WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR)
Critically Important Antimicrobials for Human Medicine 2nd Revision
Department of Food Safety and Zoonoses
WHO Library Cataloguing-in-Publication Data Critically important antimicrobials for human medicine - 2nd rev. 1.Anti-infective agents - classification. 2.Anti-infective agents adverse effects. 3.Drug resistance, microbial - drug effects. 4.Risk management. 5.Humans. I.World Health Organization. ISBN 978 92 4 150143 9 (NLM classification: QV 250)
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CONTENTS
1. 2. 3. 4. 5.
History of the current document..................................................1 What should the list be used for?.................................................1 What should the list NOT be used for?.........................................2 The criteria....................................................................................2 Interpretation of categorization ...................................................3 Table 1. Listing and categorization of antimicrobials used in human medicine...........................................................................4
6.
Prioritization within the Critically Important category...............11 Table 2. Prioritization of antimicrobials categorized as Critically Important in human medicine....................................................13
7.
The top three Critically Important Antimicrobials......................18
1. History of the current document The 1st WHO Expert Meeting on Critically Important Antimicrobials (CIA) for Human Health was held in Canberra, Australia, in 2005. During this meeting, participants considered the list of all antimicrobial classes used in human medicine and categorized antimicrobials into three groups of critically important, highly important, and important based on criteria developed. The 2nd WHO Expert Meeting on Critically Important Antimicrobials for Human Health was held in Copenhagen, Denmark, in May 2007. In this meeting, participants reviewed the two criteria and re-examined the categorization of all human antibacterial classes in light of new drug development and scientific information since 2005. Participants were also requested to prioritize agents within the critically important category in order to allow allocation of resources on the agents for which management of the risks from antimicrobial resistance are needed most urgently. The 1st AGISAR meeting held in Copenhagen, 2009 was a follow-up of these two previous expert consultations. Experts from the meeting reviewed the Copenhagen 2007 list of CIA (1st revision of the CIA list) and came up with the 2nd revision of the WHO list of critically important antimicrobials for human medicine, taking into account new scientific information and new drugs.
2. What should the list be used for? The list of Critically Important Antimicrobials can be used as a reference to help formulate and prioritize risk assessment and risk management strategies for containing antimicrobial resistance due to non-human antimicrobial use. Specific examples include: • Prioritization of the antimicrobials characterized as critically important for most urgent development of risk management strategies in order to preserve their effectiveness in human medicine. • Elevating the categorization of regions/countries where it is warranted specific antimicrobials in
• Designing antimicrobial susceptibility testing platforms for use in national programmes to monitor antimicrobial resistance
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• Informing national policies related to antimicrobial resistance • Developing appropriate new drugs and vaccines that will preserve critically important antimicrobial agents
3. What should the list NOT be used for? • As the sole source of information for developing risk management strategies. • As the sole source of treatment guidelines for either animals or humans. • To minimize the importance of other critically important antimicrobials in the same category.
4. The criteria Criterion 1: Antimicrobial agent is used as sole therapy or one of few alternatives to treat serious human disease. Explanation: It is self-evident that antimicrobials that are the sole or one of few alternatives for treatment of serious infectious diseases in humans have an important place in human medicine. Serious disease refers to those illnesses which, if left untreated, are likely to result in irreversible morbidity or mortality. Seriousness of disease may relate to the site of infection or the host (e.g. pneumonia, meningitis). Multidrug resistance alone may or may not influence patient outcomes. For instance, multidrug resistance in S. aureus limits options in the treatment of pneumonia, but incision and drainage alone appears effective without antimicrobials in the treatment of skin abscesses. Therefore drug resistance does not influence the treatment of patient outcomes in skin abscesses. It is of prime importance that the utility of such antibacterial agents should be preserved, as loss of efficacy in these drugs due to emergence of resistance would have an important impact on human health. Participants included in the Comments section of the table examples of the diseases for which the given antibacterial (or class of selected agents within a class) was considered one of the sole or limited therapies for specific infection(s). This criterion does not consider the likelihood that such pathogens may transmit, or have been proven to transmit, from non-human sources to humans.
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Criterion 2: Antimicrobial agent is used to treat diseases caused by either: (1) organisms that may be transmitted via non-human sources or (2) diseases causes by organisms that may acquire resistance genes from non-human sources. Explanation: Antimicrobial agents used to treat diseases caused by bacteria that may be transmitted to man from non-human sources are considered of higher importance, because these are most amenable to risk-management strategies related to non-human antimicrobial use. The organisms that cause disease need not be drug-resistant at the present time, but the potential for transmission shows the potential path for transmission of resistance now or in the future. The evidence for a link between non-human sources and the potential to cause human disease is greatest for certain bacteria (e.g. S. aureus, Enterococcus spp., E. coli, Campylobacter spp. and Salmonella spp.). Commensal organisms from non-human sources (animals, water, food or the environment) also may transmit resistance determinants to human pathogens and the commensals may themselves be pathogenic in immunosuppressed hosts. The Comments section of the table includes examples of the bacterial genera or species of concern. It is important to note that transmission of such organisms or their genes need not be demonstrated, the potential for such transmission remains.
5. Interpretation of categorization Critically Important Those antimicrobials which meet both criteria 1 and 2. Highly Important Those antimicrobials those which meet either criterion 1 or 2. Important Those antimicrobials those which meet neither criterion 1 nor 2. The list below is meant to show examples of members of each class of drugs, and is not meant to be inclusive of all drugs. Not all drugs listed in a given class have necessarily been proven safe and effective for the diseases listed. Comments were included in the list table when it was recognized that regional factors could affect the ranking, but these comments were not meant to be exhaustive and other regional factors could be relevant.
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Table 1. Listing and categorization of antimicrobials used in human medicine. CRITICALLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments Aminoglycosides amikacin arbekacin gentamicin netilmicin tobramycin streptomycin Yes Yes (Criterion 1) Limited therapy as part of treatment of enterococcal endocarditis and Multi-Drug Resistant (MDR) tuberculosis. (Criterion 2) May result from transmission of Enterococcus spp., Enterobacteriaceae (including Escherichia coli) and Mycobacterium spp. from non-human sources. (Criterion 1) Limited therapy as part of therapy of mycobacterial diseases including tuberculosis and single drug therapy may select for resistance. (Criterion 2) May result from transmission of Mycobacterium spp. from non-human sources. (Criterion 1) Limited therapy for infections due to MDR Enterobacteriaceae. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources.
Ansamycins rifabutin rifampin rifaximin
Yes
Yes
Carbapenems and other penems doripenem ertapenem faropenem imipenem meropenem Cephalosporins (3rd and 4th generation) cefepime cefixime cefoperazone cefoperazone/sulbactam cefoselis cefotaxime cefpirome cefpodoxime ceftazidime ceftizoxime ceftobiprole ceftriaxone
Yes
Yes
Yes
Yes
(Criterion 1) Limited therapy for acute bacterial meningitis and disease due to Salmonella in children. Additionally, 4th generation cephalosporins provide limited therapy for empirical treatment of neutropenic patients with persistent fever. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources.
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CRITICALLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments Glycopeptides teicoplanin vancomycin Yes Yes (Criterion 1) Limited therapy for infections due to MDR MRSA and MDR Enterococcus spp. (Criterion 2) May result from transmission of Enterococcus spp. And MRSA from non-human sources. (Criterion 1) Limited therapy for infections due to MRSA. (Criterion 2) May result from transmission of MRSA from non-human sources. (Criterion 1) Limited therapy for infections due to MDR MRSA. (Criterion 2) May result from transmission of Enterococcus spp. and MRSA from nonhuman sources. Macrolides and ketolides azithromycin clarithromycin erythromycin midecamycin roxithromycin spiramycin telithromycin Oxazolidinones Linezolid Yes Yes (Criterion 1) Limited therapy for Legionella, Campylobacter and MDR Salmonella infections. (Criterion 2) May result from transmission of Campylobacter spp. and Salmonella from non-human sources.
Glycylcyclines tigecycline
Yes
Yes
Lipopeptides daptomycin
Yes
Yes
Yes
Yes
(Criterion 1) Limited therapy for infections due to MDR MRSA and MDR Enterococcus spp. (Criterion 2) May result from transmission of Enterococcus spp. and MRSA from nonhuman sources.
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CRITICALLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments Penicillins (natural, aminopenicillins and antipseudomonal) amoxicillin amoxicillin/clavulanate ampicillin ampicillin/sulbactam azlocillin carbenicillin mezlocillin penicillin G penicillin V piperacillin piperacillin/tazobactam ticarcillin ticarcillin/clavulanate Quinolones cinoxacin ciprofloxacin enoxacin gatifloxacin gemifloxacin levofloxacin lomefloxacin moxifloxacin nalidixic acid norfloxacin ofloxacin pipemidic acid sparfloxacin Streptogramins quinupristin/dalfopristin, pristinamycin Yes Yes (Criterion 1) Limited therapy for syphilis (natural penicillins) Listeria, Enterococcus spp. (aminopenicillins) and MDR Pseudomonas spp. (antipseudomonal). (Criterion 2) May result from transmission of Enterococcus spp., Enterobacteriaceae including E. coli as well as Pseudomonas aeruginosa from non-human sources.
Yes
Yes
(Criterion 1) Limited therapy for Campylobacter spp., invasive disease due to Salmonella spp. and MDR Shigella spp. infections. (Criterion 2) May result from transmission of Campylobacter spp. and Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources.
Yes
Yes
(Criterion 1) Limited therapy for MDR Enterococcus faecium and MRSA infections. (Criterion 2) May result from transmission of Enterococcus spp. and MRSA from nonhuman sources.
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CRITICALLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments Tetracyclines chlortetracycline doxycycline minocycline oxytetracycline tetracycline Drugs used solely to treat tuberculosis or other mycobacterial diseases cycloserine ethambutol ethionamide isoniazid para-aminosalicylic acid pyrazinamide Yes Yes (Criterion 1) Limited therapy for infections due to Brucella, Chlamydia spp. and Rickettsia spp. (Criterion 2) Transmission of Brucella spp. from non-human sources. Yes Yes (Criterion 1) Limited therapy for tuberculosis and other Mycobacterium spp. disease and for many of these drugs, single drug therapy may select for resistance. (Criterion 2) May result from transmission of Mycobacterium spp. from non-human sources.
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HIGHLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments No* Yes (Criterion 1*) In certain geographic settings, Amdinopenicillins criterion 1 may be met: the class may be mecillinam one of limited therapies for infections with MDR Shigella spp. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli from non-human sources. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli from non-human sources. (Criterion 2) May result from transmission of Enterococcus spp., and Enterobacteriaceae including E. coli and Salmonella from non-human sources. (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for acute bacterial meningitis, typhoid and non-typhoid fever and respiratory infections. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli and Salmonella from non-human sources. (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for sepsis in children. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli from non-human sources.
Aminocyclitols spectinomycin Aminoglycosides (Other) kanamycin neomycin Amphenicols chloramphenicol thiamphenicol
No
Yes
No
Yes
No*
Yes
Cephalosporins (1st and 2nd generation) cefaclor cefamandole cefazolin cefuroxime cephalexin cephalothin cephradine loracarbef
No*
Yes
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Drug name Cephamycins cefotetan cefoxitin
HIGHLY IMPORTANT ANTIMICROBIALS C1 C2 Comments No* Yes (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for sepsis in children. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli from non-human sources. (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for infections with MRSA. (Criterion 2) May result from transmission of MRSA from non-human sources. (Criterion 2) May result from transmission of Enterobacteriaceae including E. coli from non-human sources. (Criterion 2) May result from transmission of MRSA from non-human sources. (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for staphylococcal infections (S. aureus). (Criterion 2) May result from transmission of S. aureus including MRSA from nonhuman sources. (Criterion 2) May result from transmission of S. aureus including MRSA from nonhuman sources. (Criterion 1) Limited therapy for infections with MDR Enterobacteriaceae (e.g. Klebsiella spp., E. coli, Acinetobacter, Pseudomonas spp.). (Criterion 1) Limited therapy for leprosy.
Fusidic acid
No*
Yes
Monobactams aztreonam Pseudomonic acids Mupirocin Penicillins (Antistaphylococcal) cloxacilllin dicloxacillin flucloxacillin oxacillin nafcillin Pleuromutilins retapamulin Polymyxins colistin polymyxin B
No
Yes
No No*
Yes Yes
No
Yes
Yes
No
Riminofenazines Clofazimine
Yes
No
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HIGHLY IMPORTANT ANTIMICROBIALS Drug name C1 C2 Comments No* Yes (Criterion 1*) In certain geographic settings, Sulfonamides, DHFR criterion 1 may be met: the class may be inhibitors and one of limited therapies for acute bacterial combinations* meningitis, systemic non-typhoidal para-aminobenzoic acid salmonella infections and other infections. pyrimethamine sulfadiazine (Criterion 2) May result from transmission sulfamethoxazole of Enterobacteriaceae including E. coli sulfapyridine from non-human sources. sulfisoxazole trimethoprim Yes No (Criterion 1) Limited therapy for leprosy. Sulfones apsone
Drug name Cyclic polypeptides bacitracin Cyclic ethers fosfomycin
IMPORTANT ANTIMICROBIALS C1 C2 Comments No No No* No (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for Shiga-toxin producing E. coli O157.
Lincosamides clindamycin lincomycin Nitrofurantoins furazolidone nitrofurantoin Nitroimidazoles metronidazole tinidazole
No
No
No No*†
No (Criterion 1*) In certain geographic settings, criterion 1 may be met: the class may be one of limited therapies for anaerobic infections including C. difficile. † Evaluation based on its use as an antimicrobial agent.
No
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6. Prioritization within the Critically Important category Given the mandate to prioritize agents within the Critically Important category, the Copenhagen panel (2007) focused on the two criteria developed by the Canberra panel (2005) to prioritize agents within the critically important category. The list was re-examined in the 1st AGISAR meeting (Copenhagen, 2009). Focusing criterion 1: Sole therapy or one of few alternatives to treat serious human disease • Application 1.1 – High absolute number of people affected by diseases for which the antimicrobial is the sole or one of few alternatives to treat serious human disease. • Application 1.2 – High frequency of use of the antimicrobial for any indication in human medicine, since usage may favour selection of resistance. Explanation: In order to apply criterion 1 in a focused manner, the panel developed two applications, both of which related to volume of antimicrobial usage. Increased volume of usage directly relates to development of resistance and therefore poses a greater threat to the utility as sole therapies. Furthermore, humans receiving antimicrobials for any indication have a greater susceptibility to acquiring infection by a foodborne pathogen resistant to those antimicrobial agents. Focusing criterion 2: Antibacterial used to treat diseases caused by organisms that may be transmitted via non-human sources or diseases causes by organisms that may acquire resistance genes from non-human sources. • Application 2.1 – Greater degree of confidence that there are non-human sources that result in transmission of bacteria (Campylobacter spp.) or their resistance genes to humans (high for Salmonella spp., Escherichia coli and Enterococcus spp.). Explanation: In order to apply criterion 2 in a focused manner, the panel developed one application. Risk-management strategies are most urgently
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needed in situations where evidence suggests that transmission from nonhuman sources is already occurring.
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Table 2. Prioritization of antimicrobials categorized as Critically Important in human medicine PRIORITIZATION OF CRITICALLY IMPORTANT ANTIBIOTICS Drug name 1.1 1.2 2.1 Comments No No Yes (Application 2.1) Transmission of Aminoglycosides Enterococcus spp., amikacin Enterobacteriaceae (including arbekacin Escherichia coli) and gentamicin Mycobacterium spp. from nonnetilmicin human sources. streptomycin tobramicina Yes Yes No (Application 1.1) High absolute Ansamycins number of people affected by all rifabutin diseases for which the rifampin antimicrobial is the sole/one of few Rifaximin therapies available. (Application 1.2) High frequency of any use of the antimicrobial in human medicine regardless of indication given that usage for any reason may result in selection pressure for resistance. (Application 1.1) High absolute number of people affected by all diseases for which the antimicrobial is the sole/one of few therapies available. (Application 2.1) Transmission of Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources.
Carbapenems and other penems doripenem ertapenem faropenem imipenem meropenem
Yes
No
Yes
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PRIORITIZATION OF CRITICALLY IMPORTANT ANTIBIOTICS Drug name 1.1 1.2 2.1 Comments Yes Yes Yes (Application 1.1) High absolute Cephalosporins (3rd number of people affected by all and 4th generation) diseases for which the cefepime antimicrobial is the sole/one of few cefixime therapies available. cefoperazone cefoperazone/sulbactam (Application 1.2) High frequency cefoselis of any use of the antimicrobial in cefotaxime human medicine regardless of cefpirome indication given that usage for any cefpodoxime reason may result in selection ceftazidime pressure for resistance. ceftizoxime ceftobiprole (Application 2.1) Transmission of ceftriaxone Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources Yes No No (Application 1.1) High absolute Glycopeptides number of people affected by all teicoplanin diseases for which the vancomycin antimicrobial is the sole/one of few therapies available. Yes No Yes (Application 1.1) High absolute Glycylcyclines number of people affected by all tigecycline diseases for which the antimicrobial is the sole/one of few therapies available. (Application 2.1) Transmission of Enterobacteriaceae including E. coli from non-human sources. (Application 1.1) High absolute number of people affected by all diseases for which the antimicrobial is the sole/one of few therapies available.
Lipopeptides daptomycin
Yes
No
No
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PRIORITIZATION OF CRITICALLY IMPORTANT ANTIBIOTICS Drug name 1.1 1.2 2.1 Comments Yes Yes Yes (Application 1.1) High absolute Macrolides and number of people affected by all ketolides diseases for which the azithromycin antimicrobial is the sole/one of few clarithromycin therapies available. erythromycin midecamycin (Application 1.2) High frequency roxithromycin of any use of the antimicrobial in spiramycin human medicine regardless of telithromycin indication given that usage for any reason may result in selection pressure for resistance. (Application 2.1) Transmission of Campylobacter spp. from nonhuman sources. No (Application 1.1) High absolute number of people affected by all diseases for which the antimicrobial is the sole/one of few therapies available. Yes (Application 1.1*) In certain geographic settings, application 1.1 may be met: there may be a high absolute number of people affected by all disease for which the antimicrobial is the sole/one of few therapies available. (Application 1.2) High frequency of any use of the antimicrobial in human medicine regardless of indication given that usage for any reason may result in selection pressure for resistance. (Application 2.1) Transmission of Enterobacteriaceae from nonhuman sources.
Oxazolidinones Linezolid
Yes
No
Penicillins (natural, aminopenicillins and antipseudomonal) amoxicillin amoxicillin/clavulanate ampicillin ampicillin/sulbactam azlocillin carbenicillin mezlocillin penicillin G penicillin V piperacillin piperacillin/tazobactam ticarcillin ticarcillin/clavulanate
No*
Yes
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PRIORITIZATION OF CRITICALLY IMPORTANT ANTIBIOTICS Drug name 1.1 1.2 2.1 Comments Yes Yes Yes (Application 1.1) High absolute Quinolones number of people affected by all diseases for which the antimicrobial is the sole/one of few therapies available. (Application 1.2) High frequency of any use of the antimicrobial in human medicine regardless of indication given that usage for any reason may result in selection pressure for resistance. (Application 2.1) Transmission of Campylobacter spp. and Enterobacteriaceae including E. coli and Salmonella spp. from non-human sources (Application 1.1) High absolute number of people affected by all diseases for which the antimicrobial is the sole/one of few therapies available. (Application 1.2) High frequency of any use of the antimicrobial in human medicine regardless of indication given that usage for any reason may result in selection pressure for resistance. (Application 2.1) Transmission of Enterobacteriaceae including E. coli from non-human sources.
Streptogramins quinupristin/dalfopristin, pristinamycin
Yes
No
No
Tetracyclines chlortetracycline doxycycline minocycline oxytetracycline tetracycline
No
Yes
Yes
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PRIORITIZATION OF CRITICALLY IMPORTANT ANTIBIOTICS Drug name 1.1 1.2 2.1 Comments Yes Yes No (Application 1.1) High absolute Drugs used solely to number of people affected by all treat tuberculosis or diseases for which the other mycobacterial antimicrobial is the sole/one of few diseases therapies available. cycloserine ethambutol (Application 1.2) High frequency ethionamide of any use of the antimicrobial in isoniazid human medicine regardless of para-aminosalicylic acid indication given that usage for any pyrazinamide reason may result in selection pressure for resistance.
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7. The top three Critically Important Antimicrobials Those drugs categorized as highest priority met all three applications (1.1, 1.2 and 2.1): Quinolones, 3rd and 4th generation cephalosporins and Macrolides. Quinolones are widely used in food animal production and are known to select for quinolone-resistant Salmonella spp. in animals. At the same time, quinolones are one of few available therapies for serious Salmonella infections, particularly in adults. Given the high incidence of human disease due to Salmonella spp., the absolute number of serious cases is substantial. 3rd and 4th generation cephalosporins are widely used in food animal production and are known to select for cephalosporin-resistant Salmonella spp. in animals. At the same time, 3rd and 4th generation cephalosporins are one of few available therapies for serious Salmonella infections, particularly in children. Given the high incidence of human disease due to Salmonella spp., the absolute number of serious cases is substantial. Macrolides are widely used in food animal production and are known to select for macrolide-resistant Campylobacter spp. in animals. At the same time, macrolides are one of few available therapies for serious campylobacter infections, particularly in children, in whom quinolones are not recommended for treatment. Given the high incidence of human disease due to Campylobacter spp., the absolute number of serious cases is substantial.
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