John M. Antoine Andremont. Scott A. Awa Aidara-Kane. for the World Health Organization Advisory Group, Bogotá Meeting on Integrated Surveillance of Antimicrobial Resistance WHO-AGISAR. Yvonne Agerso. Peter Collignon. John Conly. Tran Dang Ninh , Tran Dang Ninh.

Pilar Donado-Godoy. Paula Fedorka-Cray. Heriberto Fernandez. Marcelo Galas. Rebecca Irwin. Beth Karp. Gassan Matar. Patrick McDermott. Scott McEwen. Eric Mitema. Richard Reid-Smith. Morgan Scott. Ruby Singh. Caroline Smith DeWaal. John Stelling. Mark Toleman. Haruo Watanabe.

Gun-Jo Woo. a See Notes section for full list of WHO-AGISAR members. PDF Split View Views. Cite Cite Peter C. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter Clinical Infectious Diseases This issue IDSA Journals Infectious Diseases Books Journals Oxford Academic Enter search term Search.

Abstract Antimicrobial use in food animals selects for antimicrobial resistance in bacteria, which can spread to people. antimicrobials , risk management , animals , antimicrobial resistance , food production. Table 1.

Criteria Used to Categorize Antimicrobials of Importance to Human Health. Criterion 1 C1 : The antimicrobial class is the sole, or one of limited available therapies, to treat serious bacterial infections in people.

It is evident that antimicrobials that are the sole or one of few alternatives for the treatment of serious bacterial infections in humans; therefore, they occupy an important place in human medicine.

Serious infections are likely to result in significant morbidity or mortality if left untreated. Seriousness of disease may relate to the site of infection eg, pneumonia, meningitis or the host eg, infants, immunosuppression. Even though multidrug resistance alone may or may not always influence patient outcomes, in general it is associated with poorer outcomes.

It is of prime importance, then, that the use of such antibacterial agents be preserved, as loss of efficacy in these drugs due to the emergence of resistance would have a significant impact on human health, especially for people with life-threatening infections.

The comments sections of the tables include examples of the diseases for which the given antibacterial agent or class was considered the sole or one of limited therapies. This criterion does not consider the likelihood that these pathogens may be transmitted, or have been transmitted, from nonhuman sources to humans.

Criterion 2 C2 : The antimicrobial class is used to treat infections in people caused by either 1 bacteria that may be transmitted to humans from nonhuman sources, or 2 bacteria that may acquire resistance genes from nonhuman sources.

Antimicrobial agents used to treat diseases caused by bacteria that may be transmitted to humans from nonhuman sources are considered of higher importance because these are most amenable to risk-management strategies related to nonhuman antimicrobial usage.

The organisms that cause disease need not be drug resistant at the present time. However, the potential for transmission shows the path for acquisition of resistance now or in the future. The evidence for a link between nonhuman sources and the potential to cause human disease is greatest for certain bacteria eg, nontyphoidal Salmonella , Campylobacter spp, Escherichia coli , Enterococcus spp, and Staphylococcus aureus.

Commensal organisms from nonhuman sources animals, water, food, or the environment may also transmit resistance determinants to human pathogens; the commensals themselves may also be pathogenic in immunosuppressed hosts. The comments sections of the tables include examples of the bacterial genera or species of concern.

It is important to note that the transmission of such organisms or their genes need not be demonstrated; rather, it is considered sufficient that the potential for such transmission exists. The first 2 prioritization criteria relate to the antimicrobial use volume in humans.

Increased volume of use directly relates to the development of resistance and, therefore, poses a greater threat to their use as sole therapies. Prioritization criterion 2 P2 : High frequency of use of the antimicrobial class for any indication in human medicine, since use may favor selection of resistance.

Furthermore, humans receiving antimicrobials for any indication have a greater susceptibility to acquiring infection by a foodborne pathogen resistant to those antimicrobial agents.

Prioritization criterion 3 P3 : The antimicrobial class is used to treat infections in people for which there is evidence of transmission of resistant bacteria eg, nontyphoidal Salmonella and Campylobacter spp or resistance genes high for E. coli and Enterococcus spp from nonhuman sources.

Risk management strategies are most urgently needed in situations where evidence suggests that the transmission of resistant bacteria or resistance genes from nonhuman sources is already occurring, or has occurred previously. Open in new tab. Table 2. Critically important Antimicrobial classes that meet both C1 and C2 are termed critically important for human medicine.

Highly important Antimicrobial classes that meet either C1 or C2 are termed highly important for human medicine. Important Antimicrobial classes used in humans that meet neither C1 nor C2 are termed important for human medicine. Highest-priority critically important antimicrobials Antimicrobial classes that meet all 3 prioritization criteria P1, P2, and P3 are considered the highest-priority critically important antimicrobials.

Table 3. List and Classification of Antimicrobials Important for Human Medicine. Antimicrobial Class.

Google Scholar Crossref. Search ADS. February May June September Google Scholar OpenURL Placeholder Text. March Google Scholar PubMed. OpenURL Placeholder Text.

April Reducing antimicrobial resistance in the community by restricting prescribing: can it be done. Published by Oxford University Press for the Infectious Diseases Society of America.

All rights reserved. For permissions, e-mail journals. permissions oup. Issue Section:. Download all slides. Supplementary data. Supplementary Data - zip file. Comments 0.

Add comment Close comment form modal. I agree to the terms and conditions. You must accept the terms and conditions. Add comment Cancel.

Submit a comment. Comment title. You have entered an invalid code. Submit Cancel. Thank you for submitting a comment on this article. Your comment will be reviewed and published at the journal's discretion.

Please check for further notifications by email. Views 29, More metrics information. Total Views 29, Email alerts Article activity alert. Advance article alerts.

New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic Increased Antibiotic Resistance in Respiratory Tract Pathogens: PROTEKT US—An Update.

Efficacy of Antimicrobial Therapy for Mycoplasma genitalium Infections. Escherichia coli Sequence Type ST as the Major Cause of Serious Multidrug-Resistant E. coli Infections in the United States. Predicting Antimicrobial Resistance in Invasive Pneumococcal Infections. Related articles in PubMed Therapeutic potential of the medicinal mushroom Ganoderma lucidum against Alzheimer's disease.

Chaenomeles sinensis Thouin Koehne fruit polyphenols alleviate high-fat diet-induced obesity and liver steatosis by improving lipid metabolism in mice. Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6. Treat Obesity to Treat Type 2 Diabetes Mellitus. Citing articles via Web of Science Latest Most Read Most Cited HIV, HIV-specific Factors and Myocardial Disease in Women.

Project NexGen: Developing the Next Generation of COVID Vaccines and Therapeutics to Respond to the Present and Prepare for the Future. Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis. Incident Proteinuria differs by HIV Serostatus among Men with Pre-diabetes: The Multicenter AIDS Cohort Study.

Filling in the Gaps: Updates on Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections. More from Oxford Academic. Clinical Medicine. Infectious Diseases. Medicine and Health. Looking for your next opportunity? Director, Ruth L.

and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine. Assistant Professor. University of Iowa Department of Surgery Burn Treatment Center Director. Sleep Medicine Neurologist. View all jobs. About Clinical Infectious Diseases Editorial Board Author Guidelines Facebook Twitter Purchase Recommend to your Library Advertising and Corporate Services Journals Career Network.

influenzae frequently persist within dense biofilm communities that are thought to provide resistance to host clearance and bactericidal activity of some antibacterial agents [ 4 ].

pyogenes is an important human pathogen that can cause severe, life-threatening, invasive infections, such as soft tissue infection, sepsis, and streptococcal toxic shock syndrome [ 5 ]. pyogenes is generally an extracellular pathogen that can survive and persist within the host by the expression of a broad array of virulence functions directed to circumventing the host immune mechanisms [ 6 ].

It is believed that recurrent tonsillitis is caused by NTHi and S. pyogenes entering cells and escaping from the action of antibacterial agents. International guidelines recommend penicillin as the first-choice antibiotic treatment for acute sore throat suspected to be caused by S.

pyogenes [ 7 ]. However, a recent meta-analysis of clinical studies reported that cephem agents are more effective than penicillin agents [ 8 ] and are effective as short-term therapy [ 9 ]. Therefore, it has become necessary to reconsider the conventional treatment policy based on penicillin.

In Japan, β-lactamase-negative ampicillin-resistant H. influenzae BLNAR is particularly common [ 10 ]. Therefore, tonsillitis that is not cured by initial treatment requires a change of antibacterial agents or the selection of antibacterial agents against bacteria that have invaded the cells.

Levofloxacin LVFX , a broad-spectrum fluoroquinolone with potent activity against Gram-positive bacteria, is currently recommended to treat respiratory tract infections and pneumonia due to S. pneumoniae , one of the most important causative pathogens in community-acquired pneumonia CAP.

Similarly, garenoxacin GRNX is an oral des-fluoro 6 -quinolone with potent antimicrobial activity against common respiratory pathogens [ 11 ]. LVFX and GRNX show similar antimicrobial activities against Gram-negative bacteria.

However, GRNX has higher antimicrobial activity than LVFX against Gram-positive bacteria, including staphylococci, streptococci, and pneumococci [ 12 ].

Additionally, GRNX has higher broad-spectrum antimicrobial activity against anaerobes than LVFX [ 13 ]. These data suggest that GRNX may be an attractive agent for the treatment of CAP.

Clarithromycin CAM exerts its antibacterial activity through its inhibitory effect on protein synthesis and is therefore effective against atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae that do not have cell walls [ 14 ]. It also has antibacterial activity against intracellular parasites such as Legionella and nontuberculous mycobacteria, reflecting its excellent transferability from tissues to cells [ 14 ].

The present study investigated the in vitro antibacterial activity of antibacterial agents against clinical strains of NTHi and S. pyogenes isolated in Japan. In both NTHi and S. pyogenes, one bacterial strain NTHi1 or S. pyogenes 1 was used to confirm the time of cellular invasion. Similarly, the number of S.

Bacterial invasion time. In NTHi isolates, the MICs of GRNX, CDTR-PI, and LVFX were 8-fold lower than those of AMPC and fold lower than those of CAM Table 1. pyogenes isolates, the MICs of GRNX, CDTR-PI, and AMPC were 8-fold lower than those of LVFX and 4-fold lower than those of CAM Table 1.

pyogenes strains into 4 emm types, as shown in Table 1. Treatment with 1 MIC of GRNX, CAM, or LVFX significantly reduced the number of cell-invaded NTHi Fig.

However, no bactericidal effect was observed from treatment with AMPC or CDTR-PI Fig. Effects of antibacterial agents on nontypeable Haemophilus influenzae. Cells invaded by bacteria and then treated with phosphate-buffered saline PBS served as the study control.

However, no bactericidal effect was observed from treatment with AMPC or CDTR-PI a. MIC, minimum inhibitory concentration; NTHi, nontypeable Haemophilus influenzae ; GRNX, garenoxacin; LVFX, levofloxacin; CAM, clarithromycin; AMPC, amoxicillin; CDTR-PI, cefditoren pivoxil; CFU, colony-forming units.

GRNX had the highest bactericidal effect Fig. Treatment with 1 MIC of GRNX, CAM, or LVFX significantly reduced the number of cell-invaded S. pyogenes entering Fig. GRNX had a significantly higher bactericidal effect than CAM and LVFX Fig.

Effects of antibacterial agents on Streptococcus pyogenes. Cells invaded by bacteria and then treated with PBS served as the study control. When 1 MIC of GRNX, CAM, or LVFX was used, each S. However, treatment with AMPC or CDTR-PI showed no bactericidal effect a.

MIC, minimum inhibitory concentration; S. pyogenes , Streptococcus pyogenes ; GRNX, garenoxacin; LVFX, levofloxacin; CAM, clarithromycin; AMPC, amoxicillin; CDTR-PI, cefditoren pivoxil; CFU, colony-forming units.

This study investigated the effects of GRNX, CAM, AMPC, CDTR-PI, and LVFX on the invasion of Detroit cells by NTHi and S. Results showed that NTHi and S. pyogenes invaded Detroit cells.

Nevertheless, these bacteria that invaded cells were eliminated by GRNX, CAM, and LVFX, but not by AMPC and CDTR-PI. Among them, GRNX was the most effective. Fibronectin-binding protein F1 protein is mentioned as a mechanism by which S.

pyogenes invades the cells [ 15 ]. In Japan, Ma et al. pyogenes strains possessed F1 protein. Intracellular invasion ability and biofilm formation ability are negatively correlated, and it is considered that S. pyogenes avoids the attack of antibacterial agents [ 15 ].

Moreover, the clinically isolated S. pyogenes showed serotype-specific characteristics, with the emm 12 strain being detected most frequently and the emm 6 strain more likely to produce biofilms [ 17 ].

In addition, the ability to invade Detroit cells was significantly greater in the emm 4, emm 6, and emm 75 strains than in the strains of other genotypes [ 17 ]. In this study, 4 emm strains classified and the number of S.

pyogenes that invaded cells differed in each strain. However, there was no difference in the number of intracellular invasions among the 4 strains data not shown. In addition, phosphorylcholine is mentioned as a mechanism of intracellular invasion by NTHi, and the higher the expression level of phosphorylcholine, the more it penetrates into cells [ 18 ].

influenzae invades Detroit cells supports the results of the present study [ 19 ]. Since the late s, respiratory tract infections caused by antibiotic-resistant strains of S. pneumoniae and H. influenzae have increased exponentially worldwide.

Penicillin-resistant S. pneumoniae , such as penicillin intermediately-resistant S. pneumoniae PISP , penicillin-resistant S. pneumoniae PRSP , and BLNAR, are particularly common in Japan [ 10 ]. In NTHi isolates, the MICs of AMPC were eightfold higher than those of GRNX, CDTR-PI, and LVFX.

pyogenes isolates, the MICs of LVFX were eightfold higher than those of GRNX, CDTR-PI, and AMPC. Quinolone disrupts the DNA replication of type II topoisomerase, thereby inhibiting bacterial growth.

Moreover, type II topoisomerases include DNA gyrase and topoisomerase IV and consist of two dimers of subunit types A and B. The quinolone resistance-determining regions QRDRs within subunits A and B are closely related to resistance [ 20 ]. Shoji et al. pyogenes strains, 12 This is considered one of the reasons why S.

pyogenes were less sensitive to LVFX. Invasion of cells by bacteria has been cited as a cause of repeated tonsillitis. In this study, neither AMPC nor CDTR-PI was found to have a bactericidal effect on bacteria invading the cells. It is known that β-lactam antibacterial agents have low intracellular transmissibility, and their antibacterial action is reduced against H.

influenzae that has entered the cells [ 22 ]. Therefore, it is suggested that another antimicrobial treatment is necessary for recurrent tonsillitis. GRNX is highly effective in the treatment of patients with upper and lower respiratory tract infections [ 11 ].

Takagi et al. The trough concentration Cmin in plasma was 1. The efficacy rates of GRNX in otorhinolaryngological infections were In the present study, GRNX was more effective against bacteria that invaded cells than LVFX.

Moreover, LVFX was less sensitive against NTHi, and GRNX was found to be effective for recurrent tonsillitis. The present study showed that CAM was effective against bacteria invading cells. Patel et al. Chou et al. However, the concentration of CAM used in this study is far beyond the amount used in actual clinical practice and therefore could not be used in actual clinical practice.

Our study has some limitations. First, BLNAS and other resistant strains were not investigated. Since the number of strains of resistant bacteria is increasing, more resistant strains should be included in future studies.

The second limitation pertains to the epithelial cells used. Although the use of normal human epithelial cells may be more clinically relevant, we used a pharyngeal cancer-derived cell line.

Because these cells were of human origin, we consider that the results of this study were not different from those that would have been obtained with the use of normal cells.

GRNX was the most effective agent against cell-invading bacteria. Administration of GRNX should be considered when the efficacy of penicillin and cephem antibiotics and of β-lactam is insufficient in daily medical practice. The following antibacterial agents were used in the study: analytical grade powders of GRNX FUJIFILM Toyama Chemical Co.

We collected NTHi nasopharyngeal isolates and S. After washing in 0. The concentrations of NTHi and S. pyogenes were adjusted to 1. The Institutional Review Board of Kagoshima University approved this study. The susceptibility of bacteria to antibiotics was studied by the broth microdilution method, performed according to Clinical Laboratory Standards Institute guidelines [ 27 ].

Also, other drugs can increase or decrease levels of antibiotics. Many antibiotics are chemically related and are thus grouped into classes. Although drugs within each class share structural and functional similarities, they often have different pharmacology and spectra of activity.

Antibiotics should be used only if clinical or laboratory evidence suggests bacterial infection. Use for viral illness or undifferentiated fever is inappropriate in most cases; it exposes patients to drug complications without any benefit and contributes to bacterial resistance.

Certain bacterial infections eg, abscesses, infections with foreign bodies require surgical intervention and do not respond to antibiotics alone.

In general, clinicians should try to use antibiotics with the narrowest spectrum of activity and for the shortest duration. Cultures and antibiotic susceptibility testing are essential for selecting a drug for serious infections.

However, treatment must often begin before culture results are available, necessitating selection according to the most likely pathogens empiric antibiotic selection. Whether chosen according to culture results or not, drugs with the narrowest spectrum of activity that can control the infection should be used.

For empiric treatment of serious infections that may involve any one of several pathogens eg, fever in neutropenic patients or that may be due to multiple pathogens eg, polymicrobial anaerobic infection , a broad spectrum of activity is desirable.

The most likely pathogens and their susceptibility to antibiotics vary according to geographic location within cities or even within a hospital and can change from month to month. Susceptibility data should be compiled into antibiograms and used to direct empiric treatment whenever possible.

Antibiograms summarize regional facility—specific or location—specific antibiotic susceptibility patterns of common pathogens to commonly used antibiotics.

For serious infections, combinations of antibiotics are often necessary because multiple species of bacteria may be present or because combinations act synergistically against a single species of bacteria. Synergism is usually defined as a more rapid and complete bactericidal action from a combination of antibiotics than occurs with either antibiotic alone.

A common example is a cell wall—active antibiotic eg, a beta-lactam Beta-Lactams , vancomycin Vancomycin plus an aminoglycoside Aminoglycosides.

Pharmacokinetics Overview of Pharmacokinetics : The time course of antibiotic levels, which are affected by factors such as absorption Drug Absorption , distribution Drug Distribution to Tissues concentration in fluids and tissues, protein binding , rate of metabolism Drug Metabolism , and excretion Drug Excretion.

Pharmacodynamics Overview of Pharmacodynamics : The antimicrobial activity of local antibiotic concentrations on the target pathogen and that pathogen's response including resistance. Drug interactions Drug Interactions or inhibiting substances.

Host defense mechanisms Host Defense Mechanisms Against Infection. Bactericidal drugs kill bacteria. Bacteriostatic drugs slow or stop in vitro bacterial growth. These definitions are not absolute; bacteriostatic drugs may kill some susceptible bacterial species, and bactericidal drugs may only inhibit growth of some susceptible bacterial species.

More precise quantitative methods identify the minimum in vitro concentration at which an antibiotic can inhibit growth minimum inhibitory concentration [MIC] or kill minimum bactericidal concentration [MBC].

An antibiotic with bactericidal activity may improve bacterial killing when host defenses are impaired locally at the site of infection eg, in meningitis or endocarditis or systemically eg, in patients who are neutropenic or immunocompromised in other ways.

However, there are limited clinical data indicating that a bactericidal drug should be selected over a bacteriostatic drug simply on the basis of that classification. Drug selection for optimal efficacy should be based on how the drug concentration varies over time in relation to the MIC rather than whether the drug has bactericidal or bacteriostatic activity.

Antibiotics can be grouped into 3 general categories 1 Effectiveness reference Antibacterial drugs are derived from bacteria or molds or are synthesized de novo. read more based on the pharmacokinetics that optimizes antimicrobial activity pharmacodynamics :.

Concentration-dependent: The magnitude by which the peak concentration exceeds the MIC typically expressed as the peak-to-MIC ratio best correlates with antimicrobial activity. Time-dependent: The duration of the dosing interval in which the antibiotic concentration exceeds the MIC typically expressed as the percentage of time above MIC best correlates with antimicrobial activity.