim of this interim analysis is to compare (1) the total time on study drug between the micafungin and posaconazole treatment groups and (2) the percentage of patients completing the planned treatment course between the two groups. Methods:Patients > 18 years of age were eligible for study with newly diagnosed acute leukemia (either AML or ALL) or MDS who were to receive myeloablative therapy with an anticipated neutropenic period of at least 7 days following anthracycline-based chemotherapy. Patients with first relapse of AML and ALL were also eligible. Patients who were pregnant, unable to swallow, hypersensitive to azoles, taking medications known to interact with posaconazole, and those receiving dasatinib were excluded from the study. Patients with a history of invasive fungal infection requiring therapy within 30 days of randomization, prolonged QTc interval on EKG, and moderate or severe liver dysfunction were also excluded.Participants were randomized to receive micafungin (100 mg IV daily) or posaconazole (400 mg orally twice daily). The absolute neutrophil count (ANC) was monitored daily. Neutrophil recovery was defined as ANC ≥500 cells/μl for two consecutive days. Prophylaxis completion was defined as continuation of treatment until neutrophil recovery or 28 days after treatment initiation, whichever was earlier. Prophylaxis failure was defined as discontinuation of study drug due to adverse event, persistent neutropenic fever requiring change to an alternative antifungal agent, or withdrawal from the study before 28 days. Fungal markers (Galactomannan, BD glucans) were followed weekly from randomization to neutrophil recovery. Continuous and categorical variables were tested with Wilcoxon rank-sum test and chi-square tests, respectively. Kaplan-Mayer method was used to measure the completion rates of anti-fungal prophylaxis, and the log-rank test was used to compare the completion between two groups. Results:From March 2011 to May 2012, 46 patients were randomized to prophylaxis with either micafungin (n=23) or posaconazole (n=23). The two groups did not differ in age, sex, race, neutropenic duration, or liver dysfunction (p=0.35, 0.56, 0.36, 0.07 and 0.4366, respectively). Nineteen patients (83%) completed micafungin therapy while only eight (35%) completed posaconazole (p=0.001). Median number of days on prophylaxis was 18.2 days for the micafungin group and 14.8 days for the posaconazole group (p=0.0584). Eight patients (34.8%) were removed from study in the posaconazole group after developing colitis or being made NPO by the treating physician. There were no positive fungal markers during the study period. Nine patients (20%) underwent bronchoscopy because of new chest CT abnormalities while on study drug. Bronchoalveolar lavage was sent for routine cultures, cytology, Galactomannan, and pan-fungal PCR (University of Washington). Two patients (one from each treatment group) had IFI identified by PCR (Rhodotorula nothofagi and Cryptococcus species). Conclusions:For patients undergoing myeloablative therapy for the treatment of acute leukemia or MDS, micafungin prophylaxis is associated with a superior completion rate and longer time to failure of prophylaxis compared to posaconazole. In addition, there is no difference in breakthrough fungal infections between the two treatment groups. Micafungin as antifungal prophylaxis is well tolerated and appears as effective as posaconazole prophylaxis for leukemia patients with prolonged neutropenia from induction chemotherapy. Our ongoing clinical study will continue to assess the efficacy of micafungin in this patient population. Disclosures:No relevant conflicts of interest to declare.

6.0 HIV and hepatitis virus coinfections

6.0 <scp>HIV</scp> and hepatitis virus coinfections

Rabies: Still a Uniformly Fatal Disease? Historical Occurrence, Epidemiological Trends, and Paradigm Shifts

Rabies has the highest case fatality of any infectious disease. Pathobiological and clinical insights have questioned the assertion that death is inevitable after onset of acute encephalomyelitis. Relying upon national laboratory-based surveillance, we reviewed records of human rabies acquired in the United States during 1960-2009. Changes in the epidemiology of human rabies were notable, due to improved animal management, safer and more efficacious biologics, and revisions in prevention guidelines. Historically, domestic animals were the most important source of infection. Since the 1990s, more human cases were associated with rabid bats. Prior to 1980, postexposure prophylaxis failures were reported. After development of modern rabies immune globulin and vaccines, none occurred. Of 75 human cases identified, only four patients survived. Rabies remains an extremely high consequence zoonosis, but the disease is not uniformly fatal, per se. Rabies is essentially preventable when primary exposures are averted, or appropriate prophylaxis occurs before illness.

Failure of HIV Postexposure Prophylaxis after a Work-Related Needlestick Injury

Failure of HIV Postexposure Prophylaxis after a Work-Related Needlestick Injury

A cluster of Plasmodium vivax malaria in an expedition group to Ethiopia: Prophylactic efficacy of atovaquone/proguanil on liver stages of P. vivax

Complete prevention of malaria especially Plasmodium falciparum is the goal of prophylaxis. A survey, designed to ascertain reasons behind the choice of malaria prophylaxis, compliance and side effects, and to gather data on acquired malaria, identified a cluster of Plasmodium vivax infection in a cohort of 33 who travelled to Ethiopia on a scientific expedition. A questionnaire based survey of travellers who took part in a scientific survey and rafting expedition in Ethiopia between October and December 2005 on their return from the expedition and two years later. 31 of 33 subjects completed the survey fully. Evidence was obtained on factors influencing choice of, and adherence to prophylaxis and the incidence and type of malaria related to prophylaxis. Over the two year follow up period 32% of travellers developed P. vivax malaria. Of those taking Mefloquine and Doxycycline 50% and 66% respectively developed malaria, compared to none taking Atovaquone/Proguanil as prophylaxis. Awareness and management of malaria was inadequate in several cases. Failure to use Primaquine led to second relapses. Within this cluster, prophylaxis against P. falciparum was successful. Widespread failure of prophylaxis against P. vivax malaria was documented despite the use of recommended regimes of known efficacy against the parasite. Atovaquone/Proguanil had the least side effects and afforded the highest protection. Atovaquone/Proguanil may provide previously unrecognised protection against liver stages of P. vivax.

Resistance to Macrocyclic Lactones

Resistance to the macrocyclic lactones (MLs) has been confirmed or suspected in many target organisms and is a serious problem in some. For some species, such as parasitic nematodes of small ruminants, ML resistance has become severe enough to threaten effective worm control worm control. Resistance is also a major concern in horse parasites and an emerging problem in cattle. Despite this, we have insufficient understanding of the mechanisms of ML resistance, especially in nematodes. Some insect and mite agricultural pests express higher levels of detoxifying enzymes, leading to cross-resistance to other pesticide classes. A major difficulty is in the identification of true resistance and distinguishing this from other causes of treatment or prophylaxis failure--some in vitro assays for ML resistance are available but more are badly needed. Changes in the way anthelmintic drugs are used in livestock farming have been proposed, based on the treatment of those animals that would benefit most, and schemes have been devised for identifying those animals, flocks and herds. The continued sustainable use of these invaluable drugs may depend on the adoption and improvement of such schemes, as resistance is likely to become an ever more serious problem.