History of Antimicrobial Agents & Resistant Bacteria

7/23/2019 History of Antimicrobial Agents & Resistant Bacteria

1/6

Research and Reviews

History of Antimicrobial Agents and Resistant

Bacteria

Tomoo SAGA,*1Keizo 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 infectiousdiseases 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 emergedand 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, wheremultidrug-resistant bacteria have spread widely, options for treatment with antimicrobial agents are limited, andthe 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 asefforts to minimize the transmission and spread of resistant bacteria through appropriate infection control, wouldbe the first step in resolving the issue of resistant organisms.

Key words Antimicrobial agents, Resistant bacteria, History

not achieve beneficial effect, and moreover,may lead to a worse prognosis. In addition, ina situation where multidrug-resistant organismshave spread widely, there may be quite a limitedchoice of agents for antimicrobial therapy. Atpresent, fewer brand new antimicrobial agentsare coming onto the market. Considering thissituation together with the increasing awarenessof drug safety, we are now facing a situation of

severely limited options among antimicrobialagents.

This paper provides an outline of the historyof antimicrobial agents, and thereafter describesresistant organisms that have emerged in responseto antimicrobial agents and discusses practicalclues to prevent resistant microorganisms.

Introduction

Antimicrobial drugs have caused a dramaticchange not only of the treatment of infectiousdiseases but of a fate of mankind. Antimicrobialchemotherapy made remarkable advances, result-ing in the overly optimistic view that infectiousdiseases would be conquered in the near future.

However, in reality, emerging and re-emerginginfectious diseases have left us facing a counter-charge from infections. Infections with drug-resistant organisms remain an important problemin clinical practice that is difficult to solve.

If an improper antimicrobial agent happensto be chosen for the treatment of infection withdrug-resistant microorganisms, the therapy may


2/6

104

Saga T, Yamaguchi K

History of the Development ofAntimicrobial Agents1,2(Fig. 1)

Looking back on the history of human diseases,infectious diseases have accounted for a very largeproportion of diseases as a whole. It was not untilthe latter half of the 19th century that micro-organisms were found to be responsible for a

variety of infectious diseases that had been plagu-ing humanity from ancient days. Accordingly,chemotherapy aimed at the causative organismswas developed as the main therapeutic strategy.

The first antimicrobial agent in the world wassalvarsan, a remedy for syphilis that was synthe-sized by Ehrlich in 1910. In 1935, sulfonamideswere developed by Domagk and other researchers.These drugs were synthetic compounds and hadlimitations in terms of safety and efficacy.

In 1928, Fleming discovered penicillin. Hefound that the growth of Staphylococcus aureus

was inhibited in a zone surrounding a contami-

nated blue mold (a fungus from the Penicilliumgenus) in culture dishes, leading to the findingthat a microorganism would produce substancesthat could inhibit the growth of other micro-organisms. The antibiotic was named penicillin,and it came into clinical use in the 1940s. Peni-cillin, which is an outstanding agent in termsof safety and efficacy, led in the era of antimicro-bial chemotherapy by saving the lives of many

wounded solders during World War II.During the subsequent two decades, new classes

of antimicrobial agents were developed one afteranother, leading to a golden age of antimicrobialchemotherapy. In 1944, streptomycin, an amino-glycoside antibiotic, was obtained from the soilbacterium Streptomyces griseus. Thereafter, chlor-amphenicol, tetracycline, macrolide, and glyco-peptide (e.g., vancomycin) were discovered fromsoil bacteria. The synthesized antimicrobial agentnalidixic acid, a quinolone antimicrobial drug,was obtained in 1962.

Improvements in each class of antimicrobial

Discovery of penicillinDiscovery of a sulfonamideClinical application of penicillin

Discovery of aminoglycoside, chloramphenicol,tetracycline, and macrolide

Discovery of vancomycin

Synthesis of methicillin

Synthesis of nalidixic acid

Emergence of drug-resistant bacteria Development of antimicrobial agents

Emergence of penicillinase-producingStaphylococcus aureus

Emergence and spread of multidrug-resistantS.aureus

Emergence of MRSA

Emergence of PISP

Emergence of penicillinase-producingH.influenzae

Emergence of PRSP

Emergence of BLNAR H.influenzae

Emergence of ESBL-producing Gram-negativebacilli

Emergence of VRE

Increased infections with MRSA, PRSP, BLNAR,etc.

Increase of resistant gonococci

Increase of MDRP

Increase of quinolone-resistant E.coli

Development of first-generation cephems

Development of second-generation cephems

Development of third-generation cephems

Development of carbapenemand monobactam

Increased use of third-generationcephem, carbapenem, oral cephem, and

new quinolone antimicrobials

(Decrease in newly developed antimicrobial agents)

Development ofnew quinolones

Fig. 1 Trend of development of antimicrobial agents and emergence of drug-resistant bacteria


3/6

105

agents continued to achieve a broader antimicro-bial spectrum and higher antimicrobial activity. -lactam antibiotics will be described as an example.The -lactam antibiotics include penicillins (Fig. 2),cephems, carbapenems, and monobactams.

Penicillins were originally effective for Gram-positive organisms such as S.aureus. Later, toaddress penicillin-resistant S.aureuswhich pro-duces the penicillin-hydrolysing enzyme penicil-linase, methicillin was developed. On the otherhand, attempts to expand the antimicrobial spec-trum yielded ampicillin, which is also effective forGram-negative Enterobacteriaceae, and piper-acillin, which is effective even for Pseudomonasaeruginosa.

Cephems were developed in the 1960s, andcame into widespread use. Cephems are classified

into several generations according to their anti-

microbial spectra. First-generation cephems (cefaz-olin, etc.) are effective only for Gram-positiveorganisms and Escherichia coli, although theirantimicrobial activity against these organisms ispotent. Second-generation cephems (cefotiam,

etc.) have an extended antimicrobial spectrumthat covers not only Gram-positive but also Gram-negative organisms including other Enterobacte-riaceae. Third-generation cephems (ceftazidime,cefotaxime, etc.) have higher efficacy for Gram-negative organisms, and some drugs of thisgeneration are also effective for P. aeruginosa,although the antimicrobial activity against Gram-positive organisms is generally lower than that ofthe first generation.

Carbapenem is an antibiotic class includingpanipenem, imipenem, and meropenem. These

drugs are effective not only for Gram-positive

HISTORY OF ANTIMICROBIAL AGENTS AND RESISTANT BACTERIA

Penicillin antimicrobials

Penicillin G

Ampicillin

Methicillin

Piperacillin

Quinolone antimicrobials

Nalidixic acid

Norfloxacin

Levofloxacin

Fig. 2 Evolution of antimicrobial agents (penicillin and quinolone antimicrobials)


4/6

106

and Gram-negative bacteria but also anaerobes,and their antimicrobial activity is strong. Themonobactam antibiotic aztreonam exerts an anti-microbial effect only on Gram-negative bacteria.

Continuing improvements have been made forantimicrobial agents in various aspects in addi-tion to the antimicrobial spectrum and activity.The drugs have been developed to achieve betterpharmacodynamics including the absorption oforal drugs, concentration in the blood, and distri-

bution to the inflammatory focus. In addition, asantimicrobial chemotherapy has been establishedand matured, more importance has been attachedto the drug safety. Antimicrobial agents that areassociated with serious side effects have beenreplaced by other safer drugs.

Quinolone antimicrobials represent an exampleof drugs with improved pharmacodynamics andsafety (Fig. 2). Nalidixic acid, the first drug ofthis class, was active only against Gram-negativebacteria, and its use was limited to urinary tractinfections because it achieves only low blood

concentrations and poor tissue distribution, and

was metabolized rapidly in the human body.In contrast, norfloxacin, which came to marketin 1984, maintains a stable metabolic state andexhibits good tissue distribution. Its antimicro-bial spectrum is extensive, covering both Gram-positive and Gram-negative bacteria includingP.aeruginosa. Quinolone antimicrobials developedafter norfloxacin have been called new quinolones,and they have still been key drugs. Levofloxacinis the S-() enantiomer of the new quinolone

ofloxacin. This enantiomer has higher antimicro-bial activity than that of the other R-() enanti-omer of ofloxacin, and is associated with weakerside effects on the central nervous system, such asrestlessness and vertigo.

Although a large number of companies invarious countries have competed in the develop-ment of newer antimicrobial agents, the numberof brand new drugs has been remarkably decreas-ing in recent years, with few antimicrobial agentsof new classes becoming available. In contrast,infectious diseases continue to attack human

beings as emerging and re-emerging infectious

Table 1 Clinically important drug-resistant bacteria in Japan

Microorganisms Drugs Resistant bacteria Mechanism of resistanceStaphylococcus -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)

pneumoniaeMacrolide 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 effluxaeruginosa 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 Mutation in target (gyrA, parC)

gonococci

Saga T, Yamaguchi K


5/6

107

diseases, opportunistic infectious diseases, andinfection with drug-resistant microorganismsthat will be discussed in the next section. Effec-tive utilization of the current limited options ismuch more important under the dearth of newdrugs on the market.

History of the Emergence of ResistantBacteria

The capacity of microorganisms to acquire resis-tance to antimicrobial agents has surpassed ourimagination. In some cases, antimicrobial agentsformerly effective are no longer useful. The history

of resistant bacteria will be outlined below andin Table 1.

S.aureusis the resistant bacterium most familiarin the clinical setting. This bacterium rapidlyacquired resistance to sulfonamides when theywere in use. Penicillin was initially effectiveto this microorganism, but resistant strains thatproduce penicillinase increased in the 1950s.Therefore, penicillinase-stable methicillin wasdeveloped in 1960, as mentioned previously.However, as early as the following year, 1961,methicillin-resistant S. aureus (MRSA) was iso-

lated in the UK.

3

Since around 1990, nosocomial infection withMRSA became a social problem. During thisperiod, the target of new antimicrobial agentsincluding second- and third-generation cephems,shifted from Gram-positive to Gram-negativebacteria, and agents with wide spectra butweaker activity against Gram-positive bacteriawere widely used (Fig. 1). MRSA acquires resis-tance to most -lactam antibiotics through itsacquisition of the penicillin-binding protein (PBP)2 gene; PBP2 is an enzyme involved in cellwall synthesis that has low binding affinity for

-lactam antibiotics. In genetic lineage analysisof nosocomial MRSA strains, major nosocomialclones throughout the world would converge ononly seven types.4On the other hand, community-associated methicillin-resistant S. aureus (CA-MRSA), which was noticed in the US around1997, is of a different type from nosocomialMRSA.

Fortunately, MRSA so far in Japan haveresponded to glycopeptide antibiotics such asvancomycin. However, in the latter half of the1990s, vancomycin-intermediate S.aureus(VISA)

was reported in this country. It is thought that

thickening of the cell wall contributes to decreasedsensitivity to this drug. On the other hand,vancomycin-resistant S. aureus(VRSA) reportedin the US seemed to acquire the resistancegenes horizontally from vancomycin-resistantenterococci (VRE).5 In Japan, there have beenno reports of VRSA strains so far, partially atleast, due to lower detection rates of VRE thanthose in Western countries.

Although S.pneumoniae was originally sus-ceptible to penicillin, penicillin-intermediate S.pneumoniae (PISP) strains were found in thelatter half of the 1960s, and penicillin-resistantS.pneumoniae (PRSP) strains in the latter half

of the 1970s. In Japan, PRSP was found in the1980s, and the detection of PRSP strains beganto increase around 1990. Frequent use of oralcephem antibiotics seems to be responsible forthis increase in PRSP. There has also been aremarkable increase in macrolide resistance inthis species, which seems also due to the frequentuse of macrolides in this country.

Ampicillin was initially effective for Haemoph-ilus influenzae. However, in the 1980s, some ofthis species were found to produce -lactamase,thereby becoming resistant to ampicillin. In

the 1990s, such -lactamase-producing strainsdecreased in Japan, however, strains that acquiredhighly resistance to -lactam through mutationsin PBP genes, increased instead. These arecalled as -lactamase-negative ampicillin-resistant(BLNAR) strains, and they are more commonin Japan than in other Western countries. Ithas been speculated that increased use of oralcephem antibiotics is also responsible, similar tothe situation with PRSP.

Although P. aeruginosaare intrinsically resis-tant to many antimicrobial agents, the emergenceof P. aeruginosa strains resistant to all of three

classes of antimicrobials, i.e., carbapenems, quino-lones, and aminoglycosides is a recent concern.These multidrug resistant P. aeruginosa(MDRP)sometimes seems to cause an outbreak in someinstitutions. MDRP has complex mechanisms ofdrug resistance, including reduced membranepermeability due to decreased outer membraneprotein (D2 porin), overexpression of effluxpump, mutation of the quinolone target (DNAgyrase), production of aminoglycoside modifi-cation enzyme, and production of metallo--lactamase (carbapenem-hydrolysing enzyme).

Some resistance genes are horizontally trans-

HISTORY OF ANTIMICROBIAL AGENTS AND RESISTANT BACTERIA


6/6

108

ferred by conjugative plasmids.Gonococci used to be susceptible to penicillin

and quinolone, but currently they are resistantto both agents in Japan. In particular, quinolonehad been the first-choice drug for gonococcalinfection in the 1980s because of the potentialadvantage in the case of co-infection withChlamydophila. However, since almost all thestrains have become resistant to quinolones,the 1999 guidelines declared against the use ofquinolone for gonococcal infection.6

Conclusion

In summary, it is clear that the use of antimicro-bial agents resulted in the selection of resistantbacteria. Since the advent of new mighty drugsis highly difficult, the proper use of currentlyavailable antimicrobial agents as well as effortsto minimize the spread of resistant bacteriathrough appropriate infection control would bequite important, and may represent a first step insolving the issue of resistant microorganisms.7

Saga T, Yamaguchi K

History of Antimicrobial Agents & Resistant Bacteria

Documents

Transcript of History of Antimicrobial Agents & Resistant Bacteria