Summary Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on ...sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.
Summary Background Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the ...standard monotherapy in India. Methods Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5–60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov , number NCT00696969. Findings Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5–96·3) for amphotericin B, 156 (97·5%; 93·3–99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24–99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1–99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. Interpretation Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. Funding Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.
AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be ...given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh.
The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment.
601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved.
None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi).
ClinicalTrials.gov NCT01122771.
The lack of access to safe and effective antimicrobials for human populations is a threat to global health security and a contributor to the emergence and spread of antimicrobial resistance (AMR). ...The increasingly common shortages of antimicrobials are an additional threat to the emergence of AMR. While the threat of such drug shortages is most acutely experienced in low-income and middle-income settings, their consequences impact the quality and effectiveness of antimicrobials worldwide. Furthermore, there is a need for robustly conducted studies examining the impact of these increasingly prevalent shortages on patient outcomes and on the emergence and spread of AMR. In this review, we have mapped common drivers for antimicrobial shortages and propose strategies for rethinking the regulation, supply and pricing of antimicrobials to secure their sustainable access across diverse healthcare systems and to help minimise the unintended consequences of weak and ineffective supply chains. Greater government involvement in antimicrobial manufacture and supply is essential to ensure no one is left behind. Dedicated demand systems need to be developed for antimicrobials which take into consideration evolving AMR patterns, burden of diseases, pandemic events and supply and demand issues and facilitate implementation of strategies to address them. Interventions, ranging from advocacy and forecasting to public–private collaborations, new economic models and international consortia working across countries and supply chains, will help assure access to safe and effective antimicrobials to all populations around the globe and ensure that shortages no longer contribute to AMR.
Most infections are still caused by pathogens susceptible to generic antibiotics, which are often preferred to newer antibiotics because of lower risks for toxicity and resistance development.1 ...Although data for the manufacturing and distribution of antibiotics are not publicly available, reports on limited availability, shortages, and price increases of old antibiotics suggest that the current system is too fragile to provide—what should be fundamental in modern medicine—access to effective treatment for common and potentially severe bacterial infections. In a recent study, 25 (69%) of 36 selected generic antibiotics were marketed in less than half of the 39 countries surveyed.2 Additionally, shortages in supply of generic antibiotics are frequently reported, and paediatric formulations are often unavailable.3 In the USA alone, 148 antibacterial drug shortages occurred during 2001–13.4 Intravenous benzylpenicillin, the first-line treatment option for community-acquired pneumonia, was reported unavailable in 2015 in the Netherlands.5 Ceftibuten, the only recommended oral treatment for febrile urinary tract infections in children in Sweden, was withdrawn from the market in 2016.6 In 2017, the worldwide shortage of piperacillin–tazobactam, a cornerstone antibiotic and β-lactamase inhibitor combination in the treatment of patients admitted to hospital with severe infections, is reported to be the result of damage to a single factory in China.7 In practice, shortages often result in shifts to use of antibiotics that are less effective and more expensive.8 Furthermore, some countries have had substantial increases in prices for generic antibiotics in recent years that will inevitably affect prescribing patterns.9,10 These problems have multiple causes. Exploitation of business opportunities in a niche market and a paucity of competition can cause sudden price increases that will inevitably affect treatment decisions and patient outcomes.
The President of the UN General Assembly (UNGA) should initiate a One Health high-level dialogue on AMR as early as spring, 2020, to follow-up on the recent recommendations of the UN Interagency ...Coordination Group on Antimicrobial Resistance (IACG).4 During this high-level dialogue, member states at the UNGA should endorse key principles for governing the global antimicrobial commons and mandate a new high-level leaders' group to build political momentum for AMR, commit to a common vision and clear goals, ensure accountability through an agreed monitoring and evaluation framework, and propose a rank-ordered political agenda for future intergovernmental negotiations. ...AMR needs continuing discussions among national governments, civil society, academia, and the private sector. ...AMR needs a recurring scientific stock-take by independent researchers and policy makers to ensure that global discussions and decisions are informed by the best evidence.
Visceral Leishmaniasis (VL; also known as Kala-azar) is an ultimately fatal disease endemic in Bihar. A 2007 observational cohort study in Bihar of 251 patients with VL treated with 20 mg/Kg ...intravenous liposomal amphotericin B (Ambisome) demonstrated a 98% cure rate at 6-months. Between July 2007 and August 2012, Médecins Sans Frontières (MSF) and the Rajendra Memorial Research Institute (RMRI) implemented a VL treatment project in Bihar, India-an area highly endemic for Leishmania donovani-using this regimen as first-line treatment.
Intravenous Ambisome 20 mg/kg was administered in four doses of 5 mg/kg over 4-10 days, depending on the severity of disease. Initial clinical cure at discharge was defined as improved symptoms, cessation of fever, and recession of spleen enlargement. This observational retrospective cohort study describes 8749 patients with laboratory-confirmed primary VL treated over a 5-year period: 1396 at primary healthcare centers, 7189 at hospital, and 164 at treatment camps. Initial clinical cure was achieved in 99.3% of patients (8692/8749); 0.3% of patients (26/8749) defaulted from treatment and 0.4% (31/8749) died. Overall, 1.8% of patients (161/8749) were co-infected with HIV and 0.6% (51/8749) with tuberculosis. Treatment was discontinued because of severe allergic reactions in 0.1% of patients (7/8749). Overall, 27 patients (0.3%) were readmitted with post Kala-azar dermal leishmaniasis (PKDL). Risk factors for late presentation included female sex, age >15 years and being from a scheduled caste. In 2012, a long-term efficacy survey in the same area of Bihar determined relapse rates of VL after 5 years' intervention with Ambisome. Of 984 immunocompetent patients discharged between September 2010 and December 2011, 827 (84.0%) were traced in order to determine their long-term outcomes. Of these, 20 patients (2.4%) had relapsed or received further treatment for VL. Of those completing 6, 12, and 15 month follow-up, 0.3% (2/767), 3.7% (14/383), and 2.4% (4/164), respectively, had relapsed. The mean ±SD time-to-relapse was 9.6±3.0 months.
This is the largest cohort of VL patients treated with 20 mg/kg Ambisome worldwide. The drug has high initial and long-term efficacy, and a low rate of adverse reactions when administered under field conditions in Bihar, India. Although challenging, its use as first line treatment in rural settings in Bihar is safe and feasible.
Tackling antimicrobial resistance in neonatal sepsis Folgori, Laura; Ellis, Sally J; Bielicki, Julia A ...
The Lancet global health,
November 2017, 2017-11-00, 20171101, 2017-11-01, Letnik:
5, Številka:
11
Journal Article
Introduction:
Leishmaniasis is a parasitic disease transmitted by phlebotomine sandflies. Between 700,000 and 1.2 million cases of cutaneous leishmaniasis and between 200,000 and 400,000 cases of ...visceral leishmaniasis (VL), which is fatal if left untreated, occur annually worldwide. Liposomal amphotericin B (LAMB), alone or in combination with other drugs, has been extensively studied as VL treatment, but data on routine field use are limited, and several challenges to patients' access to this life-saving drug remain.
Areas covered:
This article provides a review of clinical studies on LAMB for VL and other forms of leishmaniasis. The current development of generic versions of LAMB and related challenges are also discussed.
Expert opinion:
LAMB proved to be highly efficacious and safe in over 8000 VL patients treated by MÉdecins Sans Frontières in South Asia, and its use was feasible even at primary healthcare level. Despite requiring higher doses, LAMB is the drug of choice to treat vulnerable groups (e.g., pregnant or HIV positive) and relapsing VL patients in East Africa. LAMB should be included in national VL guidelines and registered in all VL endemic countries. Its cost should be further reduced and regulatory pathways to prove bioequivalence for generic LAMB products should be implemented.
SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and ...miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.
A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments.
In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults.
No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated.
The study was registered with ClinicalTrials.gov, number NCT01067443.
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