Research and Reviews History of Antimicrobial Agents and Resistant Bacteria JMAJ 52(2): 103–108, 2009 Tomoo SAGA,*1 Keizo YAMAGUCHI*2 Abstract Antimicrobial chemotherapy has conferred huge benefits on human health. A variety of microorganisms were elucidated to cause infectious diseases in the latter half of the 19th century. Thereafter, antimicrobial chemo- therapy made remarkable advances during the 20th century, resulting in the overly optimistic view that infectious diseases would be conquered in the near future. However, in response to the development of antimicrobial agents, microorganisms that have acquired resistance to drugs through a variety of mechanisms have emerged and continue to plague human beings. In Japan, as in other countries, infectious diseases caused by drug- resistant bacteria are one of the most important problems in daily clinical practice. In the current situation, where multidrug-resistant bacteria have spread widely, options for treatment with antimicrobial agents are limited, and the number of brand new drugs placed on the market is decreasing. Since drug-resistant bacteria have been selected by the use of antimicrobial drugs, the proper use of currently available antimicrobial drugs, as well as efforts to minimize the transmission and spread of resistant bacteria through appropriate infection control, would be the first step in resolving the issue of resistant organisms. Key words Antimicrobial agents, Resistant bacteria, History not achieve beneficial effect, and moreover, Introduction may lead to a worse prognosis. In addition, in a situation where multidrug-resistant organisms Antimicrobial drugs have caused a dramatic have spread widely, there may be quite a limited change not only of the treatment of infectious choice of agents for antimicrobial therapy. At diseases but of a fate of mankind. Antimicrobial present, fewer brand new antimicrobial agents chemotherapy made remarkable advances, result- are coming onto the market. Considering this ing in the overly optimistic view that infectious situation together with the increasing awareness diseases would be conquered in the near future. of drug safety, we are now facing a situation of However, in reality, emerging and re-emerging severely limited options among antimicrobial infectious diseases have left us facing a counter- agents. charge from infections. Infections with drug- This paper provides an outline of the history resistant organisms remain an important problem of antimicrobial agents, and thereafter describes in clinical practice that is difficult to solve. resistant organisms that have emerged in response If an improper antimicrobial agent happens to antimicrobial agents and discusses practical to be chosen for the treatment of infection with clues to prevent resistant microorganisms. drug-resistant microorganisms, the therapy may *1 Assistant Professor, Department of Microbiology and Infectious Disease, Faculty of Medicine, Toho University, Tokyo, Japan ([email protected]). *2 Professor, Department of Microbiology and Infectious Disease, Faculty of Medicine, Toho University, Tokyo, Japan. This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol.137, No.3, 2008, pages 513–517). JMAJ, March/April 2009 — Vol. 52, No. 2 103 Saga T, Yamaguchi K Emergence of drug-resistant bacteria Development of antimicrobial agents Discovery of penicillin Discovery of a sulfonamide Clinical application of penicillin Emergence of penicillinase-producing Staphylococcus aureus Discovery of aminoglycoside, chloramphenicol, tetracycline, and macrolide Emergence and spread of multidrug-resistant S.aureus Discovery of vancomycin Synthesis of methicillin Emergence of MRSA Synthesis of nalidixic acid Emergence of PISP Development of first-generation cephems Emergence of penicillinase-producing H.influenzae Development of second-generation cephems Emergence of PRSP Emergence of BLNAR H.influenzae Development of third-generation cephems Emergence of ESBL-producing Gram-negative Development of carbapenem Development of bacilli and monobactam new quinolones Emergence of VRE Increased infections with MRSA, PRSP, BLNAR, etc. Increased use of third-generation Increase of resistant gonococci cephem, carbapenem, oral cephem, and new quinolone antimicrobials Increase of MDRP Increase of quinolone-resistant E.coli (Decrease in newly developed antimicrobial agents) Fig. 1 Trend of development of antimicrobial agents and emergence of drug-resistant bacteria nated blue mold (a fungus from the Penicillium History of the Development of genus) in culture dishes, leading to the finding Antimicrobial Agents1,2 (Fig. 1) that a microorganism would produce substances that could inhibit the growth of other micro- Looking back on the history of human diseases, organisms. The antibiotic was named penicillin, infectious diseases have accounted for a very large and it came into clinical use in the 1940s. Peni- proportion of diseases as a whole. It was not until cillin, which is an outstanding agent in terms the latter half of the 19th century that micro- of safety and efficacy, led in the era of antimicro- organisms were found to be responsible for a bial chemotherapy by saving the lives of many variety of infectious diseases that had been plagu- wounded solders during World War II. ing humanity from ancient days. Accordingly, During the subsequent two decades, new classes chemotherapy aimed at the causative organisms of antimicrobial agents were developed one after was developed as the main therapeutic strategy. another, leading to a golden age of antimicrobial The first antimicrobial agent in the world was chemotherapy. In 1944, streptomycin, an amino- salvarsan, a remedy for syphilis that was synthe- glycoside antibiotic, was obtained from the soil sized by Ehrlich in 1910. In 1935, sulfonamides bacterium Streptomyces griseus. Thereafter, chlor- were developed by Domagk and other researchers. amphenicol, tetracycline, macrolide, and glyco- These drugs were synthetic compounds and had peptide (e.g., vancomycin) were discovered from limitations in terms of safety and efficacy. soil bacteria. The synthesized antimicrobial agent In 1928, Fleming discovered penicillin. He nalidixic acid, a quinolone antimicrobial drug, found that the growth of Staphylococcus aureus was obtained in 1962. was inhibited in a zone surrounding a contami- Improvements in each class of antimicrobial 104 JMAJ, March/April 2009 — Vol. 52, No. 2 HISTORY OF ANTIMICROBIAL AGENTS AND RESISTANT BACTERIA Penicillin antimicrobials Quinolone antimicrobials Nalidixic acid Penicillin G Ampicillin Norfloxacin Methicillin Levofloxacin Piperacillin Fig. 2 Evolution of antimicrobial agents (penicillin and quinolone antimicrobials) agents continued to achieve a broader antimicro- microbial spectra. First-generation cephems (cefaz- bial spectrum and higher antimicrobial activity. ␤- olin, etc.) are effective only for Gram-positive lactam antibiotics will be described as an example. organisms and Escherichia coli, although their The ␤-lactam antibiotics include penicillins (Fig. 2), antimicrobial activity against these organisms is cephems, carbapenems, and monobactams. potent. Second-generation cephems (cefotiam, Penicillins were originally effective for Gram- etc.) have an extended antimicrobial spectrum positive organisms such as S. aureus. Later, to that covers not only Gram-positive but also Gram- address penicillin-resistant S. aureus which pro- negative organisms including other Enterobacte- duces the penicillin-hydrolysing enzyme penicil- riaceae. Third-generation cephems (ceftazidime, linase, methicillin was developed. On the other cefotaxime, etc.) have higher efficacy for Gram- hand, attempts to expand the antimicrobial spec- negative organisms, and some drugs of this trum yielded ampicillin, which is also effective for generation are also effective for P. aeruginosa, Gram-negative Enterobacteriaceae, and piper- although the antimicrobial activity against Gram- acillin, which is effective even for Pseudomonas positive organisms is generally lower than that of aeruginosa. the first generation. Cephems were developed in the 1960s, and Carbapenem is an antibiotic class including came into widespread use. Cephems are classified panipenem, imipenem, and meropenem. These into several generations according to their anti- drugs are effective not only for Gram-positive JMAJ, March/April 2009 — Vol. 52, No. 2 105 Saga T, Yamaguchi K Table 1 Clinically important drug-resistant bacteria in Japan Microorganisms Drugs Resistant bacteria Mechanism of resistance Staphylococcus ␤-lactam MRSA Production of an additional enzyme that avoids drug aureus (methicillin) binding (PBP2’) Vancomycin VISA Thickening of cell wall (VRSA) Consequent changes in target (vanA, vanB, etc.) Enterococcus Vancomycin VRE Consequent changes in target (vanA, vanB, etc.) Streptococcus Penicillin PISP/PRSP Mutation in target (PBP) pneumoniae Macrolide Macrolide-resistant Modification of target (erm) S.pneumoniae Drug efflux pump (mef ) Haemophilus Ampicillin BLNAR Mutation in target (PBP) influenzae Pseudomonas Multiple drugs MDRP Multiple factors including loss of porin, drug efflux aeruginosa pump, and drug-modifying enzyme Metallo-␤-lactamase- Drug-degrading enzyme producing bacteria Enterobacteriaceae ␤-lactam ESBL-producing Drug-degrading enzyme (e.g., Escherichia coli) (carbapenem) bacteria Quinolone Quinolone-resistant Mutation in target (gyrA, parC) E.coli Gonococci Quinolone Quinolone-resistant