The challenge of Antibiotic Resistance - with special emphasis on the situation in resource constrained settings. Andreas Heddini, MD, PhD

Transcription

1 The challenge of Antibiotic Resistance - with special emphasis on the situation in resource constrained settings Andreas Heddini, MD, PhD

2 A Global Challenge Antibiotics are losing their effectiveness at a pace that was unforeseen just 5-10 years ago The drug development pipeline is virtually empty from antibiotics with a novel mechanism of action

3 The Current Paradox: Antibiotic Resistance Drug Development Morbidity Mortality Costs

4 Use - Rational and Irrational Access, quality, marketing, financing Spread of resistant bacteria Poor hygiene and sanitation in hospitals and the community, travel Antibiotic Resistance Lack of new antibiotics Scientific hurdles Low return of investment

5 The dwindling antibiotic pipeline... Trimetoprim Streptogramins Quinolones Chloramphenicol Lincosamides Tetracyclines Macrolides Glycopeptides Sulphonamides Aminoglycosides Penicillins Lipopeptides Oxazolidinones 1930 s 1940 s 1950 s 1960 s 1970 s 1980 s 1990 s 2000 s

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7 Illegal OTC antibiotic sale in the EU Athens, Greece (174 pharmacies) 2008: -100% of all visited pharmacies sold Amoxicillin/clavulanic acid OTC - 53% sold Ciprofloxacin OTC, despite extra restrictions for fluoroquinolone prescriptions Plachouras et al. Euro Surveill. 2010

8 The tip of the iceberg ICU Hospital Community Ecology

9 ESBL (CTX-M) producing Enterobacteriaceae Endemicity Sporadic reports 2007 Endemicity Sporadic reports 2005

10 Orphanage in Bamako, Mali ESBL colonized 100% of the children and 63%, of the adult staff studied. Tandé et al. Emerg Infect Dis Mar;15(3): Mumhibili hospital, Tanzania The mortality rate from Gram-negative bloodstream infection was 43 %, more than double that of malaria.. Blomberg et al. BMC Infect Dis May 22;7:43.

11 Antibiotic susceptibility proportions for NDM-1-positive Enterobacteriaceae isolated in the UK and India UK (n=37) Chennai (n=44) Haryana (n=26) Imipenem 0% 0% 0% Meropenem 3% 3% 3% Piperacillin-taz 0% 0% 0% Cefotaxime 0% 0% 0% Ceftazidime 0% 0% 0% Cefpirome 0% 0% 0% Aztreonam 11% 0% 8% Ciprofloxacin 8% 8% 8% Gentamicin 3% 3% 3% Tobramycin 0% 0% 0% Amikacin 0% 0% 0% Minocycline 0% 0% 0% Tigecycline 64% 56% 67% Colistin 89% 94% 100% From Kumarasamy et al. Lancet Infect Dis 2010

12 Rolain et al. Clin Microb Inf 2010 Spread of NDM-1

13 Newborn infections, pneumonia and diarrhea acocunt for almost 40% of all child deaths globally Black et al (Lancet 2010)

14 The UN Millenium Goals and antibiotic resistance Goal 4: Reduce child mortality Goal 5: Improve maternal health

15 Haiti % of the wound infections sampled were polymicrobial, with 89% (41 of 46) involving gram-negative pathogens. These pathogens were generally resistant to the antimicrobials suggested in the current CDC and WHO guidelines Miskin et al N Engl J Med Dec 23;363(26):2571-3

16 Pakistan Floods 2010

17 Cholera Outbreak in Khairpur (Aug 15-Sept 5) 80,000 diarrhea cases in the area 50% of all severe acute watery diarrhea (> 2500 referred cases) Over two thirds of those referred required antibiotics Low case fatality due to excellent management by the University team (high input of workers & logistics) Zulfiqar Bhutta presentation at ReAct conference Sep 2010

18 % AMR in Vibrio cholera (Pakistan) Cholera screening studies carried out in Khairpur (Aug 24 Aug 31, 2010) Zulfiqar Bhutta presentation at ReAct conference Sep 2010

19 Neonatal sepsis and antibiotic resistance does it matter?

20 Case Fatality Rates (Neonatal sepsis) Organism STAPHYLOCOCCUS AUREUS Susceptibility Resistant Sensitive 15.4 % 3.5 % % KLEBSIELLA 22.8 % 16.1 % ENTEROBACTER 28.0 % 21.6 % ACINETOBACTER & PSEUDOMONAS 42.7 % 14.0 % ESCHERICHIA COLI 44.0 % 26.7 % Zulfiqar Bhutta presentation at ReAct conference Sep 2010

21 Possible contribution of AMR to neonatal sepsis deaths Model predicted 368,000 neonatal deaths due to sepsis in South Asia (cf WHO projections of 385,000 deaths)

22 Mortality outcomes are worse in neonates with resistant infections (Tanzania) Death (%) Positive Negative Culture Gram Reaction ESBL MRSA Parameter Kayange M et al, BMC Pediatrics 2010

23 Is ABR found in isolated and remote areas? In a very remote human community of the Peruvian Amazonas with minimal antibiotic exposure, high levels of acquired resistance to the oldest antibiotics (ampicillin, tetracycline, trimethoprim/sulfamethoxazole, streptomycin and chloramphenicol) were detected in commensal Escherichia coli, with remarkable diversity of resistant clones and of resistance genes and plasmids. The exception was quinolones. Bartoloni et al. Int J Antimicrob Agents. 2009

24 Multi-drug resistant enterobacteria in Senegal From November 2008 through October 2009, 11 Enterobacteriaceae isolates with reduced susceptibility to imipenem were identified at the Institut Pasteur in Dakar, Senegal. The isolates were recovered from 6 patients with urinary tract infections, 4 patients with surgical infections, and 1 patient with omphalitis Because the patients died before antibacterial drug susceptibility testing could be completed, all 5 patients with surgical infections or omphalitis received only empirical therapy with amoxicillin/clavulanate. One patient with a nosocomial urinary tract infection caused by a cotrimoxazole-susceptible strain was successfully treated with this antibacterial agent. The antibacterial drug regimens of the remaining 4 patients were not known, and they were lost to follow-up Moquet el al. EID Jan 2011

25 Childhood pneumonia are we overtreating? Double-blind, randomized trial in 4 tertiary hospitals in Pakistan 900 children aged 2 59 months with WHO defined non-severe pneumonia were randomized to receive either 3 days of oral amoxicillin or placebo; Clinical outcome in children aged 2 59 months with WHO-defined non-severe pneumonia is not different when treated with an antibiotic or placebo. Hazir et al. Clin Infect Dis. Feb 2011

26 Rational use of antibiotics More restrictive use Where there is need But Also an issue of access Not at least in low-income countries

27 Adapted from Källander 2005 Access vs. Excess

28 Access Will increased access per se lead to better health outcomes? What about quality? WHO/TDR, A. Crump

29 R&D for new antibiotics Desperate need for new classes of antibiotics Better diagnostic methods rapid diagnostic tests Vaccines

30 Simulation studies: Most lives saved from reducing disease burden accrue to Africa, while other regions benefit from reducing overuse

31 Issues Difficult to introduce a new diagnostic in a population that self-treats unless the sensitivity is high enough (~95%) to ensure that the overall number of individual lives saved is positive The benefit of any diagnostic test for severe ALRI depends on access to effective hospital care.

32 Study conclusion - diagnostics ALRI contributes annually to the deaths of >2 million children aged <5 years, 75% of whom were in Africa and southeast Asia A new diagnostic test for bacterial ALRI with at least 95% sensitivity, 85% specificity and minimal infrastructure requirements could significantly improve global efforts to control ALRI, saving at least 405,000 children s lives every year.

33 How good are dengue diagnostic tests? Test Claimed accuracy (%) Sens Spec WHO Evaluation (%) Sens Spec Core Diazyme NS NS GlobaleMed 80 >99 Minerva NS NS PanBio Standard Tulip Blacksell et al 2004

34 Antimalarial prescriptions for febrile patients Patients presenting to outpatient departments in northeast Tanzania with varying level of malaria transmission 2,425 Patients for whom a malaria test was requested were randomised to microscopy or rapid tests Outcome: proportion of malaria negative patients prescribed Antimalarial drugs Microscopy N = 1204 Rapid test N = (14%) (86%) (16%) (84%) Antimalarials prescribed 98% 51% 99% 54% Reyburn et al BMJ 2007

35 Currently 37 sites in 19 countries 24 sites in Africa 9 sites in Asia 1 site in Oceania Over 2,000,000 people under surveillance

36 Prospective monitoring of demographic and health events Intervention trials (randomised) Capturing episodes of disease and hospital admission Verbal autopsy for cause of death Measure characteristics of environment or household members (e.g. SES, vaccines, HIV, nutrition) Health and Demographic Surveillance System (HDSS)

37 INDEPTH cross-site research - 1 Mortality levels, patterns, and trends Causes of death in developing countries Model life tables Malaria transmission and mortality Health equity studies Migration and urbanization Sexual and Reproductive Health

38 INDEPTH cross-site research - 2 NCD risk factor studies in Asia Adult health and Aging Climate Change and Health Intervention trials platform Effects of ART scale-up on mortality and health systems Phase IV Effectiveness and Safety Studies of antimalarias (INESS) Antibiotic resistance

39 Surveillance in Low-Income Countries Don t let the best be the enemy of the good! Sentinel surveillance Work with available structures Few pathogens Start!

40 Strategies for the management of Antibiotic Resistance Surveillance Monitor: Resistance patterns Antibiotic use Decrease the need for antibiotics Reduce disease incidence prevent spread of bacteria Use antibiotics properly Improve diagnostics and use Non medical usage Environment, food, plants etc. Coordinate national activities Knowledge education, information research International collaboration

41 Health systems perspective

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