Journal Article > CommentaryFull Text
Surgery. 1 July 2015; Volume 158 (Issue 1); 33-36.; DOI:10.1016/j.surg.2015.04.006
Elder G, Murphy RA, Herard P, Dilworth K, Olson D, et al.
Surgery. 1 July 2015; Volume 158 (Issue 1); 33-36.; DOI:10.1016/j.surg.2015.04.006
Journal Article > ResearchFull Text
J Acquir Immune Defic Syndr. 1 November 2011; Volume 58 (Issue 3); 233-240.; DOI:10.1097/QAI.0b013e318228667f
Singh A, Sunpath H, Green TN, Padayachi N, Hiramen K, et al.
J Acquir Immune Defic Syndr. 1 November 2011; Volume 58 (Issue 3); 233-240.; DOI:10.1097/QAI.0b013e318228667f
BACKGROUND
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
METHODS
We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
RESULTS
Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
CONCLUSIONS
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
METHODS
We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
RESULTS
Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
CONCLUSIONS
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
Journal Article > ResearchFull Text
PLOS One. 11 August 2014; Volume 9 (Issue 8); DOI:10.1371/journal.pone.0101017
Ronat JB, Kakol J, Khoury M, Yun O, Brown V, et al.
PLOS One. 11 August 2014; Volume 9 (Issue 8); DOI:10.1371/journal.pone.0101017
In low- and middle-income countries, bloodstream infections are an important cause of mortality in patients with burns. Increasingly implicated in burn-associated infections are highly drug-resistant pathogens with limited treatment options. We describe the epidemiology of bloodstream infections in patients with burns in a humanitarian surgery project in Iraq.
Journal Article > ResearchFull Text
AIDS. 1 August 2019; Volume 33 (Issue 10); 1635-1644.; DOI:10.1097/QAD.0000000000002234
Shroufi A, van Cutsem G, Cambiano V, Bansi-Matharu L, Duncan K, et al.
AIDS. 1 August 2019; Volume 33 (Issue 10); 1635-1644.; DOI:10.1097/QAD.0000000000002234
Français
BACKGROUND
Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.
METHODS
To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.
FINDINGS
The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.
INTERPRETATION
As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.
Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.
METHODS
To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.
FINDINGS
The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.
INTERPRETATION
As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.
Journal Article > ResearchAbstract Only
Int J Tuberc Lung Dis. 1 September 2021; Volume 25 (Issue 9); 696-700.; DOI:10.5588/ijtld.21.0125
Murphy RA, Douglas-Jones B, Mucinya G, Sunpath H, Govender T
Int J Tuberc Lung Dis. 1 September 2021; Volume 25 (Issue 9); 696-700.; DOI:10.5588/ijtld.21.0125
The wider availability of dolutegravir (DTG) containing HIV therapy for patients living with multidrug-resistant TB (MDR-TB) presents several advantages. DTG-based antiretroviral therapy (ART) has superior potency, reduces pill burden, and may reduce overall treatment-related toxicity, giving it the potential to improve outcomes in both diseases. While the uptake of DTG-based ART in programs where drug-resistant TB is treated remains unknown, there is early evidence from three programs that uptake is increasing. The use of DTG-based ART should be scaled-up, beginning with antiretroviral-naïve or virologically suppressed patients initiating MDR-TB treatment.
Journal Article > ResearchFull Text
Int J Infect Dis. 1 June 2020; Volume 95; 459-461.; DOI:10.1016/j.ijid.2020.02.057
Shroufi A, Govender NP, Meintjes GA, Black JM, Nel J, et al.
Int J Infect Dis. 1 June 2020; Volume 95; 459-461.; DOI:10.1016/j.ijid.2020.02.057
BACKGROUND
Cryptococcal Meningitis (CM) is estimated to cause 181,000 deaths annually; with the majority occurring in Sub Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure quality assured flucytosine remains unregistered and largely inaccessible throughout Africa.
METHODS
The recently established South African flucytosine clinical access programme is an attempt to address market failure which led to a lack of public-sector access to flucytosine for cryptococcal meningitis, by making the medicine freely available to tertiary hospitals in South Africa.
RESULTS
Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observation from this experience that may have wider relevance.
CONCLUSIONS
The South African Flucytosine Access Programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.
Cryptococcal Meningitis (CM) is estimated to cause 181,000 deaths annually; with the majority occurring in Sub Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure quality assured flucytosine remains unregistered and largely inaccessible throughout Africa.
METHODS
The recently established South African flucytosine clinical access programme is an attempt to address market failure which led to a lack of public-sector access to flucytosine for cryptococcal meningitis, by making the medicine freely available to tertiary hospitals in South Africa.
RESULTS
Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observation from this experience that may have wider relevance.
CONCLUSIONS
The South African Flucytosine Access Programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.
Journal Article > ResearchFull Text
PLOS One. 9 October 2018; Volume 13 (Issue 10); DOI:10.1371/journal.pone.0205316
Kemigisha E, Nanjebe D, Boum Y II, Langendorf C, Aberrane S, et al.
PLOS One. 9 October 2018; Volume 13 (Issue 10); DOI:10.1371/journal.pone.0205316
Acute central nervous system (CNS) infections in children in sub-Saharan Africa are often fatal. Potential contributors include late presentation, limited diagnostic capacity and inadequate treatment. A more nuanced understanding of treatment practices with a goal of optimizing such practices is critical to prevent avoidable case fatality. We describe empiric antimicrobial treatment, antibiotic resistance and treatment adequacy in a prospective cohort of 459 children aged two months to 12 years hospitalised for suspected acute CNS infections in Mbarara, Uganda, from 2009 to 2012. Among these 459 children, 155 had a laboratory-confirmed diagnosis of malaria (case-fatality rate [CFR] 14%), 58 had bacterial infections (CFR 24%) and 6 children had mixed malaria and bacterial infections (CFR 17%). Overall case fatality was 18.1% (n = 83). Of 219 children with laboratory-confirmed malaria and/or bacterial infections, 182 (83.1%) received an adequate antimalarial and/or antibiotic on the day of admission and 211 (96.3%) within 48 hours of admission. The proportion of those receiving adequate treatment was similar among survivors and non-survivors. All bacterial isolates were sensitive to ceftriaxone except one Escherichia coli isolate with extended-spectrum beta-lactamase (ESBL). The observed high mortality was not a result of inadequate initial antimicrobial treatment at the hospital. The epidemiology of CNS infection in this setting justifies empirical use of a third-generation cephalosporin, however antibiotic resistance should be monitored closely.
Journal Article > CommentaryAbstract Only
Am J Infect Control. 1 November 2016; Volume 44 (Issue 11); 1381-1384.; DOI:10.1016/j.ajic.2016.03.036
Bhalla N, Hussein N, Atari M, Fakhri RM, Lepora C, et al.
Am J Infect Control. 1 November 2016; Volume 44 (Issue 11); 1381-1384.; DOI:10.1016/j.ajic.2016.03.036
Antibiotic stewardship program (ASP) implementation in humanitarian settings is a new endeavor. Doctors Without Borders/Médecins Sans Frontières introduced an ASP within a hospital in Amman, Jordan, where patients from Iraq, Syria, and Yemen with chronic, often multidrug-resistant, infections related to war are managed. Antibiotics were reviewed, and real-time recommendations were made to optimize choice, dose, duration, and route by a small team. Over the first year of implementation, acceptance of the ASP's recommendations improved. When compared with the year prior to implementation, antibiotic cost in 2014 declined considerably from approximately $252,077 (average, $21,006/month) to <$159,948 ($13,329/month), and a reduction in use of broad-spectrum agents was observed. An ASP in a humanitarian surgical hospital proved acceptable and effective, reducing antibiotic expenditures and use of broad-spectrum agents.
Journal Article > ResearchFull Text
Open Forum Infect Dis. 30 March 2015; Volume 2 (Issue 1); DOI:10.1093/ofid/ofv025
Murphy RA, Gounder L, Manzini TC, Ramdial PK, Castilla C, et al.
Open Forum Infect Dis. 30 March 2015; Volume 2 (Issue 1); DOI:10.1093/ofid/ofv025
The diagnosis of histoplasmosis in patients with human immunodeficiency virus in southern Africa is complicated by the nonspecific presentation of the disease in this patient group and the unavailability of sensitive diagnostics including antigen assays. Treatment options are also limited due to the unavailability of liposomal amphotericin and itraconazole, and the inability to perform therapeutic drug monitoring further confounds management. We present 3 clinical cases to illustrate the limits of diagnosis and management in the southern African context, and we highlight the need for additional diagnostic tools and treatment options in resource-limited settings.
Journal Article > ResearchAbstract Only
World J Surg. 25 February 2016; Volume 40 (Issue 7); 1550-1557.; DOI:10.1007/s00268-016-3458-5
Murphy RA, Nisenbaum L, Labar AS, Sheridan RL, Ronat JB, et al.
World J Surg. 25 February 2016; Volume 40 (Issue 7); 1550-1557.; DOI:10.1007/s00268-016-3458-5
BACKGROUND
Compared to high-income settings, survival in burn units in low-income settings is lower with invasive infections one leading cause of death. Médecins Sans Frontières is involved in the treatment of large burns in adults and children in Haiti.
METHODS
In 2014, we performed a review of 228 patients admitted consecutively with burn injury during a 6-month period to determine patient outcomes and infectious complications. Microbiology was available through a linkage with a Haitian organization. Regression analysis was performed to determine covariates associated with bloodstream infection and mortality.
RESULTS
102 (45 %) patients were male, the median age was 8 years (IQR, 2-28), and the majority of patients (60 %) were admitted to the unit within 6 h of injury. There were 20 patients (9 %) with culture-proven bacteremia. Among organisms in blood, common isolates were Staphylococcus aureus (42 %), Pseudomonas aeruginosa (23 %), and Acinetobacter baumannii (15 %). Among patients with burns involving <40 % total body area, 4 (2 %) of 192 died and 20 (65 %) of 31 with ≥40 % body surface area involvement died. Factors associated with mortality included involvement of ≥40 % of body surface, depth, and flame as the mechanism. Multidrug-resistant infections were common; 18 % of S. aureus isolates were methicillin resistant, and 83 % of P. aeruginosa isolates were imipenem resistant.
CONCLUSIONS
A low mortality rate was observed in a humanitarian burn surgery project in patients with burns involving <40 % of total body surface. Invasive infection was common and alarming rates of antibiotic resistance were observed, including infections not treatable with antibiotics available locally.
Compared to high-income settings, survival in burn units in low-income settings is lower with invasive infections one leading cause of death. Médecins Sans Frontières is involved in the treatment of large burns in adults and children in Haiti.
METHODS
In 2014, we performed a review of 228 patients admitted consecutively with burn injury during a 6-month period to determine patient outcomes and infectious complications. Microbiology was available through a linkage with a Haitian organization. Regression analysis was performed to determine covariates associated with bloodstream infection and mortality.
RESULTS
102 (45 %) patients were male, the median age was 8 years (IQR, 2-28), and the majority of patients (60 %) were admitted to the unit within 6 h of injury. There were 20 patients (9 %) with culture-proven bacteremia. Among organisms in blood, common isolates were Staphylococcus aureus (42 %), Pseudomonas aeruginosa (23 %), and Acinetobacter baumannii (15 %). Among patients with burns involving <40 % total body area, 4 (2 %) of 192 died and 20 (65 %) of 31 with ≥40 % body surface area involvement died. Factors associated with mortality included involvement of ≥40 % of body surface, depth, and flame as the mechanism. Multidrug-resistant infections were common; 18 % of S. aureus isolates were methicillin resistant, and 83 % of P. aeruginosa isolates were imipenem resistant.
CONCLUSIONS
A low mortality rate was observed in a humanitarian burn surgery project in patients with burns involving <40 % of total body surface. Invasive infection was common and alarming rates of antibiotic resistance were observed, including infections not treatable with antibiotics available locally.