Paradoxical reactions in Buruli ulcer after initiation of antibiotic therapy: Relationship to bacterial load

Antibiotic therapy in the cystic fibrosis (CF) mouse model has been shown to result in reduced bacterial load of the intestine and significant body mass gain. The effect was suggested to be linked to the improvement of intestinal digestion and absorption. Therefore, we aimed to assess the influence of routinely applied antibiotic therapy in CF patients on fat assimilation. Twenty-four CF patients aged 6 to 30 years entered the study. Inclusion criteria comprised confirmed exocrine pancreatic insufficiency and bronchopulmonary exacerbation demanding antibiotic therapy. Exclusion criteria comprised: antibiotic therapy six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids. In all enrolled CF subjects, (13)C-labelled mixed triglyceride breath test ((13)C MTG-BT) was performed to assess lipid digestion and absorption, before and after antibiotic therapy. Sixteen subjects were treated intravenously with ceftazidime and amikacin, eight patients orally with ciprofloxacin. Cumulative percentage dose recovery (CPDR) was considered to reflect digestion and absorption of lipids. The values are expressed as means (medians). The values of CPDR before and after antibiotic therapy did not differ in the whole studied group [4.6(3.3) % vs. 5.7(5.3) %, p = 0.100] as well as in the subgroup receiving them intravenously [4.6(3.2) % vs. 5.7(5.3) %, p = 0.327] or in that with oral drug administration [4.6(3.4) % vs. 5.7(5.4) %, p = 0.167]. In conclusion, antibiotic therapy applied routinely in the course of pulmonary exacerbation in CF patients does not seem to result in an improvement of fat digestion and absorption.

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Clinical and Bacteriological Efficacy of Rifampin-Streptomycin Combination for Two Weeks followed by Rifampin and Clarithromycin for Six Weeks for Treatment of Mycobacterium ulcerans Disease

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02165-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 1161-1166 ◽

Cited By ~ 45

Author(s):

Richard O. Phillips ◽

Fred S. Sarfo ◽

Mohammed K. Abass ◽

Justice Abotsi ◽

Tuah Wilson ◽

...

Keyword(s):

Bacterial Load ◽

Buruli Ulcer ◽

Positive Culture ◽

Mycobacterium Ulcerans ◽

Tissue Samples ◽

Content Type ◽

Western Africa ◽

Apparent Loss ◽

Before And After ◽

Tropical Areas

ABSTRACTBuruli ulcer, an ulcerating skin disease caused byMycobacterium ulceransinfection, is common in tropical areas of western Africa. We determined the clinical and microbiological responses to administration of rifampin and streptomycin for 2 weeks followed by administration of rifampin and clarithromycin for 6 weeks in 43 patients with small laboratory-confirmed Buruli lesions and monitored for recurrence-free healing. Bacterial load in tissue samples before and after treatment for 6 and 12 weeks was monitored by semiquantitative culture. The success rate was 93%, and there was no recurrence after a 12-month follow-up. Eight percent had a positive culture 4 weeks after antibiotic treatment, but their lesions went on to heal. The findings indicate that rifampin and clarithromycin can replace rifampin and streptomycin for the continuation phase after rifampin and streptomycin administration for 2 weeks without any apparent loss of efficacy.

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LATE-BREAKING ABSTRACT: Haemophilus dominance of the stable COPD microbiome is associated with greater bacterial load and inflammation and is modulated by prophylactic antibiotic therapy

10.1183/13993003.congress-2015.oa4746 ◽

2015 ◽

Author(s):

Simon Brill ◽

Phillip James ◽

Leah Cuthbertson ◽

William Cookson ◽

Miriam Moffatt ◽

...

Keyword(s):

Antibiotic Therapy ◽

Bacterial Load ◽

Prophylactic Antibiotic ◽

Prophylactic Antibiotic Therapy

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Protective Efficacy of a DNA Vaccine Encoding Antigen 85A from Mycobacterium bovis BCG against Buruli Ulcer

Infection and Immunity ◽

10.1128/iai.69.9.5403-5411.2001 ◽

2001 ◽

Vol 69 (9) ◽

pp. 5403-5411 ◽

Cited By ~ 77

Author(s):

Audrey Tanghe ◽

Jean Content ◽

Jean-Paul Van Vooren ◽

Françoise Portaels ◽

Kris Huygen

Keyword(s):

Protective Efficacy ◽

Bacterial Load ◽

Buruli Ulcer ◽

Skin Lesions ◽

Protective Role ◽

Mycobacterium Ulcerans ◽

Mycobacterial Antigen ◽

Dna Encoding ◽

Major Health Problem ◽

Western Africa

ABSTRACT Buruli ulcer, caused by Mycobacterium ulcerans, is characterized by deep and necrotizing skin lesions, mostly on the arms and legs. Together with tuberculosis and leprosy, this mycobacterial disease has become a major health problem in tropical and subtropical regions, particularly in central and western Africa. No specific vaccine is available for Buruli ulcer. There is, however, evidence in the literature that suggests a cross-reactive protective role of the tuberculosis vaccine M. bovis BCG. To identify potential mechanisms for this cross-protection, we identified and characterized the M. ulcerans homologue of the important protective mycobacterial antigen 85 (Ag85A) from BCG. The homologue is well conserved in M. ulcerans, showing 84.1% amino acid sequence identity and 91% conserved residues compared to the sequence from BCG. This antigen was sufficiently conserved to allow cross-reactive protection, as demonstrated by the ability of M. ulcerans- infected mice to exhibit strong cellular immune responses to both BCG and its purified Ag85 complex. To further address the mechanism of cross-reactive protection, we demonstrate here that prior vaccination with either BCG or plasmid DNA encoding BCG Ag85A is capable of significantly reducing the bacterial load in the footpads ofM. ulcerans- infected mice, as determined by Ziehl-Neelsen staining and by actual counting of CFU on 7H11 Middlebrook agar. Together, the results reported here support the potential of a cross-protective Ag85-based future vaccine against tuberculosis, Buruli ulcer, and leprosy.

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Risk Factors Associated with Antibiotic Treatment Failure of Buruli Ulcer

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00722-20 ◽

2020 ◽

Vol 64 (9) ◽

Cited By ~ 1

Author(s):

Daniel P. O’Brien ◽

N. Deborah Friedman ◽

Aaron Walton ◽

Andrew Hughes ◽

Eugene Athan

Keyword(s):

Risk Factors ◽

Body Weight ◽

Antibiotic Therapy ◽

Treatment Failure ◽

Immune Suppression ◽

Univariate Analysis ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Content Type ◽

Observational Cohort

ABSTRACT Combination antibiotic therapy is highly effective in curing Buruli ulcer (BU) caused by Mycobacterium ulcerans. Treatment failures have been uncommonly reported with the recommended 56 days of antibiotics, and little is known about risk factors for treatment failure. We analyzed treatment failures among BU patients treated with ≥56 days of antibiotics from a prospective observational cohort at Barwon Health, Victoria, from 1 January 1998 to 31 December 2018. Treatment failure was defined as culture-positive recurrence within 12 months of commencing antibiotics under the following conditions: (i) following failure to heal the initial lesion or (ii) a new lesion developing at the original or at a new site. A total of 430 patients received ≥56 days of antibiotic therapy, with a median duration of 56 days (interquartile range [IQR], 56 to 80). Seven (1.6%) patients experienced treatment failure. For six adult patients experiencing treatment failure, all were male, weighed >90 kg, did not have surgery, and received combination rifampin-clarithromycin (median rifampin dose, 5.6 mg per kg of body weight per day; median clarithromycin dose, 8.1 mg/kg/day). When compared to those who did not fail treatment on univariate analysis, treatment failure was significantly associated with a weight of >90 kg (P < 0.001), male gender (P = 0.02), immune suppression (P = 0.04), and a first-line regimen of rifampin-clarithromycin compared to a regimen of rifampin-fluoroquinolone (P = 0.05). There is a low rate of treatment failure in Australian BU patients treated with rifampin-based oral combination antibiotic therapy. Our study raises the possibility that treatment failure risk may be increased in males, those with a body weight of >90 kg, those with immune suppression, and those taking rifampin-clarithromycin antibiotic regimens, but future pharmacokinetic and pharmacodynamics studies are required to determine the validity of these hypotheses.

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Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis

Nature Communications ◽

10.1038/s41467-021-21475-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Matthew F. Wipperman ◽

Shakti K. Bhattarai ◽

Charles Kyriakos Vorkas ◽

Venkata Suhas Maringati ◽

Ying Taur ◽

...

Keyword(s):

Antibiotic Therapy ◽

Bacterial Load ◽

Cross Sectional Study ◽

Gastrointestinal Microbiota ◽

Cross Sectional ◽

Tb Treatment ◽

Inflammatory State ◽

Induced Changes ◽

Pathogen Burden ◽

Pathogen Clearance

AbstractThe composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.

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Co-infection of HIV in patients with Buruli ulcer disease in Central Ghana

BMC Infectious Diseases ◽

10.1186/s12879-021-06009-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yaw Ampem Amoako ◽

Aloysius Dzigbordi Loglo ◽

Michael Frimpong ◽

Bernadette Agbavor ◽

Mohammed Kabiru Abass ◽

...

Keyword(s):

Bacterial Load ◽

Buruli Ulcer ◽

Interferon Γ ◽

Mycobacterium Ulcerans ◽

Hiv Viral Load ◽

Integration Of Care ◽

Ulcer Disease ◽

Hiv Coinfection ◽

Lesion Type ◽

Lesion Severity

Abstract Background Previous studies have reported that presence and severity of Buruli ulcer (BU) may reflect the underlying immunosuppression in HIV infected individuals by causing increased incidence of multiple, larger and ulcerated lesions. We report cases of BU-HIV coinfection and the accompanying programmatic challenges encountered in central Ghana. Methods Patients with PCR confirmed BU in central Ghana who were HIV positive were identified and their BU01 forms were retrieved and reviewed in further detail. A combined 16S rRNA reverse transcriptase / IS2404 qPCR assay was used to assess the Mycobacterium ulcerans load. The characteristics of coinfected patients (BU+HIV+) were compared with a group of matched controls. Results The prevalence of HIV in this BU cohort was 2.4% (compared to national HIV prevalence of 1.7%). Eight of 9 BU+HIV+ patients had a single lesion and ulcers were the most common lesion type. The lesions presented were predominantly category II (5/9) followed by category I lesions. The median (IQR) time to healing was 14 (8–28) weeks in the BU+HIV+ compared to 28 (12–33) weeks in the control BU+HIV− group (p = 0.360). Only one BU+HIV+ developed a paradoxical reaction at week 16 but the lesion healed completely at week 20. The median bacterial load (16SrRNA) of BU+HIV+ patients was 750 copies /ml (95% CI 0–398,000) versus 500 copies/ml (95% CI 0–126,855,500) in BU+HIV− group. Similarly, the median count using the IS2404 assay was 500 copies/ml (95% CI 0–500) for BU+HIV+ patients versus 500 copies/ml (95% CI 500–31,000) for BU+HIV− patients. BU+HIV− patients mounted a significantly higher interferon-γ response compared to the BU+HIV+ co-infected patients with respective median (range) responses of [1687(81.11–4399) pg/ml] versus [137.5(4.436–1406) pg/ml, p = 0.03]. There were challenges with the integration of HIV and BU care in this cohort. Conclusion The prevalence of HIV in the BU+ infected population was not significantly increased when compared to the prevalence of HIV in the general population. There was no clear relationship between BU lesion severity and HIV viral load or CD4 counts. Efforts should be made to encourage the integration of care of patients with BU-HIV coinfection.

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Boosting Toll-like receptor 4 signaling enhances the therapeutic outcome of antibiotic therapy in pneumococcal pneumonia

10.1101/2020.02.18.955500 ◽

2020 ◽

Cited By ~ 1

Author(s):

Fiordiligie Casilag ◽

Sebastian Franck ◽

Laura Matarazzo ◽

Martin Figeac ◽

Robin Michelet ◽

...

Keyword(s):

Innate Immunity ◽

Antibiotic Therapy ◽

Lung Tissue ◽

Bacterial Load ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Term Survival ◽

Monophosphoryl Lipid A ◽

Host Innate Immunity

ABSTRACTThe emergence and spread of antibiotic resistance emphasize the need for alternative treatment strategies against bacterial infections. Boosting the host innate immunity is not only readily deployable in most individuals but can also mobilize many different antibacterial defenses. This study tested the hypothesis whereby stimulation of the innate immune receptor Toll-like receptor 4 (TLR4) can be combined with antibiotics in the treatment of invasive pneumonia. In a mouse model of Streptococcus pneumoniae infection, a single oral administration of low-dose amoxicillin (AMX) or the systemic delivery of monophosphoryl lipid A (MPLA, a clinically-approved TLR4 activator) decreased the bacterial load in lung and spleen, although this was not sufficient for long-term survival. In contrast, a single treatment with a combination of MPLA and AMX induced significant bacterial clearance with little to no regrowth over time, and was associated with longer survival. Upregulation of genes related to granulocyte infiltration in lung tissue and elevation of blood levels of pro-inflammatory cytokines was immediate and transient in MPLA-treated mice; this indicates activation of the innate immune system in a context of infection. Combination treatment was associated with a well-preserved lung tissue architecture and more rapid recovery from inflammation - suggesting that immune activation by MPLA does not exacerbate pneumonia-induced damage. After AMX administration, plasma AMX concentrations rapidly reached the maximum and declined, whereas the downstream effects of MPLA extended beyond AMX elimination; these findings suggested a two-step effect. Our results demonstrated that leveraging host innate immunity increases the efficacy of antibiotic therapy in bacterial pneumonia.

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