Bacteria Battle Back - Addressing Antibiotic Resistance

Bacteria Battle Back:Addressing Antibiotic Resistance

Authors:Ronald J. DeBellis, PharmDAssistant Professor of Clinical PharmacyMassachusetts College of Pharmacy

and Health Sciences

Martin Zdanawicz, PhDAssociate Professor of PharmacologyMassachusetts College of Pharmacy

and Health Sciences

Introduction:Stuart B. Levy, MDChairman and President, DirectorCenter for Adaptation Genetics

and Drug ResistanceProfessor, Tufts University School of MedicinePresident, Alliance for the Prudent

Use of AntibioticsBoston, Mass.

Editorial Assistance:Philip D. Walson, MDProfessor of PediatricsUniversity of CincinnatiDirector of Clinical Trials OfficeChildren’s Hospital Medical CenterCincinnati, Ohio

This continuing education program is made possible byan unrestricted educational grant from Proctor andGamble Pharmaceuticals and is cosponsored by theMassachusetts College of Pharmacy and Health Sciencesand the Alliance for the Prudent Use of Antibiotics.

Accredited by the Massachusetts College of Pharmacyand Health Sciences and the American Academy of NursePractitioners. This program is approved for 2 contacthours (0.2)ceus).

Bacteria Battle Back: Addressing Antibiotic Resistance 1

IntroductionBacterial resistance to antibiotics continues to

curb our ability to treat, cure and control infec-tious diseases. Antibiotics, often touted as one ofthe most important discoveries of modern medi-cine, are losing ground to bacteria that are nowresistant to several drugs. The irony, of course, isthat antibiotics developed to control bacteria haveinstead strengthened them, leading to drug-resis-tant bacteria against which antibiotics are ineffec-tive. Antibiotic resistance was initially found onlyin hospitals where most antibiotics are still used,but resistance is now a serious problem in thecommunity as well. Infectious diseases that wereonce easily treated with antibiotics now oftenthwart treatment. Two organisms in particular thathave become major public health threats are me-thicillin-resistant Staphylococcus aureus and peni-cillin-resistant Streptococcus pneumoniae.

The speed at which bacteria can develop antibi-otic resistance has made it clear that these drugsare less of a “miracle” than they were once toutedto be. While designed to be selective for bacteriaand not host cells, antibiotics are not selectiveenough to distinguish the pathogenic from com-mensal bacteria. Consequently, antibiotic use al-ters the microbial ecology by decimating suscep-tible flora and favoring growth of bacteria thatpossess resistance traits. These bacteria that pos-sess antibiotic resistance traits can then pass thesetraits on to future bacterial generations or topathogens.

It is clear that the fight to control bacterial patho-gens is far from won. Scientists are now attempt-ing to develop new classes of antibiotics that uti-

2 Bacteria Battle Back: Addressing Antibiotic Resistance . November 2000

lize different mechanisms for which bacteria haveyet to evolve resistance. In addition, research isongoing to develop methods to revive susceptiblecommensal flora within human and animal hosts.At the same time, there must be broad,multidisciplinary educational programs dedi-cated to teaching the public as well as health careprofessionals about the appropriate use of anti-biotics in humans, animals and agriculture.

Increasing awareness of the problem of antibioticresistance in the community and the threat that re-sistant bacteria may pose is a key first step in ad-dressing this problem. Training health care practi-tioners to identify potential pathogens accuratelyand to treat them with effective agents and appro-priate regimens are important additional steps.Patient education is also crucial in ensuring thatthe public understands and participates in effortsto control the spread of antibiotic resistant bacte-ria. This continuing education program describesthe problem and provides concrete guidelines forimproving antibiotic use in the community andwithin institutional health care settings.

Stuart B. Levy, MD


other major cause of drug-resistantinfections in hospitals and, more re-cently, in the community. Of particu-lar concern are vancomycin-resis-tant enterococci (VRE). These organ-isms are generally hospital-basedpathogens found on the skin and inthe gastrointestinal tract. They canbe easily spread from patient to pa-tient and from health care worker topatient. The prevalence of organismsresistant to vancomycin is increas-ing and is troublesome because van-comycin has been the last line of de-fense against many gram-positivebacteria resistant to other traditionalantibiotics. Penicillin-resistant pneu-mococcus (PRP) is a respiratorypathogen that generally is associ-ated with community-based respira-tory illness. As many as 40 percentof pneumococci strains in some partsof the United States are completelyresistant to penicillin and a numberof other antibiotics. In addition topenicillin-resistant strains, organ-isms that are resistant to other anti-biotics such as erythromycin,chloramphenicol and cephalospor-ins also have been reported recently.5

These organisms are designateddrug-resistant pneumococci (DRP).

Tuberculosis, caused by Mycobac-terium tuberculosis, is still a leadingcause of mortality worldwide. TheWHO predicts more than 30 millionpeople will die of tuberculosis in thenext 10 years unless global controlmeasures are successfully imple-mented. The emergence of antibiotic-resistant tuberculosis strains in devel-oping countries has further compli-cated successful treatment of this dis-

ease.6 This resistance is not just a prob-lem in the developing world. The re-cent resurgence of tuberculosis in thehomeless and HIV-infected popula-tions in developed countries has alsobecome a source of great concern tothe health care community. These or-ganisms are particularly prone to be-coming antibiotic resistant in popu-lations such as the homeless whosehealth care is monitored less closelyand who are less likely to comply withcomplex medication regimens. Otherbacteria being watched for emergingresistance to antibiotics include Neis-seria gonorrhoae,7 which is responsiblefor gonorrhea, H. pylori,8 which is as-sociated with gastric disease, andnonfermentative gram-negative bacte-ria such as Pseudomonas aeruginosa.9

Epidemiology of AntibioticResistance

The origins of antibiotic resis-tance in microorganisms are of par-ticular interest to scientists studyingthe general problem of drug resis-tance. It is not entirely clear whetherantibiotic-resistant bacteria arosewith the development and clinicaluse of antibiotics or if resistant or-ganisms were present in the envi-

ronment before the widespread useof antimicrobials. Researchers haveexamined bacteria that predate thediscovery of antibiotics taken frompopulations never exposed to anti-biotics. Investigators have reportedevidence of some low-level resis-tance to antibiotics, but overall thebacteria studied were sensitive tomost antibiotics prior to expo-sure.10,11 This finding suggests thatwhile some genes for antibiotic re-sistance likely predate widespreadantibiotic use, widespread resis-tance emerged to a major extent af-ter widespread antibiotic use. It isreasonable to assume that thesegenes served a protective function inbacteria exposed to the many natu-rally occurring antibiotics producedby other microorganisms in the en-vironment. The frequency, diversity,and specificity of these antibioticresistance genes likely all increasedas the microorganisms were ex-posed to increasing amounts of newand synthetic antibiotics being usedto treat and prevent disease.

When considering the problemof genetic resistance in bacteria, it isimportant to understand that bacte-ria multiply rapidly and continually

Table 1.

Antibiotic-Resistant Organisms of Major Concern to Health ProfessionalsHOSP ITAL-ACQUIRED COMMUN ITY-ACQUIRED

Methicillin-resistantStaphylococcus aureus (MRSA)

Vancomycin-intermediate S. aureus (VISA)Vancomycin-resistant enterococcus (VRE)EnterobacterPseudomonasKlebsiella

Penicillin-resistant pneumococcus (PRP)Eschericia coli–

extended-spectrum ß-lactamases (ESBL)Neisseria gonorrhoaeHaemophilus influenzaMycobacterium tuberculosis


Target Audience:Pharmacists, Nurse Practitioners,Physicians, Physician Assistants and otherhealthcare providers.

Goal:Address current antibiotic resistance trends,clinical treatment guidelines andpharmacological and clinical approaches tocombating increasing antibiotic resistance inthe community.

Learning Objectives:Describe the epidemiology and ecology ofantibiotic resistance (ABR) among severalbacterial agents as causes of morbidity andmortality.

Describe factors that have contributed to theemergence of antimicrobial resistance in thecommunity and nationwide.

Identify common mechanisms of bacterialresistance.

Review the organisms that have becomesignificant management problems

Review the Centers for Disease Control andPrevention (CDC & P) Treatment Guidelinesto Controlling Antibiotic Resistance.

Identify five interventions that healthcarepractitioners can utilize to decrease potentialABR emergence in their practice.

Discuss ways to address diagnostic andtreatment uncertainty among practitioners.

Discuss was to educate the patient and theirfamily on appropriate antibiotic usage.

Review the ways in which the pharmacist’sprovider relationship can be seen as acollaborative team approach to the patient’s care.

Educational Need Addressed:This home study course provides informationon decreasing the incidence of antibioticresistance and the role healthcarepractitioners can play in the community andworldwide to address this problem.

Disclosure Statement:It is the policy of the Massachusetts Collegeof Pharmacy and Health SciencesDepartment of Continuing Education, thatfaculty disclose to program participants anyreal or apparent conflict of interest. Inaddition, faculty are asked to disclose whenany discussion of unapproved use ofpharmaceuticals and devices is beingdiscussed. Faculty members for thisprogram have nothing to disclose.

Costs Related to AntibioticResistance

At the turn of the 21st century ithad been nearly 70 years since anti-biotics were first introduced to treatbacterial infections. During this timeantibiotics saved countless lives;and for a while it seemed that man-kind possessed the means to over-come almost any bacterial infection.Unfortunately, in recent years, con-cern and fear have replaced this con-fidence because antibiotic-resistantbacteria have emerged. Antibiotic re-sistance is now a global problem thatrequires action by all health careproviders, patients, industry andgovernment to decrease the preva-lence and costs (both human and fi-nancial). This action must includeresearch, education, surveillanceand behavioral change.

The cost of antibiotic resistancein terms of both lives lost and dol-lars spent has become quite signifi-cant. The World Health Organiza-tion (WHO) reports that approxi-mately 14,000 individuals die eachyear in the United States as a resultof infections from antibiotic-resistantorganisms. Worldwide, the WHO be-lieves drug-resistant bacteria accountfor up to 60 percent of hospital-ac-quired infections. A 1995 study re-ported that antibiotic-resistant S.

aureus infections were responsible fornearly 1,500 deaths just in New Yorkcity and that treatment costs were$500 million.1 Also in 1995, it wasconservatively estimated that the na-tionwide cost of antibiotic resistancewas at least $1.3 billion.

Some of the resistant pathogensof the most immediate concern tohealth care professionals are listedin Table 1. One of these organisms,methicillin-resistant S. aureus (MRSA)is one of the most common antibi-otic-resistant bacteria found in hos-pitals and health care facilities.2

MRSA residing on the skin and inthe upper respiratory passages iseasily spread from person to person,as is the closely related methicillin-resistant Staphylococcus epidermidis.More than 90 percent of S. aureusstrains are resistant to penicillin andrelated antibiotics. Several cases ofinfection caused by S. aureus inwhich the organisms were fully re-sistant to methicillin and partiallyresistant to vancomycin have beenreported in the United States. 3,4

These organisms are classified asvancomycin-intermediate S. aureusand are of particular concern be-cause they may herald the develop-ment of vancomycin-resistantstrains of this organism.

Enterococcus species are an-

Bacteria Battle Back:Addressing AntibioticResistance


exchange genetic information. Inaddition, many bacteria frequentlytransfer between animal, human andplant hosts. While antibiotic resis-tance may be an intrinsic propertyof a particular organism (with thegenes for antibiotic resistance foundwithin the chromosomal DNA), it ismore likely that most bacteria ac-quire their resistance genes fromother resistant organisms.

We now know that many of the

genes that confer antibiotic resis-tance to a particular organism arefound on circular, self-replicatingstrands of DNA called plasmids.Bacteria transfer these plasmidsduring a process called conjugation.This appears to be a major mecha-nism for spreading antibiotic resis-tance among bacteria. Moreover, theactual genes for antibiotic resis-tance often lie on regions of the plas-mid called transposons, or “jumping

genes,” which are pieces of DNAthat can readily move to and fromDNA molecules. This process ofgene exchange via transposons iscalled transposition. The secondmechanism by which genes for an-tibiotic resistance may be spreadamongst a bacterial population isbacteriophage transduction. Bacte-riophages are viruses that infectbacteria. In the course of their in-fectious cycle, they can transfer seg-ments of bacterial genomes betweenthe microorganisms they infect. Fi-nally, bacteria may acquire antibi-otic resistance genes through theprocess of transformation. When bac-teria die they release into the envi-ronment their DNA, which maycontain genes for antibiotic resis-tance. Other viable bacteria canreadily take up this DNA and in-corporate the genes into their owngenome. These resistance genes en-code information responsible for anumber of resistance mechanisms.The genetic transfer mechanisms ofgenes for antibiotic resistance aresummarized in Table 2.

Mechanisms of AntibioticResistance

With continued exposure to an-tibiotics, bacteria have developednumerous mechanisms for overcom-ing the effects of these drugs (seeTable 3). These antibiotic-resistancemechanisms are not mutually exclu-sive and most likely resistant organ-isms use various mechanisms con-currently. The antibiotic-resistancemechanisms that have been identi-fied thus far include:

Table 2

Genetic Transfer Mechanisms of Antibiotic Resistance1. TRANSPOSITION

The exchange of bacterial DNA containing antibiotic resistance genes during conjugation.

2. TRANSDUCT ION

Bacteriophage transfer of antibiotic resistance genes between the bacteria they infect.

3. TRANSFORMATION

Live bacteria incorporate antibiotic resistance genes that are released by dead bacteriainto the environment.

Table 3

Four Mechanisms of Antibiotic ResistanceENZYMATIC DESTRUCTION OR MODIFICATION OF ANTIBIOTICS

• ß-lactamases (narrow- or extended-spectrum)• Aminoglycoside-modifying enzymes (acetylase, adenylase, phosphorylase)

DECREASED UPTAKE OF ANTIBIOTIC INTO BACTERIUM

• Reduced permeability of bacterial membranes and cell wall• Altered structure or reduced number/affinity of drug (porin) channels• Reduced electrochemical gradient for transport

INCREASED REMOVAL OF ANTIBIOTIC FROM BACTERIUM

• Active efflux pumps• “Multi-drug” efflux pumps

ALTERATION OF BACTERIAL TARGETS

• Mutated penicillin-binding proteins no longer bind ß-lactam antibiotics• Mutated DNA gyrase, topoisomerase, polymerase enzymes are no longer inhibited by

fluoroquinolones and rifampicin• Altered bacterial ribosomes no longer allow aminoglycoside antibiotics to bind• Development of resistant metabolic pathways in which key enzymes are no longer

inhibited by antibiotics (e.g., trimethoprim and tetrahydrofolate reductase)


1. Enzymatic modification or de-struction of the antibiotic. The bac-terial genome may code for the pro-duction of enzymes that are capableof inactivating or destroying a par-ticular antibiotic. One common bac-terial enzyme is β-lactamase, whichis capable of splitting the β-lactamring that comprises the nucleus ofcarbapenem, cephalosporin, mono-bactam and penicillin antibiotics.Currently, more than 200 distincttypes of β-lactamases have beenidentified. These β-lactamases mayeither have a narrow spectrum andact only against a specific β-lactamantibiotic, or they may be extended-spectrum β-lactamases (ESBLs) ca-pable of conferring resistance to mul-tiple antibiotics. A second group ofaminoglycoside-modifying enzymeshas also been characterized. Theseenzymes are capable of altering thestructure of aminoglycoside antibiot-ics through acetylation, adenylationor phosphorylation. Covalent modi-fication of the aminoglycoside anti-biotics by these enzymes may lead totheir inactivation or impair their abil-ity to enter the bacterial cell. Morethan 20 of these particular enzymeshave been identified.2. Decreased uptake of antibioticinto bacteria. Many gram-negativebacteria are intrinsically somewhatresistant to β-lactam antibiotics be-cause of their outer membrane im-permeability. While membrane per-meability varies from organism to or-ganism, any genetic mutation thatfurther decreases membrane perme-ability to antibiotics will confergreater resistance to that organism.

As a consequence of their low cellmembrane permeability, gram-nega-tive bacteria must use membraneproteins called porins that act aschannels by which hydrophilic sub-stances, including antibiotics, canget inside the bacteria cell. Geneticmutations that alter the number orconfiguration of porin channels inthe bacterial membrane can reducethe ability of antibiotics to enter thatparticular organism. In cepha-losporin-resistant enterobacteria, forexample, there are reduced numbersof porin F molecules—the mainchannels by which the cephalospor-ins enter cells.12 The specific porinmolecules that allow imipenem toenter bacterial cells are essentiallyabsent in imipenem-resistant en-terobacteria.13,14 In addition to the β-lactam antibiotics, resistance tochloramphenicol, quinolones andtrimethoprim may also be partiallyattributed to changes in bacterialuptake of these agents.

A novel antibiotic-resistancemechanism was recently describedfor small-colony variants of sta-phylococcus in which these bacte-ria had a reduced rate of electrontransport chain activity. Because ofthis reduced activity, they did notproduce sufficient electrochemicalgradients necessary to transportaminoglycoside antibiotics into thecell.15 Furthermore, because theseorganisms have a slow growth rate,the overall effectiveness of cell-wallactive antibiotics such as the β-lactams is significantly reduced.3. Increased removal of antibioticfrom bacteria. Another recently

characterized mechanism of antibi-otic resistance involves active drugefflux pumps. These energy-drivenprotein pumps traverse the innerand outer membranes of bacteriaand rapidly transport antibiotics outinto the environment. It is likely thatthese membrane pumps operate tovarying degrees in almost all bacte-ria and serve as a protective mecha-nism against environmental toxins.Many bacteria have numerous drugefflux pumps with varying specific-ity. Two main types of efflux pumpswith a wide affinity for various an-tibiotics have been identified ingram-negative organisms.16

These “multi-drug” effluxpumps are likely key contributors toantibiotic resistance in gram-nega-tive organisms, along with β -lactamases and reduced cell perme-ability. Antibiotics with hydropho-bic domains (β-lactams andfluoroquinolones, for example) ap-pear to be most susceptible to re-moval by efflux pumps, while hy-drophilic compounds such asaminoglycosides and vancomycinappear to be less so. A number ofantibiotic-resistant organisms suchas Campylobacter jejuni, E. coli, N.gonorrhoea and P. aeruginosa report-edly have elevated expressions ofmulti-drug transport efflux pumps.This expression markedly reducesthe effectiveness of antibioticsagainst these particular species.4. Alteration of bacterial targets.Antibiotics act at a number of differ-ent sites in the bacterial cell. β-lactams exert their therapeutic effectsby binding bacterial proteins called


penicillin-binding proteins (PBPs).When β-lactam antibiotics are boundto intracellular PBPs, bacterial pep-tidoglycan cell wall synthesis is in-hibited and bacterial cell wall integ-rity is disrupted. In contrast,fluoroquinolone antibiotics targetDNA gyrase and topoisomerase en-zymes that regulate bacterial DNAcoiling. Aminoglycoside antibioticsbind to bacterial ribosomes and in-terfere with protein synthesis.Rifampicin exerts its effect on bacte-rial cells by blocking the enzymeRNA polymerase. Sulfonamide an-tibiotics and trimethoprim inhibit theessential metabolic pathway fortetrahydrofolic acid synthesis in bac-teria. For all of these mechanisms, ge-netic mutations have arisen in whichthe bacterial target enzyme or pro-tein becomes altered so it no longerbinds to, or is inhibited by, an anti-biotic. In the case of the β-lactam an-tibiotics, mutated penicillin-bindingproteins will no longer bind to β-lactam drugs. Similar mutations oc-cur with bacterial DNA gyrase, DNA

polymerase and ribosomal proteinsso they no longer act as substratesfor their specific antibiotics. Bacte-rial mutation also leads to the de-velopment of resistant metabolicpathways in which key enzymes areno longer inhibited by antibiotics.For example, a mutation or overpro-duction of tetrahydrofolate reduc-tase by resistant bacteria overcomestrimethoprim inhibition.

Factors Contributing toAntibiotic Resistance

Antibiotic use in human medi-cine is widely accepted as the pri-mary factor driving development ofantibiotic resistance in humanpathogens. Use of antibiotics inother settings also contributes to theresistant gene pool where antibioticresistance can emerge and spread.In recent years, the direct relation-ship between increased antibioticuse and the development of resis-tance has become increasinglyclear.17 Using antibiotics to treat andprevent bacterial disease in humans,

animals and agriculture has grownrapidly in the last few decades.18 Aresult of this increased antibiotic useis that more microorganisms are ex-posed to antibiotics. Exposure to an-tibiotics appears to be the principalrisk factor for emergence and selec-tion of antibiotic-resistant bacteria(see Table 4).

Nearly 50 percent all antibiot-ics produced are used to treat in-fected livestock and to encouragegrowth in livestock and poultry.Drugs such as streptomycin and ox-ytetracycline are now routinely usedto prevent bacterial diseases in fruitsand vegetables. Antibiotics are alsoadded to livestock feed or otherwiseadministered prophylactically todomestic animals used for meat anddairy production as well as to hon-eybees and farm-raised fish.

Another way exposure is in-creased is through the use of chemi-cal disinfectants in soaps and deter-gents—a growing trend. This hasbeen a matter for recent concern sincea number of bacterial species havearisen that are less sensitive to com-monly used biocide antiseptics, dis-infectants and preservatives.19 In-creased use is particularly distress-ing because there is no evidence ofeffectiveness. According to theAmerican Medical Association,there are no scientific data provingantimicrobial soaps have any infec-tion-fighting benefit compared tostandard soap and water. As a re-sult, the AMA’s Council on Scien-tific Affairs recently released a state-ment urging the FDA to more closelyregulate use of antimicrobial agents

Table 4

Factors Contributing to Antibiotic Resistance

1. Widespread antibiotic use in livestock, agriculture and veterinary medicine

2. Unnecessary antibiotic use

3. Patient compliance• Prescr iptions for antibiotics are not filled, not taken correctly, not taken to completion

4. Exposure to antimicrobial soaps, solutions and lotions

5. Socioeconomic consideration in developing countries• Unskilled health practitioners• Misuse of antibiotics• Poor-quality drugs• Antibiotics widely available through non-professional channels• Poor surveillance and compliance• Poverty and poor hygiene


in products such as soaps, lotionsand washes. The Centers for Dis-ease Control (CDC) currently recom-mends using ordinary soap andwater solutions instead of antimi-crobial products and the U.S. Foodand Drug Administration has re-cently issued guidelines advisingagainst adding biocides to soapproducts.

The inappropriate or unneces-sary clinical use of antibiotics is akey factor contributing to the in-creased numbers of antibiotic-resis-tant bacteria. CDC has estimated thatone-third of the total number of pre-scriptions written yearly for antibi-otics may be unnecessary. Antibiot-ics are often prescribed when theorganism causing a particular infec-tion is unknown and, as in the caseof the common cold, is of viral ori-gin. Fear of potential malpractice liti-gation may also motivate physiciansto prescribe antibiotics in caseswhere their use might not be essen-tial. Patients and health care profes-sionals (including physicians, phy-sician assistants, pharmacists, po-diatrists, nurse practitioners andphysician’s assistants) all share re-sponsibility for such inappropriateuse. Any unnecessary use, regard-less of where it occurs, contributesto the global emergence of resistance.

Patients who do not take theirmedications as directed or who donot finish the course of their treat-ment risk exposing bacteria to sub-lethal concentrations of antibiotics,thus breeding more dangerous bac-teria. The high cost of certain antibi-otics may contribute to decisions by

low-income or uninsured patients todiscontinue or not renew prescrip-tions for some drugs. Patients maychose not to complete the currentcourse of therapy and save some oftheir prescription medicationsshould another illness arise. Inad-equate doses or duration of therapycontributes to resistance whether aresult of poor patient compliance, in-adequately dispensed drug productor a poorly designed dosing regimen.

An epidemic of antibiotic resis-tance exists in many developingcountries where various socioeco-nomic and behavioral factors createa prime environment for such bacte-rial strains.20 These behavioral fac-tors include misuse of antibiotics byunskilled health professionals, poordrug quality and the widespreadover-the-counter availability of an-tibiotics through untrained or unli-censed practitioners. In many third-world countries, antibiotics can bepurchased without a prescriptionfrom pharmacies, at outdoor mar-kets or from parapharmacies withunqualified staff. Often these drugsare of dubious origin and quality.Poor compliance and a lack of eco-nomic resources may mean that evenwhen antibiotics are correctly pre-scribed, the appropriate doses andtime course are not followed. Inad-equate surveillance and unhygienicconditions that foster the spread ofresistant bacteria further compoundthe problem.

The evolution of antibiotic resis-tance is a growing problem in theUnited States and around the world.Increased exposure to antibiotics

through unnecessary and inappro-priate use in human medicine, agri-culture and food production con-tribute to the problem and help breedmore dangerous bacteria. As a mat-ter of survival, bacteria continue todevelop novel ways of resisting an-tibiotics. To address this global prob-lem, two predominant health orga-nizations, WHO and CDC, have es-tablished practical guidelines andgoals for scientists and practitionersto research and develop new drugs,monitor the development of resis-tant bacteria, prescribe accurately,prevent infection and educate thepublic on antibiotic resistance andtheir role in preventing it.

Guidelines for ControllingAntibiotic Resistance

Certain organizations includ-ing the CDC, the Alliance for thePrudent Use of Antibiotics (APUA),and WHO have long served as lead-ers in developing programs to curbantibiotic resistance and improveantibiotic use. The CDC has identi-fied surveillance, research and de-velopment, and prevention and con-trol as the major programs neededto combat antibiotic resistance.21

Surveillance of antibiotic resis-tance patterns and associated anti-biotic-use patterns, both nationallyand internationally, are of primaryimportance in demonstrating andunderstanding antibiotic resistance.Reliable drug-susceptibility and an-tibiotic use information must bemade available to health care provid-ers and governments. By identifyingknown resistance and inappropriate


antibiotic use patterns these groupscan optimize treatment strategies tocontain antibiotic resistance andmove toward eradicating importantinfections.21-23 Further, by monitoringantibiotic resistance in agriculturalsettings, plant and animal health canbe ensured, leading to a safer foodsupply and a healthier population.

Applied microbial and productdevelopment can begin once drug-susceptibility information is avail-able, linking laboratory science andbacterial resistance patterns. Byknowing the risk factors for infec-tious and chronic diseases, scien-tists and the health care communitycan develop research-derived pre-vention, control and treatment strat-egies. CDC encourages research anddevelopment of new antibiotics andvaccines to combat drug resistantillnesses. In their June 2000 draftarticle “Public Health Action Planto Combat Antimicrobial Resistance– Domestic Issues,” the followingaction plan is recommended for ap-plied microbiological and productdevelopment research. In the areaof microbiological research it is im-portant to:• increase understanding of micro-

bial physiology, ecology, genet-ics and resistance mechanisms;

• augment existing research infra-structure to support a criticalmass of resistance mechanisms;

• translate research findings intoclinically useful products, suchas novel approaches to detect-ing, preventing and treating an-timicrobial resistant infections.

With regard to product development

research, the CDC emphasizes:• ensuring that researchers and

drug manufacturers are in-formed of current and projectedgaps in the arsenal of antimicro-bial drugs, vaccines and diag-nostics, and of potential marketsfor these antibiotic-resistantproducts;

• stimulating the development ofpriority antimicrobial resistantproducts for which market in-centives are inadequate, whilefostering their appropriate use;and

• optimizing the development anduse of veterinary drugs and relatedagricultural products that reducethe transfer of resistance to patho-gens that can infect humans.The third prong of the CDC plan

involves prevention and control. Byimproving local, state and federalpublic health infrastructure, plan-ning, delivery and evaluation of im-portant public health practices canbe supported. While the CDC canserve as a reference center for diag-nosing infectious diseases and test-ing for drug-resistance, public do-mains must play an active role intraining, educating, developingpolicy and properly implementingavailable control measures. Globalcommunication and cooperation isimperative to ensure that society canrespond to emerging infectious dis-ease threats. A summary of the CDCplan, extracted from the June 2000draft of the CDC “Public Health Ac-tion Plan to Combat AntimicrobialResistance – Domestic Issues” in-cludes the following steps to be

taken by health care and health careprofessionals.• Extend the useful life of antimi-

crobial drugs through prudentuse policies that discourageoveruse and misuse.

• Improve diagnostic testingpractices.

• Prevent infection transmissionthrough improved infection-con-trol methods and vaccine use.

• Prevent and control emergingantibiotic resistance problemsin agriculture.

• Ensure that comprehensive pro-grams to prevent and control an-tibiotic resistance involve a widevariety of non-governmentalpartners, and that the public be-comes part of prevention practice.The blueprint proposal by CDC

for combating antibiotic resistanceincludes increasing worldwidepreparations to fight diseases oncebelieved to be under control such astuberculosis and Streptococcuspneumoniae, and maintaining a vigi-lant watch for new diseases. Food-,water- and blood-borne contami-nants must be addressed throughvarious public measures, and expertsin various disciplines must be watch-ful of pathogens passed from ani-mals. Public health standards shouldstrive to protect the most vulnerablein society, such as children, pregnantwomen, the sick, elderly and peoplewithout access to health care.

Complementing the efforts of theCDC, WHO suggests interventionsand global action with eight recom-mendations (listed below) to na-tional governments to curb the glo-


bal problem of antibiotic resistance:24

1. Adopt WHO strategies and poli-cies for disease prevention, treat-ment and control, the most im-portant relate to immunization.

2. Educate health care workersand the public on appropriateuse of antimicrobials.

3. Contain resistance in hospitals.4. Reduce antimicrobial use in live-

stock.5. Increase research on new drugs

and vaccines.6. Build alliances and partner-

ships to increase access to anti-microbials in countries whereavailability is a problem.

7. Increase the availability of medi-cations on WHO’s list of essen-tial drugs.

8. Make effective antimicrobialsavailable to poor people.An important aspect of the

WHO plan is that it encompassesantibiotic resistance, disease preven-tion, treatment and control issues ona global level because infectious ill-ness is an international concern. Forthe full report and specific policies,see www.who.int. While nationaland global communication and co-operation is imperative to ensurethat society can respond to emerg-ing infectious disease threats in thefuture, it is local healthcare provid-ers and facilities that can make themost difference in controlling anti-biotic resistance. Every health careprovider can play a role in buildingawareness about antibiotic resis-tance and improving antibiotic use.

Health Care PractitionerInterventions

Responsibility for many of theantibiotic-resistance-curbing strate-gies outlined here rests with healthcare practitioners. By practicing pru-dent prescription strategy, staff andpublic education, and hygienic of-fice procedures, the health care pro-vider plays a vital role. Consider thatantibiotics comprise between 10 and40 percent of hospital drug expen-ditures. Almost one-half of the anti-biotics used in institutions resultsin treatment failures and adverseevents, which lead to longer hospi-tal stays. Approximately 25 percentof all adverse drug events in hospi-talized patients are antibiotic re-lated. In the community setting, pa-tients feel the financial burden ofresistance. Treating infectionscaused by resistant organisms oftenrequires newer or parenteral thera-pies, which are more expensive.These problems are a direct result ofthe generalized use of broad-spec-trum agents without appropriate an-tibiotic management strategies.25

There are opportunities to reduceor optimize antibiotic exposure,which will, in turn, slow the micro-bial march toward resistance.

Prescribing an antibiotic is dif-ficult at best. It takes a great deal ofknowledge to make optional deci-sions regarding a patient’s antibi-otic therapy. According to DavidGreenwood of the Division of Micro-biology and Infectious Diseases atQueen’s Medical Center inNottingham, U.K., “teaching aboutantimicrobial chemotherapy in

medical schools is generally spas-modic and uncoordinated.”26 Thisstatement is true of the education ofall health care providers as well.Once out of school, practitioners of-ten rely on practice guidelines, in-dustry input and institutional man-dates to firm up their knowledgeabout rational antimicrobial pre-scribing. Now more than ever it isimperative that health care provid-ers have a good working knowledgeof resistance patterns, diagnostictechniques and updated informationsources. Given enough exposure toan antibiotic, microbes will un-doubtedly become resistant. To date,there are no antibiotics to which re-sistance has not been demonstrated.

The risks of either undertreatingor overprescribing antibiotics for bac-terial infections or misprescribing anantibiotic for a viral infection cannotbe overemphasized. Each situationcan lead to bacterial resistance,which further complicates indi-vidual treatment decisions and con-tributes to the resistant gene pool inan institution or community. Oncethe decision to treat is made, the cor-rect antibiotic in the appropriatedose for the proper duration shouldbe selected. Many factors contributeto this decision-making process.

In the community, an accuratediagnosis is required to determinethe need for and type of antibiotictherapy required. The appropriatetargeted antibiotic must be selectedbased on knowledge of the specificpathogen and knowledge of localbacterial patterns. An importantpart of any therapy decision is


whether local flora includes or doesnot include resistant organisms. Inthe community, it is important to dif-ferentiate between viral and bacte-rial infections—only patients pre-senting with bacterial infectionsshould be treated with antibiotics.Reliance on, and knowledge of, newrapid bacterial identification meth-ods (rapid strep test, for example)may be useful when obtaining cul-ture and susceptibility tests is notprudent. Practitioners should useavailable diagnostic methods andtools to identify causative pathogensand target the treatment to that mi-crobe.27 Community practitionersshould resist patient pressure for an-tibiotics; avoid prescribing antibiot-

ics for the common cold and recog-nize the importance of relieving symp-toms when appropriate through de-congestants, cough medicine orantipuretics when an antibiotic isnot required.28 Empiric antibiotictherapy for various infectious diseaseconditions can be found in medicalsociety guidelines for treating spe-cific infections (for example, Infec-tious Disease Society of America,ISDA, and CDC). Naturally, theseguidelines may need to be adaptedfor specific practice settings.

In a hospital setting, practitio-ners must be aware of their environ-ment, which includes bacterial fac-tors as well as available tools fortreatment. In these settings, patients

are more likely to contract resistantnosocomial pathogens such as ex-tended-spectrum β-lactamase(ESBL)-producing E. coli or Klebsiellapneumoniae, MRSA, VRE and drug-resistant S. pneumoniae (DRSP).29

(Guidelines for controlling thespread of MRSA and VRE are listedin Tables 5 and 6, respectively.)

Practitioners should also keep inmind the capabilities of the hospital’smicrobiology lab. For example, is thelab able to adequately test for ESBLs?If not, how should that fact alter treat-ment selection? What is the preva-lence of resistant nosocomial patho-gens within a particular institutionand on which units? A small outly-ing community hospital, for ex-

Table 5

Basic Principles for Controlling the Spread of MRSASURVEILLANCE

• Review culture and susceptibility test results regularly• Maintain a list of patients known to be colonized or infected with MRSA• Conduct culture surveys to assess the prevalence of MRSA as necessary• Obtain surveillance cultures on admission from patients transferred from institutions known to have a high prevalence of MRSA• Develop a method for evaluating patients with histories of MRSA colonization or infection when they are readmitted

CONTACT PRECAUTIONS

• Place patients in private rooms or cohort with other patients who have MRSA• Wear gloves for contact with patient and environment• Wear gowns if likely to soil clothes• Use antimicrobial soap to wash hands• Use standard housekeeping techniques

MICROBIOLOGY SUPPORT

• Use appropriate susceptibility test methods• Notify clinicians and infection-control staff when an MRSA isolate is identified• Save isolates when appropriate• Conduct or obtain molecular typing when appropriate

ADDITIONAL MEASURES

• Consider decolonizing colonized or infected patients during epidemics or periods of hyperendemic transmission• Consider decolonizing colonized health care workers during epidemics or periods of hyperendemic transmission• Decrease use of antimicrobial agents• Consider instituting an isolation ward if routine measures do not control spread of MRSA

Source: Herwaldt LA. Control of methicillin-resistant Staphylococcus aureus in the hospital setting.Am J Med 1999;106(5A):11S-8S.


Table 6

Elements of a Successful Vancomycin-Resistant Enterococcus (VRE) Prevention and Control ProgramISOLATION FOR HOSPITALIZED PATIENTS

• The isolation strategy should be identical and uniform regardless ofwhether the patient is infected or colonized

• Barrier precautions should include private room, gown and gloves• Used dedicated equipment (stethoscopes, thermometers, glucose

meters)• Use chlorhexidine gluconate or an alcohol-based product to wash hands• Disinfect items removed from a patient’s room• Terminally clean the room when a patient is discharged

ISOLATION FOR PATIENTS IN AN OUTPATIENT DEPARTMENT

• Identify patient by flag or master list• Attempt to schedule infected/colonized patients on the same day• Dedicate a room or pod• Dedicate equipment (blood pressure cuff, stethoscope) and change

it at the end of the day• Use disposable equipment if possible• Disinfect all equipment at the end of the day or when a patient

leaves the room• Isolate patient when placed in room• Use hospital isolation precautions (see above)• Designate separate bathroom for patients with VRE• Clean room or pod at end of session• Communicate isolation status to other areas/services of the hospital

DISCONTINUING ISOLATION FOR VRE

• The patient must have three stool cultures or rectal swabs, eachseparated by a week, without VRE growth

• The infection-control department should reset the isolation flag onthat patient

• On high-risk services, consider obtaining surveillance cultures whena previously colonized patient is readmitted or placed on antibioticsor immunosuppressants

USE AND CONTROL OF ANTIBIOTICS

• Limit vancomycin use to institutional-specific guidelines• Reduce cephalosporin use/vary hospital formulary• Limit perioperative antibiotic use to efficacious drugs, appropriate

time periods, agents recommended in prophylaxis guidelines

COMMUN ICAT ION

Notify unit, pharmacy, infection control, medical and nursingpersonnel when a patient is:

• Admitted in the clinic either colonized or infected with VRE• Colonized/infected with VRE and isolated• Readmitted and isolated• Removed from isolation precautions

EDUCAT ION

All personnel• Families and volunteers, physicians, medical and pharmacy

students, nurses, nursing students and nurses aids, other healthcare workers (e.g. phlebotomists, radiology technicians) ancillarypersonnel (e.g. housekeepers, contractors) patients and families

Organism’s epidemiology• Significance and magnitude of the problem (US/state/hospital)• Transmission• Control measures including hand washing, isolating patients,

cleaning the environment, culturing patientsMethods• Didactic lectures• Training sessions• Cultures of hands, the environment• Data feedback

MICROBIOLOGY LABORATORY

• Speciate strains• Test all clinical isolates for resistance• Use a susceptibility technique that detects vancomycin resistance• Confirm vancomycin resistance• Determine percentage of isolates resistant to vancomycin• Save isolates• Examine phenotype and genotype (fingerprints) of VRE isolates

OUTBREAK MANAGEMENT

• Verify the diagnosis and define the problem (who, what, when, where)• Isolate all patients whether VRE colonized/infected or not• Group all patients geographically (this may require a VRE ward)• Group nursing staff• See non-infected before infected patients• Perform routine surveillance weekly• Save/type all isolates• Perform molecular epidemiology and use epidemiologic studies to

determine whether there is a point source outbreak• Obtain environmental and hand cultures when appropriate

Source: Per l TM. The threat of vancomycin resistance. Am J Med1999;106(5A):26S-37S.


ample, may not be confronted withthe types of resistance present in alarge teaching facility.30

Another important consider-ation is whether the patient is onlycolonized or has an infection. Is thepatient demonstrating signs of anovert infection presenting with feverand increased white blood cells, oris the patient simply colonized with-out objective signs of infection?31

When considering antibiotictherapy for an infection caused by aknown resistant pathogen, the prin-ciples for controlling institutionalantimicrobial resistance must bekept in mind.32-35 Empiric and/orspecific antibiotic therapies for sus-pected or documented pathogens areillustrated in Table 7.

Factors such as patient disabil-ity level and carry-over infectionfrom a prior hospital stay also factor

into treatment decisions. Infectionscontracted nosocomially may needto be treated with different agentsthan community-acquired infec-tions. In cases where culture andsusceptibility reports are not readilyavailable, such as in outlying facili-ties, practitioners must decide bothwhen to treat and what organismsare the most likely pathogens.

Prescribing antibiotics in long-term care facilities presents uniquechallenges in part because patientsare typically admitted from otherinstitutional settings and could havebeen exposed to resistant bacteria.The following are suggested guide-lines for antibiotic use in long-termcare facilities.36

• Maintain an antibiotic reviewprogram to monitor use of allsystemic and topical antibiotics.

• Develop and enforce antibiotic

restriction policies, especiallyfor oral and intravenous vanco-mycin, third-generation cepha-losporins and fluoroquinolonesantibiotics.

• Avoid treating asymptomaticbacteriuria; patients must dem-onstrate clinical or pre-deter-mined laboratory evidence ofinfection.

• Treatment of patients residingin long-term care facilitiesshould be cared out by healthcare practitioners who are fa-miliar with the nature of the pa-tient population.

• Use narrow-spectrum antibiot-ics whenever possible for em-piric coverage; when culturesusceptibilities have been veri-fied, the antibiotic spectrumshould be narrowed if possible.Because institutional settings

Table 7

Suggested Drug Therapy for Resistant OrganismsINTERVENTION COMMENT

Extended Spectrum ß-lactamase-Producing Organisms Carbapenems Drug of Choice(E. coli, K. pneumoniae)

ß-lactam/ß-lactamase inhibitor combo Must use high dosesAminoglycosides, Fluoroquinolones,Trimethoprim/Sulfamethoxazole Useful if organism is susceptible

Methicillin-Resistant Staphylococcus aureusVancomycin Drug of choice, adhere to recommendations for use in Table 8

Vancomycin-Resistant EnterococcusQuinupristin/Dalfopristin I.V. requires a central venous accessLinezolid Can be given as both P.O. and I.V.

Drug-Resistant Streptococcus pneumoniaeExtended-spectrum macrolides Use as outpatient or inpatient agentsNon-antipseudomonal, third generation Cephalosporin Ceftriaxone is most commonly usedFluoroquinolones targeted for respiratory use Levofloxacin, gatifloxacin, sparfloxacin, moxifloxacin, trovafloxacinVancomycin No demonstrated resistance at this point

Sources: Overcoming antimicrobial resistance. World health repor t on infectious diseases 2000. (http://www.who.int/infectious-disease-repor t).McKinnon PS. Managing antibiotic treatment costs: pharmacoeconomic considerations. ASHP 1999 Midyear Clinical Meeting. Orlando, Fla.Greenwood D. Preserving the miracle of antibiotics. Lancet 1995;345:1371.


can be a breeding ground for resis-tant bacteria, guidelines for control-ling antimicrobial resistance aremuch more stringent than in thecommunity. In addition to empha-sizing effective prescriptions, waysof controlling institutional antimi-crobial resistance include:37

• introducing limited antibioticchoices to the hospital formu-lary along with guidelines for ra-tional antibiotic use,

• changing empiric therapy to se-lected, narrow-spectrum therapyin response to culture and sus-ceptibility results as they be-come available,

• using antibiotics for the short-est effective duration,

• dosing antibiotics optimally,• using local susceptibility pat-

terns to aid in appropriate em-piric antibiotic selection,

• treating infections in outpa-tients with oral or home intra-venous antibiotics as soon aspossible,

• not prescribing antibiotics forviral syndromes,

• correctly interpreting cultureand sensitivity results, and

• limiting antimicrobial prophy-laxis to accepted indications.Institutions also commonly

overuse broad-spectrum, third-gen-eration cephalosporins, vancomycinand clindamycin, which select forVRE.38 Overusing ceftazidime mayselect for an ESBL strain of K.pneumoniae.39 Guidelines for usingvancomycin suggest that patientsneeding this therapy should meetone of six treatment criteria (see

Table 8). Vancomycin use outsidethese guidelines can promote drug-resistant enterococcus.

Patients in long-term care facili-ties with conditions such as persis-tent cough following a viral illnessor asymptomatic bacteriuria are of-ten unnecessarily treated with broad-spectrum antibiotics such asfluoroquinolones. The decision totreat may be based on patient andnursing convenience or an attemptto avoid a hospitalization. Unneces-sary therapy gives rise to bacterialselection and subsequent antibioticresistance that could lead to an in-stitutional epidemic. The followingguidelines can help reducefluoroquinolone resistance when useof this antibiotic class is indicated.40

• When using fluoroquinolones,optimize the drug’s naturalpharmacokinetic properties toachieve adequate concentration-dependant organism killing.

• Administer adequate dosage/duration for infection type andlocation.

• Avoid co-administration ofchelating medications such as

sucralfate or antacids that maybind to and chemically inacti-vate the fluoroquinolone.

• When treating difficult infec-tions such as P. aeruginosa, com-bine fluoroquinolones with an-other anti-pseudomonal drugthat has an alternate mechanismof action to maximize killing.

• Avoid excessively long (greaterthan 14 to 28 days) fluoro-quinolone treatment in hospi-talized patients.

• Avoid using fluoroquinolonesfor non-serious infections (cys-titis in young women and simpleupper respiratory tract infec-tions, for example).

• Consider fluoroquinolones insituations where therapeuticfailure is imminent (colonizingbacteria in severely ill patients,patients with MRSA infections,ischemic skin ulcer infections,non-correctable structural ab-normalities and patients withnon-removable foreign bodies).Once practitioners have the ap-

propriate information to effectivelyprescribe antimicrobials, they must

Table 8

Guidelines for Prudent Vancomycin UseVANCOMYCIN USE SHOULD BE LIMITED TO:

• Infections caused by gram-positive cocci that are resistant to ß-lactam antibiotics• Severe ß-lactam allergy• Antibiotic-associated diarrhea, unresponsive to metronidazole• Infective endocarditis prophylaxis as per the American Heart Association• Use of prosthetic material in high MRSA and coagulase-negative staphylococci-prevalent

areas• Empiric use only in areas with a high prevalence of MRSA and coagulase-negative

staphylococci and for pneumococcal meningitis until susceptibilities are availableSource: Virk A, Steckelberg JM. Clinical aspects of antimicrobial resistance. Mayo ClinProc 2000;75:200-14.


ensure that all members of theirhealth care team practice not onlyinfection-control procedures butproper and appropriate antibioticprescribing. To accomplish this, allstaff must be kept up to date on localinfection-control guidelines thatavoid or minimize the spread of re-sistant organisms. Prescribersshould be specifically aware of mi-crobiological susceptibility patternsand available methods for identify-ing pathogens. It is vital that the cor-rect antibiotic be used in the properamounts to effectively kill bacterialinfectious while promoting the leastamount of resistance. Cycling anti-biotics, a technique of systematic ro-tation of antibiotics, sometimescalled “crop rotation,” can keep po-tentially resistant organisms off-bal-ance. Additionally, reserving newerantibiotics for last-choice agents willhelp preserve their spectrum of an-timicrobial activities. Also, insteadof treating a suspected viral infec-tion with antibiotics, practitionersshould focus on symptom relief.41,42

Beyond accurate diagnosis anda carefully selected prescription,practitioners can further aid thebattle against resistant bacteriawhen treating infections in the com-munity at-large by educating pa-tients about antibiotics.

Patient EducationResponsibilities

Antibiotics are powerful medi-cations that only effectively eradi-cate bacterial infections such as strepthroat. They are useless against vi-ral infections such as the commoncold or flu. In fact, if an antibiotic istaken for a viral infection, the risk ofdeveloping an infection from an an-tibiotic-resistant bacteria increases,and if the antibiotic is taken for toolong or too short a time, the greaterthe chance a resistant organism willprevail. Health care providers in-cluding physicians, nurses andpharmacists have a key role in edu-cating patients about the importanceof antibiotic resistance and carefulantibiotic use. All health care pro-viders should discuss with their pa-tients the following ways to can catchan antibiotic-resistant infection.43,44

• Simply taking an antibiotic in-creases the risk because bacteriadevelop ways to resist theantibiotic’s effects in order to sur-vive. If enough bacteria arepresent, they can multiply andbecome problematic. These bac-teria can be transmitted to others.

• Infections can be contracted frompeople or objects around that areinfected with or contain resis-tant bacteria.

• Resistant bacteria are com-monly found among people inhospitals, nursing homes andday care centers.

• Improper hand washing in-creases the risk of catching alltypes of infections.Bacteria enter the body through

the nose, mouth and open wounds;however, the bacteria are oftentransmitted to those areas from thehands. Hand washing is the mosteffective way to prevent the spreadof any type of infection. Most Ameri-cans are untruthful about how of-ten they wash their hands. Typi-cally, hands should be washedprior to food preparation or insert-ing or removing contact lenses andafter treating a cut or wound onsomeone who is sick. Hands shouldalso be washed after using the bath-room, handling uncooked foodssuch as raw meat, poultry or fish,changing diapers, nose blowing,sneezing or coughing, playing withor touching a pet (especially reptilesand exotic animals), handling gar-bage or tending to someone who issick or injured. Patients should bereminded that antibiotic resistancenot only affects the sick, but otherfamily members and people the pa-tient comes in contact with.45

• Prescribers and consumers canhelp limit the emergence andspread of antibiotic resistant or-ganisms by following hygieneguidelines that have becomecommonplace in the medicalwork environment as well as inmany homes.

• An integral part of controllingantibiotic resistance is combat-ing the spread of resistant con-tagions. Several organizations,including the CDC, have pub-lished specific resistance pre-vention tips that can be appliedin both health care settings andat home. 24,44,45


To help prevent infection andlimit antibiotic resistance allhealth care providers shouldremind patients to:

• Handle, prepare and store foodcorrectly, wash fruits and veg-etables thoroughly; avoid raweggs and undercooked meat (es-pecially ground beef).

• Avoid using antibacterial soapsexcept when caring for someonewho is ill.

• Wash hands thoroughly usingsoap and water for 10 to 30seconds.

• Take all medication as directedfor the full course of treatment

• Discard unused antibiotics. Donot save for later use or to sharewith others. Do not take antimi-crobial drugs for viral infectionssuch as colds, coughs or the flu.

• Ask health care providers aboutways to help relieve symptoms forinfections not caused by bacteria.

• Not share medications that re-quire a delivery device (nasal in-halers, oral inhalers and eyedrops, for example) because theycan transmit infection betweenpatients.

• Get immunized and ask theirhealth care provider which im-munizations they or their chil-dren should receive.

ConclusionAddressing the growing prob-

lem of antibiotic resistance requiresa global approach. This issuecrosses the boundaries betweenmany disciplines. In order to retainthe effectiveness of the current anti-biotic drug arsenal and stay a stepahead of bacterial adaptation, prac-titioners must be vigilant about edu-cating themselves, their colleaguesand their patients. Practitionersmust also be vigilant about their ownhygiene practices, whether at homeor in clinics or institutions. To re-duce transmission of antibiotic re-sistance it is imperative that practi-tioners follow strict infection controland hygiene guidelines, such ashand washing between patient vis-its and isolation of hospitalized pa-tients with multi-drug resistant in-fections. They must take time to rec-ommend or prescribe the most ap-propriate antibiotic agent for eachsituation and do everything in theirpower to make sure patients under-stand the implications of not follow-ing dosing instructions—for them-selves and society at large.


1 . Hanson PF, Lederberg J (Editors). Antimicrobial re-sistance: issues and options. Washington (DC): NationalAcademy Press; 1998. pp. 10-11.

2 . Smith TL, Jarvis WR. Antimicrobial resistance in Sta-phylococcus aureus. Microbes Infection 1999;1:795-805.

3 . Turco TF, et al. Vancomycin intermediate-resistant Sta-phylococcus aureus. Ann Pharmacother 1998;32:758-60.

4 . Aeschilmann JR, et al. Analysis of vancomycin popu-lation susceptibility profiles, killing activity, postantibioticeffect against vancomycin-intermediate Staphylococcusaureus. Antimicrob Agents Chemother 1999;43:1914-8.

5 . Austrian R. Confront ing drug-resistant pneumo-cocci. Ann Intern Med 1994;121:807-9.

6 . Blower SM, Gerberding JL. Understanding, predict-ing and controlling the emergence of drug-resistant tu-b e rcu los is : a th e or e t ic a l fr a m e work . J Mo l M e d1998;76:624-36.

7 . Fox KK, Knapp JS. Antimicrobial resistance in Neis-seria gonorrhoea. Curr Opin Urology 1999;9:65-70.

8 . Hoffman PS. Antibiotic resistance mechanisms ofHelicobacter pylori. Can J Gastroenterol 1999;13:243-9.

9 . Hancock RE. Resistance mechanisms in Pseudomo-nas aeruginosa and other non-fermentative bacteria .Clin Infect Dis 1998;27(suppl.):S93-9.

10. Datta N, Hughes VM. Plasmids of the same Inc groupsin enterobacteria before and after the medical use ofantibiotics. Nature 1983;306:616-7.

11. Dancer SJ, et al. Isolation and characterization ofcoliforms from glacial ice and water in Canada’s HighArctic. J Appl Bacteriol 1997;82:597-609.

12. Nikaido H, et al. Porin channels in Eschericia coli:studies w ith be ta- lactam in intact ce l ls. J Bacteriol1983;153:237-40 .

13. Neu HC. The crisis in antibiotic resistance. Science1992;257:1064-73 .

14. Yoneyama H, Nakae T. Mechanism of efficient elimi-nation of protein D2 in outer membrane of imipenem-resistant Pseudomonas aeruginosa. Antimicrob AgentsChemother 1993;37:2385-90.

15. Proctor RA, et al. Staphylococcal small colony vari-ants have novel mechanisms for antibiotic resistance.Clin Infect Dis 1998;27(suppl 1):S68-74.

16. Nika ido H. Antibiotic resistance caused by gram-n e g a t iv e mu l t idrug e f f lux pumps . C l in In f e c t D is1998;27(suppl. 1):S32-41.

17. Cristino JM. Corre lation between consumption ofantimicrobials in humans and development of resistantbacteria. Int J Antimicrob Agents 1999;12:199-202.

18. van den Bogaard AE, Stobberingh EE. Epidemiol-ogy of resistance to antibiotics. Links between animalsa nd hum a ns . In t J An t im icrob Ag e n ts 2000May;14(4):327-35.

19. Russe l AD. Bacter ia l resistance to disinfectants:present knowledge and future problems. J Hosp Infect1998;43(suppl):S57-68.

20. Okeke IN, et al. Socioeconomic and behavioral fac-tors leading to acquired bacterial resistance in devel-oping countries. Emerg Infect Dis 1999;5:18-27.

21. Centers for Disease Control and Prevention. Address-ing emerging infectious disease threats: a preventionstrategy for the United States. Atlanta (GA): US Dept. ofHealth and Human Services, Public Health Service; 1994.

22. Centers for Disease Control and Prevention. Pre-venting emerging infectious diseases: a strategy for the21st century. Atlanta(GA): U.S. Dept. of Health and Hu-man Services, Public Health Service; 1998.

23. NCID: Prevent ing emerging infect ious diseases.(http://www.cdc.gov/ncidod/emergplan/3executive.htm).Accessed 8/10/0 .

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26. McKinnon PS. Managing antibiotic treatment costs:pharmacoeconomic considerations. ASHP 1999 Mid-year Clinical Meeting. Orlando, F la.

27. Greenwood D. Preserving the mir acle of antibiotics.Lance t 1995;345:1371.

28. Ta lbot J . Ant ibiot ic resistance : de tect ion/mecha-n isms/con tro l . (h t tp : //bugs . u a h . u a lb e r t a . c a / e du/labantib/tsld008.htm). Accessed 8/10/00.

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___________________________________REFERENCES


1. The mechanism by whichgenes for antibiotic resistanceare spread by bacteriophage iscalled:a) transformationb) conjugationc) transpositiond) transduction

2. Porin proteins:a) are pumps that remove

antibiotics from bacterial cellsb) are penicillin-binding proteinsc) allow hydrophobic molecules

to enter bacteriad) are channels by which water-

soluble antibiotics can enterbacteria

3. Resistance to fluoroquinoloneantibiotics may be caused by:a) mutation of bacterial penicillin-

binding proteinsb) mutation of bacterial ribo-

somesc) mutation of bacterial DNA

gyrased) mutation of bacterial DNA

polymerase

4. Resistance to this antibioticmay occur when bacteriadevelop alternate metabolicpathways.a) vancomycin c) imipenemb) trimethoprim d) chloramphenicol

5. Antibiotics are currently usedin which of the following?a) livestock feedb) farm animalsc) farm-raised fishd) all of the above

6. According to the AmericanMedical Association there is noscientific data proving thatantimicrobial soaps have anyinfection-fighting benefit overstandard soap and water.a) true b) false

7. Which of the following factorsmay contribute to the develop-ment of antibiotic resistance indeveloping countries?a) unregulated antibiotic useb) poor drug qualityc) unskilled health practitionersd) all of the above

8. Transposons are:a) small viruses that infect bacteriab) self-replicating, circular

strands of bacterial RNAc) also called “jumping genes”d) not associated with antibiotic

resistance

9. According to the Centers forDisease Control, _____ percentof all yearly prescriptions forantibiotics may be unnecessary.a) 10 c) 25b) 15 d) 33

10.The Centers for DiseaseControl recommendations forpreventing the spread ofantibiotic resistance include allof the following except:a) proper immunizationsb) counseling patients to take

antibiotics exactly as prescribedc) not using antibiotics for viral

infectionsd) counseling patients to take

antibiotics until they feel better

11. Which of the following globalobjectives does the Centers forDisease Control plan to developin the future?a) implement a national plan for

resistance surveillance; ensurereliability of susceptibility datafor surveillance; monitorpatterns of antibiotic use

b) survey antibiotic resistance andencourage applied microbiologi-cal and product developmentresearch as well as resistanceprevention and control

c) increase understanding ofmicrobial physiology, ecologyand mechanisms of resis-tance; augment existingresearch infrastructure;translate research findingsinto clinically useful products

d) extend useful life of antimicro-bial drugs; improve diagnostictesting practices; improveinfection control methods andvaccine use

12.All of the following are consideredantibiotic resistance control tipsexcept:a) take medicine exactly as

prescribed by health careprovider

b) take the antibiotic until it isfinished, even if you feel better

c) use antibacterial soaps whenwashing hands

d) do not pressure your healthcare provider into prescribingantibiotics

Bacteria Battle Back:Addressing AntibioticResistanceAntibiotic Resistance Assessment Questions


13.Which of the following state-ments best characterizes theeconomics of antibiotic use?a) developing resistance

patterns in the communityallow for cheaper, morecommon antibiotic use

b) antibiotics comprise between50 and 70 percent of a hospitalpharmacy’s drug budget

c) antibiotic failures in the hospitallead to rapid discharges backto the community in an effort toevade resistance

d) antibiotic cost escalationsprevail when newer, moreexpensive agents or intrave-nous therapy is warranted totreat infections

14.Education is the key to overcoming antibiotic resistance. Allof the following principles areimportant to overcome resis-tance except:a) antibiotics should routinely be

prescribed post viral illness toward off bacterial infection

b) antibiotics should be usedappropriately with the correctindication, dose, and identifi-cation and adherence todefinitive monitoring parameters

c) antibiotics can be cycled toavoid resistance

d) practitioners should adhere toinfection control guidelines

15.Under which circumstancesshould vancomycin be used?a) when there is a low preva-

lence of methicillin-resistantStaphylococcus aureus(MRSA)

b) this drug is always a good firstchoice

c) when there is no b-lactamallergy

d) when infections are caused bygram-positive cocci resistantto b-lactam antibiotics

16.A three-year-old child in thecommunity has received acourse of amoxicillin for an otitismedia infection. The childattends a child-care program fulltime. The course of amoxicillinfails. The child returns to thepractitioner’s office four daysafter starting the amoxicillincontinuing to be febrile andtugging at the ears. Which of thefollowing would be the mostreasonable antibiotic selectionfor home therapy for this childfrom the selections provided?c) antibiotics can be cycled to

avoid resistancea) tetracyclineb) extended-spectrum macrolidec) fluoroquinoloned) vancomycin

17.Fluoroquinolones are powerfulantibiotics that retain a broadspectrum of activity and areuseful agents in treating a widearray of both inpatient andoutpatient infections.Fluoroquinolone resistance isproblematic in that the organismthat is resistant to onefluoroquinolone will be resistantto all agents in thefluoroquinolone class. All of thesteps listed below are aimed atreducing fluoroquinoloneresistance except:a) fluoroquinolones should be

used as first line therapy intreating many infections

b) the natural pharmacokineticproperties of thefluoroquinolones should bemaximized for adequateconcentration-dependantkilling

c) avoid therapy that lasts longerthan 14 to 28 days

d) avoid prescribing for simpleupper respiratory tractinfections and uncomplicatedcystitis in young women

18. Which of the following areantibiotic control measures thatshould be followed in long-termcare facilities?a) develop and enforce antibiotic

restriction policies especiallywith oral and intravenousvancomycin, third-generationcephalosporins andfluoroquinolone antibiotics

b) avoid treating asymptomaticbacteriuria, require patients todemonstrate clinical or pre-determined laboratoryevidence of infection

c) narrow-spectrum antibioticsshould be used wheneverpossible for empiric coverage

d) all of the above controlmeasures should be followed

19.In the era of antibiotic resistanceand the publicity of the problem,“catching” a resistant organismis concerning. All of the followingare ways to contract a resistantorganism except:a) simply taking an antibiotic

because this allows somebacteria to fight off the effect ofthe antibiotic in order to survive

b) having contact with peoplewho are in hospitals, nursinghomes or day care centers

c) improper hand washingd) catching a cold

20.The basic principles for control-ling the spread of MRSA include:a) notify clinicians and infection-

control staff when an MRSAisolate is identified

b) increase use of antimicrobialagents

c) maintain a list of patientsknown to be colonized orinfected with MRSA

d) a and c only


CE Registration, Answer Sheet and Program EvaluationThis lesson affords 2 (two) contact hours (0.2CEU) of continuing education credit in all states that recognizethe American Council on Pharmaceutical Education (ACPE) approved providers.

The Massachusetts College of Pharmacy and Health Sciences and/or the American Academy of NursePractitioners will grant 2 contact hours to pharmacists and/or nurse practitioners who obtain a grade of70% or higher on the post test. Those not successfully completing the post test on the first try will receive noticeand be offered another chance to answer the post-test at an additional charge of $6.No post-test questionnaires will be processed after November, 2003.To receive statements of credit return the completed answer sheet and a processing fee of $6.00 to:

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Make checks payable to MCPHS. Fees not refundable or transferable.Fax copy accepted with credit card payment. Please indicate Master Card or Visa.

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Massachusetts College of Pharmacy and Health Sciences is approved by the American Councilon Pharmaceutical Education as a provider of continuing pharmaceutical education.Pharmacists successfully participating in this program will receive a statement of credit for 2contact hours (0.2CEUs) within 3-4 weeks after receiving the completed answer sheet.Initial release date November, 2000. ACPE# 026-999-00-206-H01

……………………………………………………………………………………………….............................…….........Answer each question by circling the correct answer in the space provided

Bacteria Battle Back: Addressing Antibiotic Resistance – ACPE # 026-999-00-206-H01

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Bacteria Battle Back - Addressing Antibiotic Resistance