Recrudescence Of Infection Research Articles

Successful Treatment of Nannizziopsis guarroi Infection using Systemic Terbinafine in a Central Bearded Dragon (Pogona vitticeps)

Nannizziopsis guarroi infection in lizards presents therapeutic challenges as reports of poor clinical outcomes, including antifungal toxicity, incomplete clearance of infection and recrudescence of infection are common. The case presented here describes the successful treatment of a N. guarroi infection using systemic terbinafine and environmental disinfection in a captive-bred central bearded dragon (Pogona vitticeps). The lizard presented with darkly colored cutaneous lesions and mycologic culture samples were identified as N. guarroi using Matrix-Assisted Laser Desorption/Ionization – Time Of Flight (MALDI-TOF). Based upon the lack of clinical resolution of cutaneous lesions, weight loss, and reduced appetite, initial treatment with voriconazole was discontinued. Terbinafine was prescribed and weekly environmental disinfection with sodium hypochlorite was initiated until cutaneous clearance of the fungus was confirmed by negative culture, histopathology, and N. guarroi qPCR from cutaneous swab. Terbinafine treatment was discontinued after 80 days. There were no clinical signs of toxicity associated with the prolonged treatment and the lizard has not developed any cutaneous lesions or illness in more than two years of clinical follow up. While the most ideal treatment of N. guarroi is still being investigated, this case demonstrates a promising and safe treatment option for an increasingly common and devastating disease.

Prevalence of Helicobacter pylori infection and its Associated Risk Factors among symptomatic Residents of Sulaimani city, Kurdistan region, Iraq, 2020

Helicobacter pylori (H. pylori) bacteria are a microaerobic Gram negative that colonizes in the gastric and duodenum of human. It can cause prolong infection in the human life if not treated. Many of the studies showed that infection by H. pylori can cause some important gastrointestinal illness, such as peptic ulcer, chronic gastritis, gastric adenocarcinoma and mucosa associated lymphoid tissue lymphoma. Recurrence is generally considered as H. pylori recrudescence infection after one year of eradicated treatment. There are many factors involved in the H pylori reinfection, such as the epidemiology of H. pylori infection, condition of the live, development of economical state, and health conditions. The Objectives of this study were to estimate the incidence and determine the risk factors of infection by H. pylori bacteria in dyspeptic patients in Sulaimani city. And the Aims are to estimate prevalence of the Helicobacter pylori and patients’ characteristics in Sulaimani city. This is a cross-sectional study, using a Urea breath test or stained the gastric sample with Giemsa stain, which is including adult participants aged (12-87) years during the period starting from 1 January until 31 December 2020 on Iraqi male and female patients were visiting –Center for Gastroenterology and Hepatology in Sulaimani, city, Iraq. Three hundred and four patients were included, all of them underwent Urea breath test only but eighty-one of the participants underwent endoscopy and stained the gastric sample with Giemsa stain. Urea breath test for Helicobacter pylori was positive in54.9% which have significant correlation with risk factor findings. Results: the incidence rate of H. pylori infection in our study is 54.9%, and mean age of the study participants was (40.49 ±16.39) one hundred and ninety-one cases 62.8% were female and 113 cases 37.2%were male. Infection by H. pylori bacteria is rife in dyspeptic patients; and is more common in the age group of 31-40 years. One of noninvasive test to diagnosis H. pylori is Urea breath test. In conclusions the rate of helicobacter pylori infection in our study is 54.9% among the symptomatic patients, and the overall incidence of H. pylori UBT and Giemsa stain detection rate were 73.4 and 26.6% respectively.

Neospora caninum and Toxoplasma gondii infections and their relationship with reproductive losses in farmed red deer (Cervus elaphus).

The aims of the present study were to determine the Neospora caninum and Toxoplasma gondii seropositivity rates in farmed red deer hinds from Argentina and their relationship with reproductive losses. Over a 2-year period, 449 hinds from 4 commercial farms were serologically tested at late gestation for N. caninum and T. gondii by IFAT. During the first year, a sequential serological analysis was carried out at 3 different time points to analyze antibody dynamics from mating until the end of the gestation period. Fetal and postnatal mortality rates were estimated by 3 successive ultrasound scannings (us) annually and a breeding control carried out after the calving period. Ultrasound fetal measurements were used to estimate conception date and gestational age of abortions. The seropositivity rate for N. caninum was 25.5% (37/145) for the yearlings and 34.2% (104/304) for the adults, while for T. gondii was 64.3% (93/145) and 78.3% (238/304), respectively. Abortions detected at us1 and us2 were 13/21 (61.9%) with a range of gestational age of 30-87 days, while abortions detected at us3 were 8/21 (38.1%) with a range of gestational age of 49-209 days. The fetal mortality rate was 4% and 5.8%, while the postnatal mortality rate was 18.8% and 4.1% of 101 yearlings and 294 adult pregnant hinds, respectively. Most seropositive hinds to both protozoans showed a stable antibody titer pattern from mating to the end of gestation, and a lower proportion developed an increase in titers suggesting infection recrudescence. Seroconversion during the gestational period was demonstrated in 6 and 50 hinds for N. caninum and T. gondii, respectively. Hinds with fetal mortality were more likely to be seropositive to N. caninum (OR = 3.1) or have N. caninum titers ≥400 (OR = 27.4) than hinds that weaned a fawn. No statistical associations were detected for T. gondii seropositivity and reproductive losses. The pregnancy rate was not affected by N. caninum or T. gondii infection, while the serological evidence of N. caninum causing postnatal mortality was marginal. Based on serological evidence, N. caninum would be a potential abortigenic agent in red deer hinds.

The impact of ivermectin on onchocerciasis in villages co-endemic for lymphatic filariasis in an area of onchocerciasis recrudescence in Burkina Faso.

In Burkina Faso, onchocerciasis was no longer a public health problem when the WHO Onchocerciasis Control Programme in West Africa closed at the end in 2002. However, epidemiological surveillance carried out from November 2010 to February of 2011, showed a recrudescence of infection in the Cascades Region. This finding was made at a time when ivermectin, a drug recommended for the treatment of both onchocerciasis and lymphatic filariasis, had been distributed in this area since 2004 for the elimination of lymphatic filariasis. It was surprising that ivermectin distributed for treating lymphatic filariasis had not prevented the recrudescence of onchocerciasis. Faced with this situation, the aim of our study was to evaluate the effectiveness of ivermectin on the onchocerciasis parasite. The percentage reduction in microfilarial load after treatment with ivermectin was used as a proxy measure for assessing possible resistance. A cohort study was carried out with 130 individuals who had tested positive for microfilariae of Onchocerca volvulus in 2010 using microscopic examination of skin-snip biopsies from five endemic villages. Subjects were followed from July 2011 to June 2012. The microfilarial load of each individual was enumerated by skin-snip biopsy in 2010, prior to the first ivermectin treatment against onchocerciasis under community guidelines. All individuals received two ivermectin treatments six months apart. In 2012, the microfilarial loads were determined again, six months after the second round of ivermectin and the reductions in parasite loads were calculated to measure the impact of the drug. The percentage reduction of the microfilarial loads ranged from 87% to 98% in the villages. In all villages, there was a statistically significant difference between the average microfilarial loads in 2010 and 2012. The level of reduction of microfilarial loads suggests that ivermectin is effective against the recrudescent population of O. volvulus in Cascades Region of Burkina Faso. Further investigations would be necessary to determine the causes of the recrudescence of onchocerciasis. (For French language abstract, see S1 Alternative Language —Translation of the into French by the authors.)

Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate\u2010amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar

BackgroundThe anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate–amodiaquine (AS–AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar.MethodsDried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS–AQ and artemether-lumefantrine in 2002–2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher’s exact test.ResultsThe allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4–19.7) and 2.7 % (95 % CI 1.8–3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8–54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4–67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1–54.0 vs. 28.1 %; 95 % CI 21.9–35.0, respectively; P = 0.003).ConclusionsCYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS–AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to amodiaquine-based malaria chemotherapy warrants further investigation.

Impact of seven years of mass drug administration and recrudescence of Schistosoma haematobium infections after one year of treatment gap in Zanzibar: Repeated cross-sectional studies.

BackgroundConsiderable progress towards the elimination of urogenital schistosomiasis was made by the Zanzibar Elimination of Schistosomiasis Transmission project from 2012 till 2016, when biannual praziquantel mass drug administration (MDA) alone or with additional snail control or behaviour change interventions were implemented. Annual MDA was continued in 2017 and 2018, but not in 2019, imposing a 16-month treatment gap. We monitored the Schistosoma haematobium prevalence from 2012 till 2020 and assessed recrudescence patterns with focus on 2020.MethodologyRepeated cross-sectional surveys were conducted from 2011/12 till 2020 in 90 communities and 90 schools in Zanzibar. Annually, around 4,500 adults and up to 20,000 schoolchildren were surveyed. The S. haematobium prevalence was detected by urine filtration and reagent strips. In 2020, risk factors for infection were investigated using generalized estimated equation models.Principal findingsIn adults, the apparent S. haematobium prevalence was 3.9% in 2011 and 0.4% in 2020. In schoolchildren, the prevalence decreased from 6.6% in 2012 to 1.2% in 2019 with vicissitudes over the years. Prominent recrudescence of infection from 2.8% in 2019 to 9.1% (+225%) in 2020 was observed in 29 schools with historically moderate prevalences (≥10%). Compared with 2019, reinfection in 2020 was particularly striking in boys aged 9–16 years. Being male was a risk factor for infection in 2020 (adults: odds ratio (OR): 6.24, 95% confidence interval (95% CI): 1.96–19.60; schoolchildren: OR: 2.06, 95% CI: 1.52–2.78). Living near to a natural freshwater body significantly increased the odds of infection in adults (OR: 2.90, CI: 1.12–7.54).Conclusions/SignificanceAfter 11 rounds of MDA over 7 years and a 16-month treatment gap, the urogenital schistosomiasis prevalence considerably rebounded in hotspot areas. Future elimination efforts in Zanzibar should focus on re-intensifying MDA plus additional interventions in hotspot areas. In low-prevalence areas, the strategy might be adapted from MDA to targeted surveillance-response.

Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria.

BackgroundThe World Health Organization (WHO) in 2015 stated atovaquone‐proguanil can be used in travellers, and is an option in malaria‐endemic areas in combination with artesunate, as an alternative treatment where first‐line artemisinin‐based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.ObjectivesTo assess the efficacy and safety of atovaquone‐proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.Search methodsThe date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.Selection criteriaRandomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone‐proguanil or atovaquone‐proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.Data collection and analysisFor this update, two review authors re‐extracted data and assessed certainty of evidence. We meta‐analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)‐adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.Main resultsSeventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South‐America, and South‐East Asia. Eight trials reported PCR‐adjusted data to distinguish between new and recrudescent infection during the follow‐up period. In this abstract, we report only the comparisons against the three WHO‐recommended antimalarials which were included within these trials.There were two comparisons with artemether‐lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone‐proguanil compared to none with artemether‐lumefantrine (PCR‐adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR‐adjusted treatment failures at day 42).There was only one comparison with artesunate‐amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone‐proguanil at day 28 and two with artesunate‐amodiaquine (PCR‐adjusted treatment failures at day 28: 9.4% with atovaquone‐proguanil compared to 2.9% with artesunate‐amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low‐certainty evidence), although there was a similar number of PCR‐unadjusted treatment failures (9 (14.1%) with atovaquone‐proguanil and 8 (11.8%) with artesunate‐amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low‐certainty evidence).There were two comparisons with artesunate‐mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi‐resistant malaria. There were similar numbers of PCR‐adjusted treatment failures between groups at day 42 (2.7% with atovaquone‐proguanil compared to 2.4% with artesunate‐mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high‐certainty evidence). There were also similar PCR‐unadjusted treatment failures between groups (5.3% with atovaquone‐proguanil compared to 6.6% with artesunate‐mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low‐certainty evidence).When atovaquone‐proguanil was combined with artesunate, there were fewer treatment failures with and without PCR‐adjustment at day 28 (PCR‐adjusted treatment failures at day 28: 2.16% with atovaquone‐proguanil compared to no failures with artesunate‐atovaquone‐proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low‐certainty evidence) and day 42 (PCR‐adjusted treatment failures at day 42: 3.82% with atovaquone‐proguanil compared to 2.05% with artesunate‐atovaquone‐proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate‐certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate‐atovaquone‐proguanil group compared to the atovaquone‐proguanil group at day 42 with PCR‐adjustment.Whilst there were some small differences in which adverse events were more frequent in the atovaquone‐proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone‐proguanil is strongly associated with any specific adverse event.Authors' conclusionsAtovaquone‐proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone‐proguanil may reduce treatment failure rates. Artesunate‐atovaquone‐proguanil and the development of parasite resistance may represent an area for further research.

Clinical outcomes of temocillin use for invasive Enterobacterales infections: a single-centre retrospective analysis.

BackgroundWith increasing frequency of resistant Gram-negative bacteria, temocillin has potential utility in reducing carbapenem use. The 2020 EUCAST guideline changes temocillin breakpoints and reclassifies isolates with an MIC of 0.001–16 mg/L as ‘susceptible, increased exposure’ necessitating 6 g/day rather than the previous 4 g/day, associated with significant cost implications.ObjectivesWe explore the clinical utility and treatment failure rate of temocillin at 4 g/day dosing.MethodsAll adult inpatient electronic prescriptions of temocillin (3 days or greater) from March 2016 to October 2019 were retrieved using a clinical decision support system (ICNET®). Treatment success was defined as survival, no switch to broad-spectrum agent for the same indication and no subsequent recrudescence of infection, occurring within 30 days.ResultsTemocillin was used in 205 eligible patient-episodes, median age 79 years (IQR : 71–87 years), 42.4% female. Median temocillin course length was 5.9 days (IQR : 4.6–7.8 days). Indications for use: urinary tract infection (UTI) (n = 141), pneumonia (n = 53), other (n = 11). In total, 144 (70.2%) patients had targeted treatment; 74 (36.1%) against Escherichia coli, 70 (34.4%) other Enterobacterales. A total of 130 (63%) patients received 4 g/day; the remaining patients had reduced renal function with dosing in accordance with guidance. Overall temocillin treatment success was 79.5%; highest when used to treat UTI 85.8% (versus 67.9% in respiratory infections, P = 0.008). Empirical treatment demonstrated 82.0% (50/61) success [versus 78.5% (113/144) among targeted treatment, P = 0. 71].ConclusionsTemocillin at 4 g/day is an effective and safe alternative in treating patients with Gram-negative infections, but should be considered in the context of patient age and comorbidities. Increased dosing or alternate strategies may be indicated when the infection is not of a urinary source.

Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care

BackgroundEbola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient—perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD.MethodsSeveral different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood.ResultsThe findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a ‘fatal’ outcome to a ‘survival’ outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence—such as defective interfering genomes.ConclusionsThe data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.

1251. Prevention of Pneumocystis Pneumonia by Ibrexafungerp in a Murine Prophylaxis Model

Background Pneumocystis pneumonia (PCP) is an opportunistic fungal infection that affects immunocompromised patients. Ibrexafungerp (IBX) is an oral and intravenous antifungal from a novel class of glucan synthase inhibitors, triterpenoids, and has shown activity against Candida, Aspergillus, and PCP in a murine therapy model. We evaluated the ability of IBX to prevent PCP in a prophylaxis model of murine PCP.Methods Experiment 1: Balb/c mice (10 mice/group) were infected by intranasal inoculation with Pneumocystis murina, immune-suppressed with dexamethasone in acidified drinking water and treated with 30-, 15- and 7.5 mg/kg, IBX/BID. Control groups treatment included TMP-SMX (50/250 mg/kg QD) and vehicle. After 6 weeks, mice were sacrificed, and prevention was determined by organism burdens (asci and total nuclei). Experiment 2: Balb/c mice were immune-suppressed and infected as in Exp. 1. Treatment groups included: 1) 30 mg/kg BID x 6wk; 2) 30 mg/kg/BID x 6wk followed by cessation of treatment with IBX but with immune-suppression for 3 additional weeks; 3) 15 mg/kg BID 1 week prior and 6 wks after infection and immune suppression; 4) 15mg/kg BID for 8 wks; 5) 15 mg/kg BID for 6 wks then IBX was discontinued but with immune suppression; 6) untreated, vehicle control.Results Experiment 1: No P. murina nuclei or asci were observed after 6 weeks of treatment at a dose of 30 mg/kg/BID in the prophylaxis mouse model of PCP, similar to positive control, TMP/SMX. Some nuclei and asci were observed in the lower dose IBX groups. Experiment 2: To investigate whether any P. murina remained after different regimens of prophylaxis, treatment of IBX was withdrawn at both doses for an additional 3 wks of immune suppression to provoke the growth of any remaining fungi. Group 1 showed reduction in total nuclei and asci to undetectable. Group 2 did not result in any recrudescence of infection. Group 3 and 4 showed similar reduction in organism burden. Group 5 was similar to untreated control.ConclusionThese results demonstrate that 30 mg/kg BID IBX prevented PCP in a murine model. We suggest that IBX could be a viable option for preventing PCP in immunocompromised patients.DisclosuresKatyna Borroto-Esoda, PhD, SCYNEXIS, Inc. (Employee, Shareholder) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) Alan Ashbaugh, PhD, SCYNEXIS, Inc. (Grant/Research Support) Melanie Cushion, PhD, SCYNEXIS, Inc. (Grant/Research Support) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Asymptomatic recrudescence after artemether\u2013lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis

BackgroundIn clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.MethodsA systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.ResultsAcross 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.ConclusionsAL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.

Clinical presentation and immunological features of Post-Malaria Neurologic Syndrome: a case report and review of literature

BackgroundMalaria still represents a major health threat, in terms of both morbidity and mortality. Complications of malaria present a diversified clinical spectrum, with neurological involvement leading to the most serious related-conditions. The authors recently encountered a case of a 60-year old Italian man presenting with confusion, language disturbances and Parkinson-like syndrome 3 weeks after complete remission from severe Plasmodium falciparum cerebral malaria. Chemical and microbiological analysis revealed aseptic meningitis, diffuse encephalitis and abnormal immune-activation. Re-infection and recrudescence of infection were excluded. Further analysis excluded paraneoplastic and autoimmune causes of encephalitis. A diagnosis of Post-Malaria Neurological Syndrome (PMNS) was finally formulated and successfully treated with high dose of steroids.MethodsA systematic research of current literature related to PMNS was performed.Results151 cases of PMNS were included, the majority of which occurred after severe P. falciparum infections. Four main clinical pattern were identified: 37% of the cases presented as “classical” PMNS, 36% presented as delayed cerebellar ataxia (DCA), 18% resembled acute inflammatory demyelinating polyneuropathy (AIDP), and 8% presented as acute disseminated encephalomyelitis (ADEM)-like form. Differentiation between different forms was not always simple, as clinical and radiological findings frequently overlap. Overall, in almost all of the tested cases, cerebrospinal fluid was found pathological; EEG revealed nonspecific encephalopathy in 30% of classical PMNS and 67% ADEM; imaging tests were found abnormal in 92% of ADEM-like forms. Pathogenesis remains unclear. An autoimmune mechanism is the most corroborated pathogenic hypothesis. Overall, the majority of PMNS cases revert without specific treatment. In most severe forms, high dose steroids, intravenous immunoglobulins, and plasmapheresis have been shown to improve symptoms.ConclusionsPMNS is a disabling complication of malaria. The overall incidence is not known, due to frequent misdiagnosis and under-reporting. Pathogenesis is not also fully understood, but rapid response to immune-modulating treatment along with similarities to auto-immune neurological disease, strongly support a dysregulated immunological genesis of this condition. The lack of randomized controlled studies regarding therapeutic approaches is a major unmet need in this setting. A systematic collection of all the PMNS cases would be desirable, in order to increase awareness of this rare condition and to prospectively investigate the most appropriate management.

Molecular Assessment of Chelonid Alphaherpesvirus 5 Infection in Tumor-Free Green (Chelonia mydas) and Loggerhead (Caretta caretta) Sea Turtles in North Carolina, USA, 2015-2019.

Simple SummaryFibropapillomatosis is a debilitating tumor disease of sea turtles that is sometimes fatal. This disease is a key concern for sea turtle rehabilitation facilities due to its infectious nature, as it is associated with a virus called chelonid alphaherpesvirus 5. This is the first study to analyze antibodies to this virus in loggerhead sea turtles and represents the most complete dataset on viral detection in sea turtles encountered in the more northern latitudes of their habitat in the western Atlantic.Fibropapillomatosis is associated with chelonid alphaherpesvirus 5 (ChHV5) and tumor formation in sea turtles. We collected blood samples from 113 green (Chelonia mydas) and 112 loggerhead (Caretta caretta) turtles without fibropapillomatosis, including 46 free-ranging turtles (20 green turtles, 26 loggerheads), captured in Core Sound, North Carolina, and 179 turtles (93 green turtles, 86 loggerheads) in rehabilitative care in North Carolina. Blood samples were analyzed for ChHV5 DNA using quantitative polymerase chain reaction (qPCR), and for antibodies to ChHV5 peptides using an enzyme-linked immunosorbent assay (ELISA). None of the samples from foraging turtles tested positive for ChHV5 by qPCR; ELISA was not used for foraging turtles. Samples from 18/179 (10.1%) rehabilitating turtles tested positive for ChHV5 using qPCR, and 32/56 (57.1%) rehabilitating turtles tested positive for antibodies to ChHV5 using ELISA. Five turtles that tested positive by qPCR or ELISA at admission converted to being undetectable during rehabilitation, and five that initially tested negative converted to being positive. Both sea turtle species were significantly more likely to test positive for ChHV5 using ELISA than with qPCR (p < 0.001). There was no difference in the proportions of green turtles versus loggerheads that tested positive for ChHV5 using qPCR, but loggerheads were significantly more likely than green turtles to test positive for ChHV5 using ELISA. This finding suggests that loggerheads infected with ChHV5 at some point in their life may be more able than green turtles to mount an effective immune response against recrudescent infection, pointing to species-specific genetic differences in the two species’ immune response to ChHV5 infection. This is the first study to analyze antibodies to ChHV5 in loggerhead turtles and represents the most complete dataset on ChHV5 DNA detection in sea turtles encountered in the more northern latitudes of their western Atlantic habitat.

Antibacterial self-assembled nanodrugs composed of berberine derivatives and rhamnolipids against Helicobacter pylori

The prevalence of infections with Helicobacter pylori (H. pylori) has progressively increased worldwide, which demonstrated to be closely correlated to its biofilm formation. H. pylori biofilms protect the bacteria by significantly decreasing their sensitivity to antibiotics. Moreover, H. pylori colonizes on the gastrointestinal tract epithelium which is covered by mucus layer, acting as another barrier to prevent antibacterial agents from reaching the colonization sites. Herein, we prepared four types of versatile self-assembled nanodrugs (BD/RHL NDs) containing lipophilic alkyl berberine derivatives (BDs) and rhamnolipids (RHL) to overcome the dual obstructions of both mucus layer and biofilms. Molecular dynamics simulations estimated that the driving forces for self-assembly of BD/RHL NDs were electrostatic and hydrophobic interactions. BD/RHL NDs, characterized by appropriate size, negative charge and enhanced hydrophilicity, successfully penetrated through mucus layer without interacting with mucins. In in vitro experiments, BD/RHL NDs exhibited substantial ability to eradicate H. pylori biofilms by destroying their extracellular polymeric substances (EPS) and killing planktonic H. pylori. Furthermore, BD/RHL NDs inhibited the adherence of H. pylori on both biotic and abiotic surfaces, therefore cut off the critical step of the biofilm re-formation which was associated with the recrudescence of infections. In an H. pylori-infected mice model, C10-BD/RHL NDs group showed 40 folds less remnant H. pylori and greater mucosal protection compared with the conventional clinical triple therapy. In conclusion, BD/RHL NDs could penetrate through mucus layer and effectively eradicate H. pylori biofilms in vitro and in vivo, providing a novel strategy for clinical treatment of biofilm-related infections.

Dormant Plasmodium falciparum Parasites in Human Infections Following Artesunate Therapy.

Artemisinin monotherapy of Plasmodium falciparum infection is frequently ineffective due to recrudescence. Artemisinin-induced dormancy, shown in vitro and in animal models, provides a plausible explanation. To date, direct evidence of artemisinin-induced dormancy in humans is lacking. Blood samples were collected from Plasmodium falciparum 3D7- or K13-infected participants before and 48-72 hours after single-dose artesunate (AS) treatment. Parasite morphology, molecular signature of dormancy, capability and dynamics of seeding in vitro cultures, and genetic mutations in the K13 gene were investigated. Dormant parasites were observed in post-AS blood samples of 3D7- and K13-infected participants. The molecular signature of dormancy, an up-regulation of acetyl CoA carboxylase, was detected in 3D7 and K13 samples post-AS, but not in pre-AS samples. Posttreatment samples successfully seeded in vitro cultures, with a significant delay in time to reach 2% parasitemia compared to pretreatment samples. This study provides strong evidence for the presence of artemisinin-induced dormant parasites in P. falciparum infections. These parasites are a likely reservoir for recrudescent infection following artemisinin monotherapy and artemisinin combination therapy (ACT). Combination regimens that target dormant parasites or remain at therapeutic levels for a sufficient time to kill recovering parasites will likely improve efficacy of ACTs.

Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

BackgroundViral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the virus can have different phenotypes in patients. Additionally, due to the error-prone nature of viral RNA synthesis in an individual patient, the EBOV genome exists around a dominant viral genome sequence. The minor variants within a patient may contribute to the overall phenotype in terms of viral protein function. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced.ResultsWe examine the minor variant frequency between patients with acute EVD who survived infection with those who died. Non-synonymous differences in viral proteins were identified that have implications for viral protein function. The greatest frequency of substitution was identified at three codon sites in the L gene—which encodes the viral RNA-dependent RNA polymerase (RdRp). Recapitulating this in an assay for virus replication, these substitutions result in aberrant viral RNA synthesis and correlate with patient outcome.ConclusionsTogether, these findings support the notion that in patients who survived EVD, in some cases, the genetic variability of the virus resulted in deleterious mutations that affected viral protein function, leading to reduced viral load. Such mutations may also lead to persistent strains of the virus and be associated with recrudescent infections.

Can we eradicate trachoma? A survey of stakeholders

Background/AimsAlthough tremendous progress towards the 2020 goal of global elimination of trachoma as a public health problem has been made, it will not be achieved. Future targets are now being...

A data-based mathematical modelling study to quantify the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica during treatment and relapse.

Antibiotic therapy has drastically reduced the mortality and sequelae of bacterial infections. From naturally occurring to chemically synthesized, different classes of antibiotics have been successfully used without detailed knowledge of how they affect bacterial dynamics in vivo. However, a proportion of patients receiving antimicrobial therapy develop recrudescent infections post-treatment. Relapsing infections are attributable to incomplete clearance of bacterial populations following antibiotic administration; the metabolic profile of this antibiotic-recalcitrant bacterial subpopulation, the spatio-temporal context of its emergence and the variance of antibiotic-bacterial interactions in vivo remain unclear. Here, we develop and apply a mechanistic mathematical model to data from a study comparing the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica serovar Typhimurium in murine infections. Using the inferential capacity of our model, we show that the antibiotic-recalcitrant bacteria following ampicillin, but not ciprofloxacin, treatment belong to a non-replicating phenotype. Aligning with previous studies, we independently estimate that the lymphoid tissues and spleen are important reservoirs of non-replicating bacteria. Finally, we predict that post-treatment, the progenitors of the non-growing and growing bacterial populations replicate and die at different rates. Ultimately, the liver, spleen and mesenteric lymph nodes are all repopulated by progenitors of the previously non-growing phenotype in ampicillin-treated mice.

Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria.

Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.).

Genomic analysis of natural intra-specific hybrids among Ethiopian isolates of Leishmania donovani.

Parasites of the genus Leishmania (Kinetoplastida: Trypanosomatidae) cause widespread and devastating human diseases. Visceral leishmaniasis due to Leishmania donovani is endemic in Ethiopia where it has also been responsible for major epidemics. The presence of hybrid genotypes has been widely reported in surveys of natural populations, genetic variation reported in a number of Leishmania species, and the extant capacity for genetic exchange demonstrated in laboratory experiments. However, patterns of recombination and the evolutionary history of admixture that produced these hybrid populations remain unclear. Here, we use whole-genome sequence data to investigate Ethiopian L. donovani isolates previously characterized as hybrids by microsatellite and multi-locus sequencing. To date there is only one previous study on a natural population of Leishmania hybrids based on whole-genome sequences. We propose that these hybrids originate from recombination between two different lineages of Ethiopian L. donovani occurring in the same region. Patterns of inheritance are more complex than previously reported with multiple, apparently independent, origins from similar parents that include backcrossing with parental types. Analysis indicates that hybrids are representative of at least three different histories. Furthermore, isolates were highly polysomic at the level of chromosomes with differences between parasites recovered from a recrudescent infection from a previously treated individual. The results demonstrate that recombination is a significant feature of natural populations and contributes to the growing body of data that shows how recombination, and gene flow, shape natural populations of Leishmania.