Containing Antimicrobial Resistance

WHO 10 Policy Perspectives on Medicines Containing antimicrobial resistance

April 2005 World Health Organization Geneva

The problem of antimicrobial resistance In many countries, antimicrobials are bought directly from drug outlets without a prescription or advice from ntimicrobial resistance (AMR) is one of the world’s a trained health professional. Amost serious public health problems. Many of the microbes (bacteria, viruses, protozoa) that cause infectious disease no longer respond to common Figure 1 Correlation between penicillin-resistant antimicrobial drugs (antibacterial drugs including antibiotics, antiviral and antiprotozoal drugs). The (non-susceptible) pneumococci and out-patient problem is so serious that unless concerted action is antibiotic use (showing bands with 95% taken worldwide, we run the risk of returning to the confidence intervals) pre-antibiotic era when many more children than now died of infectious diseases and major surgery was 60 impossible due to the risk of infection. The major in- Taiwan, China fectious diseases kill over 11 million people per year. 50 Spain Box 1 shows some AMR prevalence rates, which can vary widely between and within countries, and over France time. 40 USA Greece 30 Portugal Box 1 AMR global prevalence rates 20 Canada Malaria Ireland Luxembourg Iceland enicillin-resistant S.pneumoniae (%) enicillin-resistant S.pneumoniae • chloroquine resistance in 81/92 countries P Austria Belgium Italy Tuberculosis (TB) 10 Germany UK Australia Sweden • 0–17% primary multi-drug resistance Denmark Finland Netherlands Norway HIV/AIDS 0 • 0–25% primary resistance to at least one 0 10 20 30 40 antiretroviral drug Total antibiotic use (DDD/1000 population/day) Gonorrhoea • 5–98% penicillin resistance in Neisseria gonorrhoeae Source: Albrich WC, Monnet DL and Harbarth S, Emerg Infect Dis.; 2004; 10(3):514–7 Pneumonia and bacterial meningitis • 0–70% penicillin resistance in Streptococcus Doctors’ response to AMR has been to switch patients pneumoniae from older antibiotics to newer ones, but new devel- Diarrhoea: shigellosis opment of these is declining as the pharmaceutical • 10–90% ampicillin resistance, industry has shifted from antibiotics to developing 5–95% cotrimoxazole resistance other medicines with potentially larger markets (e.g. Hospital infections for chronic non-infectious illness). Even if new antibi- • 0–70% resistance of Staphylococcus aureus to all penicillins and cephalosporins otics are developed, resistance to them would also develop; so prudent use of antibiotics is essential to maintain their effectiveness for future generations. Source: WHO country data, 2000–03 Serious clinical and financial consequences result Emergence of AMR is a natural phenomenon that from AMR. Morbidity and mortality are increased by follows use of antimicrobials but it is being acceler- delays in administering effective treatment for infec- ated by inappropriate antimicrobial use. Higher tions caused by resistant microorganisms. Prolonged consumption is associated with higher resistance illness and hospitalisation are costly and the use of levels (Fig.1). Estimates suggest that perhaps half drugs other than first-line drugs may increase costs of all antibiotic consumption may be unnecessary. 100-fold (Fig. 2) making them unaffordable for many

Page 1: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance well-established methods exist. Aggregate antimicro- Figure 2 Cost ratio of alternative drugs to first- bial drug consumption data can be used to identify the most expensive and highly used antimicrobials, line antimicrobials for common acute infections or to compare actual consumption with expected consumption (from morbidity data). Anatomical Therapeutic Classification (ATC) / Defined Daily Dose (DDD) methodology can be used to compare 80 70 antimicrobial consumption across institutions, regions 60 and countries. Indicators can be used to investigate

50 Alternative drugs antimicrobial use in primary health care, e.g.: 40 30 •% patients prescribed antibiotics; 4th 20 •% of upper respiratory tract cases (usually viral) 3rd 10 Cost ratio to first-line drug 2nd treated with antibiotics; 0 Gonorrhoea Malaria Shigellosis Pneumonia •% of diarrhoeal cases (usually viral) treated with antibiotics; 0.03 0.05 0.06 0.14 Cost per patient with first-line drug (US$) •% cases with infections treated in accordance with clinical guidelines. Source: Adapted from WHO Model Formulary, WHO clinical guidelines and Man- agement Sciences for Health’s 2004 International Drug Price Indicator Guide Focused antimicrobial use evaluation (drug utilization review) can identify problems concerning the use of specific antimicrobials or the treatment of specific governments and patients especially in developing infections, particularly in hospitals. countries. Reasons underlying inappropriate use should be Measuring the problem through investigated intermittently and include diagnostic in- security, prescriber knowledge and habit, unrestricted surveillance availability of antimicrobials, overwork, inappropriate Surveillance is critical to containing the problem of promotion of antimicrobials, profit motives and fear of AMR and requires monitoring over time the magni- litigation. Understanding such reasons allows appro- tude and trends in AMR and antimicrobial use and priate, effective corrective strategies to be chosen. using the data to design interventions and measure their impact. Core national strategies to contain AMR Epidemiological surveillance of antimicrobial Core national strategies to contain AMR are summa- resistance rised below, based on WHO’s Global Strategy for Containment of AMR and Promoting Rational Use of Resistance varies widely with geographical location, Medicines: Core Components. type of community and level of health facility. There- fore local surveillance data should be used to guide clinical management and update clinical guidelines, 1. Mandated multidisciplinary national task educate prescribers and guide infection control force to coordinate policies and strategies to policies. Data should distinguish between hospital contain AMR nosocomial and community-acquired infections and should exclude duplicate isolates from the same Many factors contribute to how antimicrobials patient. are used. Therefore, a multidisciplinary approach is needed to develop, implement and evaluate inter- A national antimicrobial surveillance system should ventions to promote optimal use of antimicrobials and consist of: improve infection control programmes. • national reference microbiology laboratory facilities to coordinate epidemiologically sound surveillance An adequately resourced task force is needed to of AMR in common pathogens in the community, coordinate policy and strategies at national level, in hospitals and other health care facilities; both the public and private health sectors. The form •a network of laboratories, all with adequate inter- of the task force may vary, but it should always involve nal and external quality assurance, that regularly government (ministry of health), the national refer- collect and report relevant resistance data and pro- ence microbiology laboratory, the health professions vide quality microbiological diagnostic services. (doctors, pharmacists, nurses), academia, the national drug regulatory authority, pharmaceutical industry, Surveillance of antimicrobial use consumer groups and NGOs involved in health care. The impact on AMR and use is better if multiple inter- Antimicrobial use should be monitored in terms of ventions are implemented in a coordinated way. the type and degree of irrational use and several Single interventions are likely to have little impact.

Page 2: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance The task force should liaise with all the stakeholders •malaria through the use of bed nets impregnated involved in non-human use (including the ministry of with insecticide; agriculture) to develop a national containment pro- • sexually transmitted infections through the use of gramme (see section 10). In addition, the task force condoms; should liaise with those responsible for implementing • certain infectious diseases through routine child- and monitoring population-wide infection control hood vaccination (diptheria, measles, pertussis, programmes. Such programmes include: Haemohilus influenzae, pneumococcus) and epidemic vaccination (meningitis, typhoid); • safe water and sanitation; • HIV/AIDS and hepatitis B and C through the avoid- • immunization – if people do not contract infec- ance of injections (unless oral medicines cannot tious diseases they do not need antibiotics; be used, in which case a sterile needle and • public education on hygiene and prevention, e.g. syringe must be used). hand washing, bed nets, condoms; • TB, HIV and malaria control programmes; Governments have a responsibility to provide un- •cross-infection control in hospitals. biased information to the community. They can run targeted public education campaigns, taking into Knowing how well these programmes are being account cultural beliefs and the influence of social implemented is essential in deciding where to focus factors. The important message is that antimicrobials efforts to contain resistance. should only be used to treat certain specific diseases; their use in other contexts is ineffective and counter- 2. National reference microbiology laboratory productive, since they can accelerate the emergence coordinating a network of reliable diagnostic of AMR. Education on preventive measures can be introduced into school health education or into adult microbiology laboratories education, e.g. literacy and antenatal programmes. Epidemiologically sound surveillance of AMR in key pathogens, using standardised microbiological 4. Provider education on diagnosis and methods, can be developed on the basis of existing management of common infections, anti- laboratories undertaking diagnostic services and surveillance. To ensure reliable, good quality, epi- microbial use, containment of AMR, disease demiologically sound data, a coordinating national prevention, infection control reference laboratory is needed. This laboratory should All providers, including doctors, pharmacists, nurses, establish standardised methods, provide external paramedical workers, and drug sellers, should be quality assurance for all the participating laborato- taught about the issues surrounding AMR. Topics ries and take part in external quality assurance. include accurate diagnosis and management of Many antimicrobials are prescribed unnecessarily common infections, antimicrobial use, infection con- because prescribers are unsure of the diagnosis. trol and disease prevention. This education should be Diagnostic procedures help to ensure that anti- provided through: microbials are prescribed only when needed. For ex- • undergraduate training for pre-service students; ample, using malaria blood smears in hospitals helps • postgraduate training and continuing professional to ensure that patients with malaria are treated with development (CPD) programmes for all cadres of antimalarials and not with unnecessary antibiotics. in-service personnel including intern doctors. Sputum microscopy for TB helps to ensure that TB Unfortunately, relevant AMR topics are often omitted patients are treated with anti-TB drugs and not with in education programmes, opportunities for CPD are inappropriate antibiotics. Quality control for diagnos- limited, and CPD is not a compulsory licensure require- tic procedures, including microscopy, is vital, or false ment. Also, CPD activities are often heavily depend- diagnoses will be made or true diagnoses missed, and ent upon pharmaceutical companies, which may be prescribers will not trust the laboratory. more interested in promoting their own antimicrobial sales. Governments should therefore support finan- 3. Public education on preventing infection and cially efforts by universities and national professional reducing transmission associations to give independent CPD covering AMR issues; promote the provision of unbiased infor- People should have the skills and knowledge to make mation to prescribers; and regulate drug promotional informed decisions about how to prevent infection activities. and reduce transmission of infectious diseases through simple, cheap and effective measures. Such meas- 5. Development, updating and use of essential ures include prevention of: medicines lists and clinical guidelines • diarrhoeal disease through hand washing, using safe water sources and containers, boiling unsafe Evidence-based, regularly updated essential medi- water and using latrines; cines lists and clinical guidelines, for each level of care,

Page 3: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance are vital for promoting rational use of medicines. • active surveillance of infections and AMR in order Antimicrobial guidelines and treatment algorithms to detect, and manage, outbreaks of nosocomial for infectious diseases may further aid rational use of (hospital-acquired) infection; this requires regular antimicrobials. If there are reliable data, local AMR collation and assessment of resistance data from trends for infectious diseases should be considered a microbiology laboratory; when deciding upon inclusion of each antimicrobial. •investigation and management of outbreaks or Governments should ensure that: clusters of susceptible and resistant infections; • public sector medicine procurement is based on •interventions to prevent infections, including health the national medicines list; worker and patient education; • all training institutions include the national clinical •development and implementation of policies guidelines in their training programmes; and procedures to prevent the transmission of • public sector reimbursement policies are based infections (Box 2). on the national essential medicines list or clinical guidelines. 7. Drug and Therapeutics Committees and When possible the shortest effective course of anti- antimicrobial subcommittees to promote the microbial therapy (as indicated by the evidence) safe, effective use of antimicrobials should be adopted in the guidelines. Shorter courses of antimicrobial therapy are associated with the de- Drug and Therapeutics Committees (DTCs) and their velopment of less resistance than longer courses. The antimicrobial sub-committees have been successful use of fixed-dose combinations, particularly for HIV, in industrialised countries in promoting more rational, TB and malaria is associated with increased patient cost-effective use of medicines and antimicrobials adherence and will be less likely to stimulate AMR in hospitals (Box 3). Governments may encourage emergence as compared to single-drug treatments. hospitals and local health authorities to have DTCs by making it an accreditation requirement. Mem- bers should represent all the major specialities, the 6. Infection Control Committees to implement pharmacy and the administration, and declare any infection control programmes in hospitals potential conflict of interest (such as shares in a whole- saler supplying the hospital). A clinical microbiologist Hospitals and nursing homes are breeding grounds and infectious disease specialist should sit on both the for the development and spread of AMR due to the antimicrobial subcommittee (or DTC) and the ICC. close proximity of patients who have infections and are receiving antimicrobials. An Infection Control Committee (ICC) is responsible for administering 8. Restriction of availability of antimicrobials infection control programmes in hospitals. The ICC should include, as a minimum, an infection control This reduces misuse and may be done in two ways. nurse in small hospitals and a clinical microbiologist, infectious disease specialist and surgeon in larger (1) Restricting antimicrobial availability to prescription-only hospitals. The ICC should liaise closely with the Drug from licensed outlets and Therapeutics Committee (DTC) or its antimicrobial Misuse of antimicrobials may be curbed by enforc- sub-committee. An ICC should undertake: ing regulations to limit their availability to licensed

Box 2 Preventing transmission of infections in hospitals

1. Hand washing or alcohol-based rinses by staff between • adequate ventilation; patients and before undertaking any procedures e.g. • cleaning of the wards, operating theatre, laundry, etc.; injections. • provision of adequate water supply and sanitation; 2. Use of barrier precautions, e.g. wearing gloves and gowns • safe food handling; • safe disposal of infectious equipment, e.g. dirty needles; for certain agreed procedures. • safe disposal of infectious body fluids, e.g. sputum. 3. Adequate sterilization and disinfection of supplies and 6. Isolation of infectious patients from other non-infected equipment. patients, e.g. separation of suspected and proven sputum- 4. Use of sterile techniques, together with protocols, for positive TB cases (particularly from HIV-positive patients). medical and nursing procedures, e.g. bladder 7. Visiting policies such as preventing visitors with infections catheterization, administration of injections, insertion of from visiting patients who may be immuno-compromised, intravenous cannulas, use of respirators, sterilization of e.g. patients with AIDS or leukaemia or premature babies. equipment, other surgical procedures. 8. Training of health-care staff in appropriate sterile 5. Maintenance of appropriate disinfection or sanitary control techniques and infection control procedures. of the hospital environment, including:

Page 4: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance testing has indicated resistance to other effective and less expensive antimicrobials. Approval for use in Box 3 Responsibilities of the DTC or each individual patient must be given by the clinical antimicrobial committee microbiologist or the DTC itself. • developing, adapting, or adopting clinical guidelines for infectious diseases and antimicrobial guidelines, using 9. Granting marketing authorisation only to local AMR data if possible; antimicrobials meeting international standards • selecting cost-effective, safe antimicrobials for the formulary, using local AMR data if possible; of quality, safety and efficacy • monitoring antimicrobial consumption and use patterns; Poor quality antimicrobials may result in under-dosage, • developing policies on the use of antimicrobials by level leading to poor patient outcome and increased of prescriber; this includes limiting certain anti- AMR through the selection of resistant organisms. The microbials to use only with approval by the DTC or increasing quantity of counterfeit and substandard senior prescriber; antimicrobials available worldwide requires vigilance • implementing and evaluating strategies to improve by governments, importers, retailers, the pharma- antimicrobial use (including drug use evaluation, and ceutical industry and health professionals. Ensuring liaison with the ICC); quality through enforced regulation, good procure- • providing on-going staff education on antimicrobial use ment practice and post-marketing surveillance is (training and printed materials); essential to containing AMR. • liaising with the ICC with regard to assessing and using local AMR data. 10. Controlling non-human use of antimicrobials outlets upon receipt of a prescription written by a Only about half of all antibiotics are consumed by licensed prescriber. If the availability of all anti- humans. Most of the rest are added to animal feed microbials cannot be controlled by this method, certain ones (e.g. vancomycin for methicillin-resistant Staphylococcus aureus and the newer cephalosporins and fluoroquinolones) should be restricted Box 4 Controlling non-human use of in this way. antimicrobials (2) Classification of antimicrobials by level of prescriber and (1) Surveillance by data collection from manufacturers, distributors based on local conditions including feed mills, pharmacies, veterinarians, farmers, and Classification of antimicrobials is applicable at all animal producers. The data should cover: • AMR in animals; levels of health care. In primary health care facilities • antimicrobial use in food animals for infections, prophylaxis and hospitals without laboratories, it may not be and as growth promoters; possible to distinguish between “restricted” and “very • national import and export of bulk chemicals with potential restricted” and the two categories may be treated antimicrobial use; as one. • levels of antimicrobial agent residues in food from animal sources. Antimicrobials for non-restricted use by any prescriber are safe, effective and reasonably priced, e.g. (2) Reducing and eventually stopping use of all antimicrobial growth promoters in food animals by: amoxicillin, and may be prescribed without approval • banning growth promoters used in human therapeutics, or by senior prescribers or the antimicrobial and infec- known to select for cross-resistance to antimicrobials used in tion control subcommittees. humans, as soon as possible; Restricted antimicrobials may be more expensive • replacing all growth promoters with safer non-antimicrobial alternatives (e.g. improved animal hygiene) as soon as possible. and/or have a wider spectrum of activity, e.g. cef- triaxone or vancomycin. They should only be used for (3) Establishing an effective regulatory and control system for all (1) specific infections known to be sensitive to the antimicrobials used in agriculture: antimicrobial (after culture and susceptibility testing), •registration of all antimicrobial products used for food animals and in agriculture; or (2) empirical emergency treatment of suspected •ensuring that all antimicrobial products used for food animals serious or life-threatening infections pending the and in agriculture are of adequate quality and are result of culture and sensitivity testing. Use of these manufactured according to good manufacturing practices; antimicrobials would require countersignature by a •licensing of manufacturers, distributors, and personnel selling senior physician who has the approval of the DTC for or prescribing any antimicrobial products used for food such an activity. animals or in agriculture. Very restricted antimicrobials are those such as (4) Education of all stakeholders in the agricultural sector on AMR and the appropriate use of antimicrobial products. linezolid or meropenem that should be reserved for life- threatening infections where culture and sensitivity

Page 5: WHO Policy Perspectives on Medicines — Containing antimicrobial resistance WHO/PSM/2005.1 Original: English

(particularly pigs and poultry) for mass treatment a WHO Consultation. Geneva: WHO; 2002 (WHO/CDS/CSR/ against infectious diseases or for growth promotion. EPH/2002.11). Antimicrobials are also added to water to treat fish World Health Organization. Implementing Antimicrobial Drug diseases and sprayed on to food crops to treat dis- Resistance Surveillance and Containment for HIV, Tuberculo- ease (e.g. fire blight in apples). Most antimicrobials sis and Malaria: An Outline for National Programmes. registered for human use are also registered for Geneva: WHO; 2003 (WHO/CDS/RMD/2003.2). animal use but regulation, such as licensing of pre- World Health Organization. Drug and Therapeutics Committees: scribers, dispensers and outlets, is much less stringently A Practical Guide. Geneva: WHO; 2004 (WHO/EDM/PAR/ applied in the agricultural sector. Although the ma- 2004.1). jority of human AMR results from human use, there is All documents available on http://www.who.int/medicines evidence of significant spread of certain resistant bacteria (e.g. salmonella, campylobacter, entero- coccus) from animals to humans. Box 4 lists the major recommendations to control non-human use. Contacts in WHO Regional Offices:

Regional Office for Africa: Dr Jean-Marie Trapsida Conclusion Coordinator, Essential Drugs and Medicines Policy A national programme is needed to undertake sur- Tel: +242 8 39258 E-mail: [email protected] veillance of antimicrobial use and resistance and, Regional Office for the Americas: based on this data, to develop, implement and evalu- Dr Jorge A.Z. Bermudez ate strategies to contain AMR. Critical to success are: Essential Medicines, Vaccines and Health Technologies Tel: +1 202 974 3104 E-mail: [email protected] 1. an adequately funded, mandated, multidisciplinary, Regional Office for the Eastern Mediterranean: national task force to coordinate strategies to Dr Zafar Mirza contain AMR; Regional Adviser, Essential Medicines and Biologicals 2. a national reference microbiology laboratory to Tel: +00 202 276 55 61 E-mail: [email protected] coordinate a network of reliable diagnostic Regional Office for Europe: microbiology laboratories; Mr Kees de Joncheere 3. government investment in the health system Pharmaceuticals infrastructure to ensure the controlled availability Tel: +45 3 917 14 32 E-mail: [email protected] of appropriate antimicrobials, and adequately Regional Office for South-East Asia: trained personnel to prescribe and dispense them. Dr Krisantha Weerasuriya Regional Adviser, Essential Drugs and Medicines Policy Tel: +91 11 2337 0804 (ext 26314) Key Documents E-mail: [email protected] Regional Office for the Western Pacific: World Health Organization. How to Investigate Drug Use in Dr Budiono Santoso Health Facilities: Selected Drug Use Indicators. Geneva: Regional Adviser WHO; 1993 (WHO/DAP/93.1). Tel: +63 2 528 9846 E-mail: [email protected] World Health Organization. WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food: Report of a WHO Consultation. Geneva: Contacts at WHO Headquarters: WHO; 2000 (WHO/CDS/CSR/APH/2000.4). Medicines Policy and Standards World Health Organization. WHO Global Strategy for Contain- Health Technology and Pharmaceuticals Cluster ment of Antimicrobial Resistance. Geneva: WHO; 2001 WHO Headquarters, Geneva, Switzerland: (WHO/CSR/DRS/2001.2). World Health Organization. Surveillance Standards for Antimicro- Dr Hans V. Hogerzeil bial Resistance. Geneva: WHO; 2001 (WHO/CSR/DRS/2001.5). Director, Medicines Policy and Standards Tel: +41 22 791 3528 E-mail: [email protected] World Health Organization. Infection Control Programmes to Control Antimicrobial Resistance. Geneva: WHO; 2001 Dr Clive Ondari (WHO/CSR/DRS/2001.5). Team Coordinator, Policy, Access and Rational Use Tel: +41 22 791 3676 E-mail: [email protected] World Health Organization. Promoting Rational Use of Medi- cines: Core Components. WHO Policy Perspectives on Dr Lembit Rägo Medicines No.5, Geneva: WHO; 2002 (WHO/EDM/2002.3). Team Coordinator, Quality and Safety: Medicines Tel: +41 22 791 4420 E-mail: [email protected] World Health Organization. Monitoring Antimicrobial Usage in Food Animals for the Protection of Human Health: Report of

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