Journal Article > CommentaryFull Text
J Antimicrob Chemother. 2019 April 10; Volume 1 (Issue 1); dlz002.; DOI:10.1093/jacamr/dlz002
Kanapathipillai R, Malou N, Hopman J, Bowman C, Yousef N, et al.
J Antimicrob Chemother. 2019 April 10; Volume 1 (Issue 1); dlz002.; DOI:10.1093/jacamr/dlz002
Médecins Sans Frontières (MSF) has designed context-adapted antibiotic resistance (ABR) responses in countries across the Middle East. There, some health systems have been severely damaged by conflict resulting in delayed access to care, crowded facilities and supply shortages. Microbiological surveillance data are rarely available, but when MSF laboratories are installed we often find MDR bacteria at alarming levels. In MSF’s regional hospital in Jordan, where surgical patients have often had multiple surgeries in field hospitals before reaching definitive care (often four or more), MSF microbiological data analysis reveals that, among Enterobacteriaceae isolates, third-generation cephalosporin and carbapenem resistance is 86.2% and 4.3%, respectively; MRSA prevalence among Staphylococcus aureus is 60.5%; and resistance types and rates are similar in patients originating from Yemen, Syria and Iraq. These trends compel MSF to aggressively prevent and diagnose ABR in Jordan, providing ABR lessons that inform the antibiotic choices, microbiological diagnostics and anti-ABR strategies in other Middle Eastern MSF trauma projects (such as Yemen and Gaza).
As a result, MSF has created a multifaceted, context-adapted, field experience-based, approach to ABR in hospitals in Middle Eastern conflict settings. We focus on three pillars: (1) infection prevention and control (IPC); (2) microbiology and surveillance; and (3) antibiotic stewardship.
As a result, MSF has created a multifaceted, context-adapted, field experience-based, approach to ABR in hospitals in Middle Eastern conflict settings. We focus on three pillars: (1) infection prevention and control (IPC); (2) microbiology and surveillance; and (3) antibiotic stewardship.
Journal Article > ResearchAbstract
J Antimicrob Chemother. 2020 March 1; Volume 75 (Issue 3); 7-0-717.; DOI:10.1093/jac/dkz487
Maataoui N, Langendorf C, Berthé F, Bayjanov JR, van Schaik W, et al.
J Antimicrob Chemother. 2020 March 1; Volume 75 (Issue 3); 7-0-717.; DOI:10.1093/jac/dkz487
Objectives
Routine amoxicillin for children with uncomplicated severe acute malnutrition raises concerns of increasing antibiotic resistance. We performed an ancillary study nested within a double-blind, placebo-controlled trial in Niger testing the role of routine 7 day amoxicillin therapy in nutritional recovery of children 6 to 59 months of age with uncomplicated severe acute malnutrition.
Methods
We screened 472 children for rectal carriage of ESBL-producing Enterobacteriaceae (ESBL-E) as well as their household siblings under 5 years old, at baseline and Week 1 (W1) and Week 4 (W4) after start of therapy, and characterized strains by WGS. ClinicalTrials.gov: NCT01613547.
Results
Carriage in index children at baseline was similar in the amoxicillin and the placebo groups (33.8% versus 27.9%, P = 0.17). However, acquisition of ESBL-E in index children at W1 was higher in the amoxicillin group than in the placebo group (53.7% versus 32.2%, adjusted risk ratio = 2.29, P = 0.001). Among 209 index and sibling households possibly exposed to ESBL-E transmission, 16 (7.7%) had paired strains differing by ≤10 SNPs, suggesting a high probability of transmission. This was more frequent in households from the amoxicillin group than from the placebo group [11.5% (12/104) versus 3.8% (4/105), P = 0.04].
Conclusions
Among children exposed to amoxicillin, ESBL-E colonization was more frequent and the risk of transmission to siblings higher. Routine amoxicillin should be carefully balanced with the risks associated with ESBL-E colonization.
Routine amoxicillin for children with uncomplicated severe acute malnutrition raises concerns of increasing antibiotic resistance. We performed an ancillary study nested within a double-blind, placebo-controlled trial in Niger testing the role of routine 7 day amoxicillin therapy in nutritional recovery of children 6 to 59 months of age with uncomplicated severe acute malnutrition.
Methods
We screened 472 children for rectal carriage of ESBL-producing Enterobacteriaceae (ESBL-E) as well as their household siblings under 5 years old, at baseline and Week 1 (W1) and Week 4 (W4) after start of therapy, and characterized strains by WGS. ClinicalTrials.gov: NCT01613547.
Results
Carriage in index children at baseline was similar in the amoxicillin and the placebo groups (33.8% versus 27.9%, P = 0.17). However, acquisition of ESBL-E in index children at W1 was higher in the amoxicillin group than in the placebo group (53.7% versus 32.2%, adjusted risk ratio = 2.29, P = 0.001). Among 209 index and sibling households possibly exposed to ESBL-E transmission, 16 (7.7%) had paired strains differing by ≤10 SNPs, suggesting a high probability of transmission. This was more frequent in households from the amoxicillin group than from the placebo group [11.5% (12/104) versus 3.8% (4/105), P = 0.04].
Conclusions
Among children exposed to amoxicillin, ESBL-E colonization was more frequent and the risk of transmission to siblings higher. Routine amoxicillin should be carefully balanced with the risks associated with ESBL-E colonization.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2023 September 20; Online ahead of print; dkad286.; DOI:10.1093/jac/dkad286
Verrest L, Roseboom IC, Wasunna M, Mbui J, Njenga SN, et al.
J Antimicrob Chemother. 2023 September 20; Online ahead of print; dkad286.; DOI:10.1093/jac/dkad286
OBJECTIVES
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
METHODS
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
RESULTS
Data from 265 patients (59% =12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0–24h 187 (162–203) and 242 (217–328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0–28 517 (464–552) and 524 (456–567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25–28) and 30 (28–32) days, respectively] were comparable to previously observed values in adults.
CONCLUSIONS
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure–response and exposure–toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
METHODS
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
RESULTS
Data from 265 patients (59% =12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0–24h 187 (162–203) and 242 (217–328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0–28 517 (464–552) and 524 (456–567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25–28) and 30 (28–32) days, respectively] were comparable to previously observed values in adults.
CONCLUSIONS
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure–response and exposure–toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2008 February 1; Volume 61 (Issue 2); DOI:10.1093/jac/dkm484
Cohen K, van Cutsem G, Boulle AM, McIlleron HM, Goemaere E, et al.
J Antimicrob Chemother. 2008 February 1; Volume 61 (Issue 2); DOI:10.1093/jac/dkm484
BACKGROUND AND OBJECTIVES: Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients. METHODS: Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy. RESULTS: Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for Cmax, 0.64 (90% CI 0.52-0.80) for area under the curve up to 12 h (AUC(0-12)) and 0.68 (90% CI 0.53-0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC(0-12) to the AUC(0-12) of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism. CONCLUSIONS: Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2010 July 1; Volume 65 (Issue 7); DOI:10.1093/jac/dkq120
Plinke C, Cox HS, Zarkua N, Karimovich HA, Braker K, et al.
J Antimicrob Chemother. 2010 July 1; Volume 65 (Issue 7); DOI:10.1093/jac/dkq120
Mechanisms of resistance to ethambutol in Mycobacterium tuberculosis remain inadequately described. Although there is mounting evidence that mutations of codon 306 in embB play a key role, a significant number of phenotypically ethambutol-resistant strains do not carry mutations in this codon. Here, other mutations in the embCAB operon are suggested to be involved in resistance development.
Journal Article > Meta-AnalysisFull Text
J Antimicrob Chemother. 2006 October 1; Volume 58 (Issue 4); 811-815.; DOI:10.1093/jac/dkl342
Mueller M, Balasegaram M, Koummuki Y, Ritmeijer KKD, Santana MR, et al.
J Antimicrob Chemother. 2006 October 1; Volume 58 (Issue 4); 811-815.; DOI:10.1093/jac/dkl342
OBJECTIVES: Little is known about the treatment of visceral leishmaniasis (VL) in pregnancy, especially in resource-poor settings. We present a series of pregnant women with VL treated with either sodium stibogluconate or liposomal amphotericin B (AmBisome), or both, in eastern Sudan over 16 months.
METHODS: We did a retrospective analysis of all pregnant VL patients treated in the Médecins sans Frontières (MSF) Um el Kher centre between January 2004 and April 2005. We diagnosed VL with laboratory confirmation of clinical suspects, and recorded the outcomes of treatment for pregnant women and their foetuses. We carried out a manual search of relevant publications and a systematic search of the literature in the MEDLINE database.
RESULTS: We treated 23 women with sodium stibogluconate, 4 with AmBisome and sodium stibogluconate and 12 with AmBisome alone. There were 13 (57%) spontaneous abortions in the sodium stibogluconate monotherapy group, and none in either of the other two groups. All spontaneous abortions occurred in the first two trimesters. All patients, except one in the sodium stibogluconate group who defaulted, were discharged as cured in good clinical condition.
CONCLUSIONS: AmBisome treatment for VL appears to be safe and effective for pregnant women and their foetuses. We recommend the use of AmBisome as first-line treatment for these patients.
METHODS: We did a retrospective analysis of all pregnant VL patients treated in the Médecins sans Frontières (MSF) Um el Kher centre between January 2004 and April 2005. We diagnosed VL with laboratory confirmation of clinical suspects, and recorded the outcomes of treatment for pregnant women and their foetuses. We carried out a manual search of relevant publications and a systematic search of the literature in the MEDLINE database.
RESULTS: We treated 23 women with sodium stibogluconate, 4 with AmBisome and sodium stibogluconate and 12 with AmBisome alone. There were 13 (57%) spontaneous abortions in the sodium stibogluconate monotherapy group, and none in either of the other two groups. All spontaneous abortions occurred in the first two trimesters. All patients, except one in the sodium stibogluconate group who defaulted, were discharged as cured in good clinical condition.
CONCLUSIONS: AmBisome treatment for VL appears to be safe and effective for pregnant women and their foetuses. We recommend the use of AmBisome as first-line treatment for these patients.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2014 September 18; Volume 70 (Issue 1); 225-32.; DOI:10.1093/jac/dku348
Bhatt NB, Baudin E, Meggi B, da Silva C, Barrail-Tran A, et al.
J Antimicrob Chemother. 2014 September 18; Volume 70 (Issue 1); 225-32.; DOI:10.1093/jac/dku348
OBJECTIVES
We describe nevirapine and efavirenz exposure on and off tuberculosis treatment and consequences for virological efficacy and tolerance in patients included in the ANRS 12146/12214-CARINEMO trial.
METHODS
Participants were randomly selected to receive either nevirapine at 200 mg twice daily (n = 256) or efavirenz at 600 mg daily (n = 270), both combined with two nucleoside analogues. Blood samples were drawn 12 h after nevirapine or efavirenz administration, while on tuberculosis treatment and after tuberculosis treatment discontinuation. In 62 participants, samples taken 12 h after drug administration were drawn weekly for the first month of ART. Sixteen participants participated in an extensive pharmacokinetic study of nevirapine. Concentrations were compared with the therapeutic ranges of 3000-8000 ng/mL for nevirapine and 1000-4000 ng/mL for efavirenz.
RESULTS
Nevirapine concentrations at the end of the first week of treatment (on antituberculosis drugs) did not differ from concentrations off tuberculosis treatment, but declined thereafter. Concentrations at steady-state were 4111 ng/mL at week 12 versus 6095 ng/mL at week 48 (P < 0.0001). Nevirapine concentrations <3000 ng/mL were found to be a risk factor for virological failure. Efavirenz concentrations were higher on than off tuberculosis treatment (2700 versus 2450 ng/mL, P < 0.0001).
CONCLUSIONS
The omission of the 2 week lead-in dose of nevirapine prevented low concentrations at treatment initiation but did not prevent the risk of virological failure. Results support the WHO recommendation to use efavirenz at 600 mg daily in patients on rifampicin-based antituberculosis therapy.
We describe nevirapine and efavirenz exposure on and off tuberculosis treatment and consequences for virological efficacy and tolerance in patients included in the ANRS 12146/12214-CARINEMO trial.
METHODS
Participants were randomly selected to receive either nevirapine at 200 mg twice daily (n = 256) or efavirenz at 600 mg daily (n = 270), both combined with two nucleoside analogues. Blood samples were drawn 12 h after nevirapine or efavirenz administration, while on tuberculosis treatment and after tuberculosis treatment discontinuation. In 62 participants, samples taken 12 h after drug administration were drawn weekly for the first month of ART. Sixteen participants participated in an extensive pharmacokinetic study of nevirapine. Concentrations were compared with the therapeutic ranges of 3000-8000 ng/mL for nevirapine and 1000-4000 ng/mL for efavirenz.
RESULTS
Nevirapine concentrations at the end of the first week of treatment (on antituberculosis drugs) did not differ from concentrations off tuberculosis treatment, but declined thereafter. Concentrations at steady-state were 4111 ng/mL at week 12 versus 6095 ng/mL at week 48 (P < 0.0001). Nevirapine concentrations <3000 ng/mL were found to be a risk factor for virological failure. Efavirenz concentrations were higher on than off tuberculosis treatment (2700 versus 2450 ng/mL, P < 0.0001).
CONCLUSIONS
The omission of the 2 week lead-in dose of nevirapine prevented low concentrations at treatment initiation but did not prevent the risk of virological failure. Results support the WHO recommendation to use efavirenz at 600 mg daily in patients on rifampicin-based antituberculosis therapy.
Journal Article > ReviewAbstract Only
J Antimicrob Chemother. 2020 December 21; Volume 76 (Issue 5); 1160-1167.; DOI:10.1093/jac/dkaa519
Mashe T, Leekitcharoenphon P, Mtapuri-Zinyowera S, Kingsley RA, Robertson V, et al.
J Antimicrob Chemother. 2020 December 21; Volume 76 (Issue 5); 1160-1167.; DOI:10.1093/jac/dkaa519
BACKGROUND
Typhoid fever, caused by S. enterica ser. Typhi, continues to be a substantial health burden in developing countries. Little is known of the genotypic diversity of S. enterica ser. Typhi in Zimbabwe, but this is key for understanding the emergence and spread of this pathogen and devising interventions for its control.
OBJECTIVES
To report the molecular epidemiology of S. enterica ser. Typhi outbreak strains circulating from 2012 to 2019 in Zimbabwe, using comparative genomics.
METHODS
A review of typhoid cases records from 2012 to 2019 in Zimbabwe was performed. The phylogenetic relationship of outbreak isolates from 2012 to 2019 and emergence of antibiotic resistance was investigated by whole-genome sequence analysis.
RESULTS
A total 22 479 suspected typhoid cases, 760 confirmed cases were reported from 2012 to 2019 and 29 isolates were sequenced. The majority of the sequenced isolates were predicted to confer resistance to aminoglycosides, β-lactams, phenicols, sulphonamides, tetracycline and fluoroquinolones (including qnrS detection). The qnrS1 gene was associated with an IncN (subtype PST3) plasmid in 79% of the isolates. Whole-genome SNP analysis, SNP-based haplotyping and resistance determinant analysis showed that 93% of the isolates belonged to a single clade represented by multidrug-resistant H58 lineage I (4.3.1.1), with a maximum pair-wise distance of 22 SNPs.
CONCLUSIONS
This study has provided detailed genotypic characterization of the outbreak strain, identified as S. Typhi 4.3.1.1 (H58). The strain has reduced susceptibility to ciprofloxacin due to qnrS carried by an IncN (subtype PST3) plasmid resulting from ongoing evolution to full resistance.
Typhoid fever, caused by S. enterica ser. Typhi, continues to be a substantial health burden in developing countries. Little is known of the genotypic diversity of S. enterica ser. Typhi in Zimbabwe, but this is key for understanding the emergence and spread of this pathogen and devising interventions for its control.
OBJECTIVES
To report the molecular epidemiology of S. enterica ser. Typhi outbreak strains circulating from 2012 to 2019 in Zimbabwe, using comparative genomics.
METHODS
A review of typhoid cases records from 2012 to 2019 in Zimbabwe was performed. The phylogenetic relationship of outbreak isolates from 2012 to 2019 and emergence of antibiotic resistance was investigated by whole-genome sequence analysis.
RESULTS
A total 22 479 suspected typhoid cases, 760 confirmed cases were reported from 2012 to 2019 and 29 isolates were sequenced. The majority of the sequenced isolates were predicted to confer resistance to aminoglycosides, β-lactams, phenicols, sulphonamides, tetracycline and fluoroquinolones (including qnrS detection). The qnrS1 gene was associated with an IncN (subtype PST3) plasmid in 79% of the isolates. Whole-genome SNP analysis, SNP-based haplotyping and resistance determinant analysis showed that 93% of the isolates belonged to a single clade represented by multidrug-resistant H58 lineage I (4.3.1.1), with a maximum pair-wise distance of 22 SNPs.
CONCLUSIONS
This study has provided detailed genotypic characterization of the outbreak strain, identified as S. Typhi 4.3.1.1 (H58). The strain has reduced susceptibility to ciprofloxacin due to qnrS carried by an IncN (subtype PST3) plasmid resulting from ongoing evolution to full resistance.
Journal Article > ResearchFull Text
Effect of high-dose rifampicin on efavirenz pharmacokinetics: drug-drug interaction randomized trial
J Antimicrob Chemother. 2020 January 30; Volume 75 (Issue 5); DOI:10.1093/jac/dkz557
Atwine D, Baudin E, Gele T, Muyindike WR, Mworozi K, et al.
J Antimicrob Chemother. 2020 January 30; Volume 75 (Issue 5); DOI:10.1093/jac/dkz557
Background: High-dose rifampicin is considered to shorten anti-TB treatment duration but its effect on antiretroviral metabolism is unknown.
Objectives: To assess the effect of doubling the rifampicin dose (to 20 mg/kg/day, R20) on efavirenz pharmacokinetics (PK) in HIV/TB coinfected patients.
Methods: Open-label Phase 2 drug-drug interaction randomized trial. Pulmonary TB, ART-naive adults were randomized to R20 and either efavirenz 600 mg (EFV600) or 800 mg (EFV800), or rifampicin 10 mg/kg/day (R10) and EFV600 with a 1:1:1 ratio. Patients were first started on TB treatment and 2-4 weeks later started on ART. They were switched to R10 and EFV600 after 8 weeks. Full PK sampling was done 4 weeks (on rifampicin) and 24 weeks (off rifampicin) after ART initiation. Transaminases, plasma HIV-1 RNA and sputum cultures were monitored. The efavirenz geometric mean ratio (GMR) of AUC at 4 and 24 weeks after ART initiation within the same patient was calculated in each arm and its 90% CI was compared with a preset range (0.70-1.43).
Results: Of 98 enrolled patients (32 in the R20EFV600 arm, 33 in the R20EFV800 arm and 33 in the R10EFV600 arm), 87 had full PK sampling. For the R20EFV600, R20EFV800 and R10EFV600 arms, GMRs of efavirenz AUC were 0.87 (90% CI: 0.75-1.00), 1.12 (90% CI: 0.96-1.30) and 0.96 (90% CI: 0.84-1.10). Twelve weeks after ART initiation, 78.6%, 77.4% and 72.4% of patients had HIV-1 RNA below 100 copies/mL and 85.7%, 86.7% and 80.0% had Week 8 culture conversion, respectively. Two patients per arm experienced a severe increase in transaminases.
Conclusions: Doubling the rifampicin dose had a small effect on efavirenz concentrations and was well tolerated.
Objectives: To assess the effect of doubling the rifampicin dose (to 20 mg/kg/day, R20) on efavirenz pharmacokinetics (PK) in HIV/TB coinfected patients.
Methods: Open-label Phase 2 drug-drug interaction randomized trial. Pulmonary TB, ART-naive adults were randomized to R20 and either efavirenz 600 mg (EFV600) or 800 mg (EFV800), or rifampicin 10 mg/kg/day (R10) and EFV600 with a 1:1:1 ratio. Patients were first started on TB treatment and 2-4 weeks later started on ART. They were switched to R10 and EFV600 after 8 weeks. Full PK sampling was done 4 weeks (on rifampicin) and 24 weeks (off rifampicin) after ART initiation. Transaminases, plasma HIV-1 RNA and sputum cultures were monitored. The efavirenz geometric mean ratio (GMR) of AUC at 4 and 24 weeks after ART initiation within the same patient was calculated in each arm and its 90% CI was compared with a preset range (0.70-1.43).
Results: Of 98 enrolled patients (32 in the R20EFV600 arm, 33 in the R20EFV800 arm and 33 in the R10EFV600 arm), 87 had full PK sampling. For the R20EFV600, R20EFV800 and R10EFV600 arms, GMRs of efavirenz AUC were 0.87 (90% CI: 0.75-1.00), 1.12 (90% CI: 0.96-1.30) and 0.96 (90% CI: 0.84-1.10). Twelve weeks after ART initiation, 78.6%, 77.4% and 72.4% of patients had HIV-1 RNA below 100 copies/mL and 85.7%, 86.7% and 80.0% had Week 8 culture conversion, respectively. Two patients per arm experienced a severe increase in transaminases.
Conclusions: Doubling the rifampicin dose had a small effect on efavirenz concentrations and was well tolerated.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 2017 June 22; Volume 72 (Issue 9); 2596-2601.; DOI:10.1093/jac/dkx180
Sperandio da Silva G, Felix Mediano M, Hasslocher-Moreno A, Holanda M, Silvestre de Sousa A, et al.
J Antimicrob Chemother. 2017 June 22; Volume 72 (Issue 9); 2596-2601.; DOI:10.1093/jac/dkx180
BACKGROUND
Up to half of patients with Chagas' disease under benznidazole treatment present adverse drug reactions (ADRs) and up to one-third do not complete standard treatment.
OBJECTIVES
To verify the incidence and possible factors associated with the suspension of benznidazole treatment in a large cohort of patients.
METHODS
We included 2075 patients treated with benznidazole during the projects managed by the medical humanitarian organization Doctors Without Borders (Médecins Sans Frontières) in Bolivia from 2009 to 2013. Benznidazole treatment was provided two or three times per day for ∼60 days at 5-7.5 mg/kg/day. A multiple logistic regression model was developed to evaluate the factors associated with permanent suspension of benznidazole treatment.
RESULTS
Permanent benznidazole treatment suspension occurred in 211 patients (10.2%) and the average time until permanent treatment suspension was 23 days. Multifactorial analysis revealed that female sex (adjusted OR = 1.70), moderate ADRs (adjusted OR = 10.57), mild ADRs (adjusted OR = 1.69) and skin disorders (adjusted OR = 4.18) were significantly associated with the permanent suspension of benznidazole treatment. Women with mild or moderate skin ADRs presented a probability of treatment interruption of 18.6% and 59.0%, respectively.
CONCLUSIONS
Benznidazole treatment was safe and a large proportion of patients were able to complete a full course of benznidazole treatment under close treatment surveillance. Female sex, skin disorders and mild and moderate ADRs were independently associated with the permanent suspension of benznidazole treatment. In particular, women with moderate skin ADRs had the highest risk of benznidazole treatment interruption.
Up to half of patients with Chagas' disease under benznidazole treatment present adverse drug reactions (ADRs) and up to one-third do not complete standard treatment.
OBJECTIVES
To verify the incidence and possible factors associated with the suspension of benznidazole treatment in a large cohort of patients.
METHODS
We included 2075 patients treated with benznidazole during the projects managed by the medical humanitarian organization Doctors Without Borders (Médecins Sans Frontières) in Bolivia from 2009 to 2013. Benznidazole treatment was provided two or three times per day for ∼60 days at 5-7.5 mg/kg/day. A multiple logistic regression model was developed to evaluate the factors associated with permanent suspension of benznidazole treatment.
RESULTS
Permanent benznidazole treatment suspension occurred in 211 patients (10.2%) and the average time until permanent treatment suspension was 23 days. Multifactorial analysis revealed that female sex (adjusted OR = 1.70), moderate ADRs (adjusted OR = 10.57), mild ADRs (adjusted OR = 1.69) and skin disorders (adjusted OR = 4.18) were significantly associated with the permanent suspension of benznidazole treatment. Women with mild or moderate skin ADRs presented a probability of treatment interruption of 18.6% and 59.0%, respectively.
CONCLUSIONS
Benznidazole treatment was safe and a large proportion of patients were able to complete a full course of benznidazole treatment under close treatment surveillance. Female sex, skin disorders and mild and moderate ADRs were independently associated with the permanent suspension of benznidazole treatment. In particular, women with moderate skin ADRs had the highest risk of benznidazole treatment interruption.