Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 13) ppt

Chemotherapy of infectionsSYNOPSIS Infection is a major category of human disease and skilled management of antimicrobial drugs is of the first importance.The term chemotherapy is used f

SECTION 3

INFECTION AND INFLAMMATION

Chemotherapy of infections

SYNOPSIS

Infection is a major category of human disease

and skilled management of antimicrobial drugs

is of the first importance.The term

chemotherapy is used for the drug treatment of

parasitic infections in which the parasites

(viruses, bacteria, protozoa, fungi, worms) are

destroyed or removed without injuring the

hostThe use of the term to cover all drug or

synthetic drug therapy needlessly removes a

distinction which is convenient to the clinician

and has the sanction of long usage By

convention the term is also used to include

therapy of cancer.

• Classification of antimicrobial drugs

• How antimicrobials act

• Principles of optimal antimicrobial therapy

• Use of antimicrobial drugs: choice;

combinations; chemoprophylaxis and

pre-emptive suppressive therapy

• Problems with antimicrobial drugs:

resistance; opportunistic infection; masking

of infections

• Antimicrobial drugs of choice (Reference

table)

HISTORY

Many substances that we now know to possess

therapeutic efficacy were first used in the distant

past The Ancient Greeks used male fern, and the Aztecs chenopodium, as intestinal anthelminthics The Ancient Hindus treated leprosy with chaul-moogra For hundreds of years moulds have been applied to wounds, but, despite the introduction of mercury as a treatment for syphilis (16th century), and the use of cinchona bark against malaria (17th century), the history of modern rational chemo-therapy did not begin until Ehrlich1 developed the idea from his observation that aniline dyes selec-tively stained bacteria in tissue microscopic prepa-rations and could selectively kill them He invented the word 'chemotherapy' and in 1906 he wrote:

In order to use chemotherapy successfully, we must search for substances which have an affinity for the cells of the parasites and a power of killing them greater than the damage such substances cause to the organism itself This means we must learn

to aim, learn to aim with chemical substances.

The antimalarials pamaquin and mepacrine were developed from dyes and in 1935 the first sulphonamide, linked with a dye (Prontosil), was introduced as a result of systematic studies by Domagk.2 The results obtained with sulphonamides

1 Paul Ehrlich (1854-1915), the German scientist who was the pioneer of chemotherapy and discovered the first cure for syphilis (Salvarsan).

2 Gerhard Domagk (1895-1964), bacteriologist and pathologist, who made his discovery while working in Germany Awarded the 1939 Nobel prize for Physiology or Medicine, he had to wait until 1947 to receive the gold medal because of Nazi policy at the time.

II

in puerperal sepsis, pneumonia and meningitis

were dramatic and caused a revolution in scientific

and medical thinking

In 1928, Fleming3 accidentally rediscovered the

long-known ability of Penicillium fungi to suppress

the growth of bacterial cultures but put the finding

aside as a curiosity

In 1939, principally as an academic exercise,

Florey4 and Chain5 undertook an investigation of

antibiotics, i.e substances produced by

microorgan-isms that are antagonistic to the growth or life of

other microorganisms.6 They prepared penicillin

and confirmed its remarkable lack of toxicity.7

When the preparation was administered to a

policeman with combined staphylococcal and

strepto-coccal septicaemia there was dramatic

improve-ment; unfortunately the manufacture of penicillin

(in the local Pathology Laboratory) could not keep

pace with the requirements (it was also extracted

from the patient's urine and re-injected); it ran out

and the patient later succumbed to infection

3 Alexander Fleming (1881-1955) He researched for years on

antibacterial substances that would not be harmful to

humans His findings on penicillin were made at St Mary's

Hospital, London.

4 Howard Walter Florey (1898-1969), Professor of Pathology

at Oxford University.

5 Ernest Boris Chain (1906-79) Biochemist Fleming, Florey

and Chain shared the 1945 Nobel prize for Physiology or

Medicine.

6 Strictly, the definition should refer to substances that are

antagonistic in dilute solution because it is necessary to

exclude various common metabolic products such as

alcohols and hydrogen peroxide The term antibiotic is now

commonly used for antimicrobial drugs in general, and it

would be pedantic to object to this Today, many

commonly-used antibiotics are either fully synthetic or are produced by

major chemical modification of naturally produced

molecules: hence, 'antimicrobial agent' is perhaps a more

accurate term, but 'antibiotic' is much the commoner usage.

7 The importance of this discovery for a nation at war was

obvious to these workers but the time, July 1940, was

unpropitious, for invasion was feared The mood of the time

is shown by the decision to ensure that, by the time invaders

reached Oxford, the essential records and apparatus for

making penicillin would have been deliberately destroyed;

the productive strain of Penicillium mould was to be secretly

preserved by several of the principal workers smearing the

spores of the mould into the linings of their ordinary clothes

where it could remain dormant but alive for years; any

member of the team who escaped (wearing the right clothes)

could use it to start the work again (Macfarlane G 1979

Howard Florey, Oxford).

Subsequent development amply demonstrated the remarkable therapeutic efficacy of penicillin

Classification of antimicrobial drugs

Antimicrobial agents may be classified according to the type of organism against which they are active and in this book follow the sequence:

Antibacterial drugs Antiviral drugs Antifungal drugs Antiprotozoal drugs Anthelminthic drugs

A few antimicrobials have useful activity across several of these groups For example, metronida-zole inhibits obligate anaerobic bacteria (such as

Clostridium perfringens) as well as some protozoa

that rely on anaerobic metabolic pathways (such as

Trichomonas vaginalis).

Antimicrobial drugs have also been classified broadly into:

• bacteriostatic, i.e those that act primarily by

arresting bacterial multiplication, such as sulphonamides, tetracyclines and chloramphenicol

• bactericidal, i.e those which act primarily by

killing bacteria, such as penicillins, cephalosporins, aminoglycosides, isoniazid and rifampicin

Less used in modern clinical practice, the classi-fication is somewhat arbitrary because most bact-eriostatic drugs can be shown to be bactericidal at high concentrations, under certain incubation conditions in vitro and against some bacteria Bactericidal drugs act most effectively on rapidly dividing organisms Thus a bacteriostatic drug, by reducing multiplication, may protect the organism from the killing effect of a bactericidal drug Such mutual antagonism of antimicrobials may be clinically important, but the matter is complex because of the multiple and changing factors that determine each drug's efficacy at the site of infection In vitro tests of antibacterial synergy and

P R I N C I P L E S O F A N T I M I C R O B I A L C H E M O T H E R A P Y 11

antagonism may only distantly replicate these

conditions

Probably more important than whether an

anti-biotic is bacteriostatic or bactericidal in vitro is

whether its antimicrobial effect is

concentration-dependent or h'rae-concentration-dependent Examples of the

former include the quinolones and

aminoglyco-sides in which the outcome is related to the peak

antibiotic concentration achieved at the site of

infection in relation to the minimum concentration

necessary to inhibit multiplication of the organism

(the Minimum Inhibitory Concentration, or MIC)

These antimicrobials produce a prolonged

inhibi-tory effect on bacterial multiplication (the

Post-Antibiotic Effect, or PAE) which suppresses growth

until the next dose is given In contrast, agents

such as the f3-lactams and macrolides have more

modest PAEs and exhibit time-dependent killing;

for optimal efficacy, their concentrations should be

kept above the MIC for a high proportion of the

time between each dose (Fig 11.1)

Figure 11.1 shows the results of an experiment

in which a culture broth initially containing 106

bacteria per ml is exposed to various concentrations

of two antibiotics one of which exhibits

concentra-tion- and the other time-dependent killing The

'Control' series contains no antibiotic, and the other

series contain progressively higher antibiotic

con-centrations from 0.5 x to 64 x the MIC Over 6 hours

incubation, the time-dependent antibiotic exhibits

killing but there is no difference between the 1 x MIC

and 64 x MIC The additional cidal effect of rising

concentrations of the antibiotic which has

concen-tration-dependent killing can be clearly seen

How antimicrobials act

It should always be remembered that drugs are

seldom the sole instruments of cure but act together

with the natural defences of the body

Antimicro-bials act at different sites in the target organism as

follows:

The cell wall This gives the bacterium its

charac-teristic shape and provides protection against the

much lower osmotic pressure of the environment

Bacterial multiplication involves breakdown and

extension of the wall; interference with these pro-cesses prevents the organism from resisting osmotic pressures, so that it bursts As the cells of higher, e.g human, organisms do not possess this type of wall, drugs that act here may be especially selective; obviously, the drugs are effective only against grow-ing cells They include: penicillins, cephalosporins, vancomycin, bacitracin, cycloserine

The cytoplasmic membrane inside the cell wall is the site of most of the microbial cell's biochemical activity Drugs that interfere with its function include: polyenes (nystatin, amphotericin), azoles (fluconazole, itraconazole, miconazole), polymyxins (colistin, polymyxin B)

Protein synthesis Drugs that interfere at various points with the build-up of peptide chains on the ribosomes of the organism include: chlorampheni-col, erythromycin, fusidic acid, tetracyclines, amino-glycosides, quinupristin/dalfopristin, linezolid Nucleic acid metabolism Drugs may interfere

• directly with microbial DNA or its replication or repair, e.g quinolones, metronidazole, or with RNA, e.g rifampicin

• indirectly on nucleic acid synthesis, e.g

sulphonamides, trimethoprim

Principles of antimicrobial chemotherapy

The following principles, many of which apply

to drug therapy in general, are a guide to good practice with antimicrobial agents

Make a diagnosis as precisely as is possible and define the site of infection, the organism(s) respons-ible and their sensitivity to drugs This objective will be more readily achieved if all relevant biolo-gical samples for the laboratory are taken before treatment is begun Once antimicrobials have been administered, isolation of the underlying organism may be inhibited and its place in diagnostic samples may be taken by resistant, colonizing bacteria which obscure the true causative pathogen

Concentration dependent killing

Fig I I I Efficacy of antimicrobials: examples of

concentration-dependent and time-concentration-dependent killing (see text) (cfu =

colony-forming units).

Remove barriers to cure, e.g lack of free drainage

of abscesses, obstruction in the urinary or

respira-tory tracts, infected intravenous catheters

Decide whether chemotherapy is really necessary.

As a general rule, acute infections require

chemo-therapy whilst other measures may be more

impor-tant for resolution of chronic infections For

example, chronic abscess or empyema respond

poorly to antibiotics alone, although

chemothera-peutic cover may be essential if surgery is undertaken

in order to avoid a flare-up of infection or its

dissemination during the breaking down of tissue

barriers Even some of the acute infections are better

managed symptomatically than by antimicrobials;

thus the risks of adverse drug reactions for

previously healthy individuals may outweigh the

modest clinical benefits that follow antibiotic therapy

throat

Select the best drug This involves consideration

of:

— specificity; ideally the antimicrobial activity of

the drug should match that of the infecting organisms Indiscriminate use of broad-spectrum drugs promotes antimicrobial resistance and encourages opportunistic infections (see p 210) At the beginning of treatment, empirical 'best guess' chemotherapy

of reasonably broad spectrum must often be given because of the absence of precise identification of the responsible microbe The spectrum of cover should be narrowed once the causative organisms have been identified

— pharmacokinetic factors; to ensure that the chosen

drug is capable of reaching the site of infection

in adequate amounts, e.g by crossing the blood-brain barrier

— the patient; who may previously have exhibited

allergy to antimicrobials or whose routes of elimination may be impaired, e.g by renal disease

Administer the drug in optimum dose and

fre-quency and by the most appropriate route(s) Inadequate dose may encourage the development

of microbial resistance In general, on grounds of practicability, intermittent dosing is preferred to continuous infusion Plasma concentration monitor-ing can be performed to optimise therapy and reduce adverse drug reactions (e.g aminoglycosides, vancomycin, 5-flucytosine)

Continue therapy until apparent cure has been

achieved; most acute infections are treated for 5-10 days There are many exceptions to this, such

as typhoid fever, tuberculosis and infective endo-carditis, in which relapse is possible long after apparent clinical cure and so the drugs are continued for a longer time, determined by comparative or observational trials Otherwise, prolonged therapy is

to be avoided because it increases costs and the risks of adverse drug reactions

Test for cure In some infections, microbiological

U S E O F A N T I M I C R O B I A L D R U G S 11

proof of cure is desirable because disappearance of

symptoms and signs occurs before the organisms

are eradicated This is generally restricted to

espe-cially susceptible hosts e.g urinary tract infection in

pregnancy Microbiological culture must be done, of

course, after withdrawal of chemotherapy

Prophylactic chemotherapy for surgical and

dental procedures should be of very limited

dura-tion, often only a single large dose being given It

should start at the time of surgery to reduce the risk

of selecting resistant organisms prior to surgery

(see p 207)

Carriers of pathogenic or resistant organisms, in

general, should not routinely be treated to remove

the organisms for it may be better to allow natural

re-establishment of a normal flora The potential

benefits of clearing carriage must be weighed

carefully against the inevitable risks of adverse

drug reactions

Use of antimicrobial drugs

CHOICE

The general rule is that selection of antimicrobials

should be based on identification of the microbe

and sensitivity tests All appropriate specimens

(blood, pus, urine, sputum, cerebrospinal fluid)

must therefore be taken for examination before

administering any antimicrobial

This process inevitably takes time and therapy at

least of the more serious infections must usually be

started on the basis of the 'best guess' With the

worldwide rise in prevalence of multiply-resistant

bacteria during the past decade, knowledge of local

antimicrobial resistance rates is an essential

pre-requisite to guide the choice of local 'best guess' (or

'empirical') antimicrobial therapy Publication of

these rates (and corresponding guidelines for choice

of empirical antibiotic therapy for common

infec-tions) is now an important role for clinical

diag-nostic microbiology laboratories Such guidelines

must be reviewed regularly to keep pace with

changing resistance rates

When considering 'best guess' therapy, infections may be categorised as those in which:

1 Choice of antimicrobial follows automatically from the clinical diagnosis because the causative organism is always the same, and is virtually always sensitive to the same drug, e.g

meningococcal septicaemia (benzylpenicillin), some haemolytic streptococcal infections, e.g scarlet fever, erysipelas (benzylpenicillin), typhus (tetracycline), leprosy (dapsone with rifampicin)

2 The infecting organism is identified by the clinical diagnosis, but no safe assumption can be made as to its sensitivity to any one

antimicrobial, e.g tuberculosis

3 The infecting organism is not identified by the clinical diagnosis, e.g in urinary tract infection

or abdominal surgical wound infection

In the second and third categories particularly, choice of an antimicrobial may be guided by:

Knowledge of the likely pathogens (and their

current local susceptibility rates to antimicrobials)

in the clinical situation Thus cephalexin may be a reasonable first choice for lower urinary tract infection (coliform organisms — depending on the prevalence of resistance locally), and benzylpeni-cillin for meningitis in the adult (meningococcal or pneumococcal)

Rapid diagnostic tests Use of tests of this type is

about to undergo a revolution with the widespread introduction of affordable, sensitive and specific nucleic acid detection assays (especially those based

on the Polymerase Chain Reaction, PCR) Classi-cally, antimicrobials were selected in the knowledge that the organism was a positive or Gram-negative coccus or bacillus, observed by direct staining of body secretions or tissues It is necessary

to know the current local sensitivities to anti-microbial drugs for organisms so classified Thus flucloxacillin may be indicated when clusters of Gram-positive cocci are found (indicating staphylo-cocci), but vancomycin is preferred in many hospitals with a high prevalence of

methicillin-resistant Staphylococcus aureus (MRSA) The use of

Ziehl-Neelsen staining may reveal acid-fast tubercle bacilli Light microscopy will remain useful in this

way for many years to come, but use of PCR to

detect DNA sequences specific for individual

micro-bial species or resistance mechanisms greatly speeds

up the institution of definitive, reliable therapy

These methods are already widely used for

diag-nosing meningitis (detecting Neisseria meningitidis,

Streptococcus pneumoniae and Haemophilus influenzae)

and tuberculosis (including detection of rifampicin

resistance)

Modification of treatment can be made later

if necessary, in the light of culture and sensitivity

tests Treatment otherwise should be changed only

after adequate trial, usually 2-3 days, for over-hasty

alterations cause confusion and encourage the

emergence of resistant organisms

Route of administration Parenteral therapy (which

may be i.m or i.v.) is preferred for therapy of

serious infections because high therapeutic

concen-trations are achieved reliably and rapidly Initial

parenteral therapy should be switched to the oral

route whenever possible once the patient has

improved clinically and as long as they are able

to absorb the drug i.e not with vomiting, ileus

or diarrhoea Many antibiotics are, however, well

absorbed orally, and the long-held assumption that

prolonged parenteral therapy is necessary for

adequate therapy of serious infections (such as

osteomyelitis) is often not supported by the results

of clinical trials

Although i.v therapy is usually restricted to

hospital patients, continuation parenteral therapy

of certain infections, e.g cellulitis, in patients in the

community is sometimes performed by

specially-trained nurses The costs of hospital stays are

avoided, but this type of management is suitable

only when the patient's clinical state is stable and

oral therapy is not suitable

Oral therapy of infections is usually cheaper

and avoids the risks associated with maintenance

of intravenous access; on the other hand, it may

expose the gastrointestinal tract to higher local

con-centrations of antibiotic with consequently greater

risks of antibiotic-associated diarrhoea Some

anti-microbial agents are available only for topical use

to skin, anterior nares, eye or mouth; in general it

is better to avoid antibiotics that are also used for

systemic therapy because topical use may be

espe-cially likely to select for resistant strains Topical

therapy to the conjunctival sac is used for therapy

of infections of the conjunctiva and the anterior chamber of the eye

Other routes used for antibiotics on occasion include inhalational, rectal (as suppositories), intra-ophthalmic, intrathecal (to the CSF), and by direct injection or infusion to infected tissues

COMBINATIONS

Treatment with a single antimicrobial is sufficient for most infections The indications for use of two

or more antimicrobials are:

• To avoid the development of drug resistance, especially in chronic infections where many bacteria are present (hence the chance of a resistant mutant emerging is high), e.g

tuberculosis

• To broaden the spectrum of antibacterial activity: (1) in a known mixed infection, e.g peritonitis following gut perforation or (2) where the infecting organism cannot be predicted but treatment is essential before a diagnosis has been reached, e.g septicaemia complicating

neutropenia or severe community-acquired pneumonia; full doses of each drug are needed

• To obtain potentiation (or 'synergy'), i.e an effect unobtainable with either drug alone, e.g

penicillin plus gentamicin for enterococcal endocarditis

• To enable reduction of the dose of one component and hence reduce the risks of adverse drug reactions, e.g flueytosine plus

amphotericin B for Cryptococcus neoformans

meningitis

Selection of agents A bacteriostatic drug, by

red-ucing multiplication, may protect the organism from a bactericidal drug (see above, Antagonism) When a combination must be used blind, it is theo-retically preferable to use two bacteriostatic or two bactericidal drugs, lest there be antagonism

CHEMOPROPHYLAXIS AND PRE-EMPTIVE SUPPRESSIVE THERAPY

It is sometimes assumed that what a drug can cure

it will also prevent, but this is not necessarily so

U S E O F A N T I M I C R O B I A L D R U G S 11

The basis of effective, true, chemoprophylaxis is

the use of a drug in a healthy person to prevent

infection by one organism of virtually uniform

susceptibility, e.g benzylpenicillin against a group

A streptococcus But the term chemoprophylaxis is

commonly extended to include suppression of

existing infection To design effective

chemopro-phylaxis it is essential to know the organisms

causing infection and their local resistance patterns,

and the period of time the patient is at risk A

narrow-spectrum antibiotic regimen should be

administered only during this period — ideally for

a few minutes before until a few hours after the

risk period It can be seen that it is much easier to

define chemotherapeutic regimens for short-term

exposures (e.g surgical operations) than it is for

longer-term and less well defined risks The main

categories of chemoprophylaxis may be summarised

as follows:

• True prevention of primary infection: rheumatic

fever,8 recurrent urinary tract infection

• Prevention of opportunistic infections, e.g due to

commensals getting into the wrong place

(bacterial endocarditis after dentistry and

peritonitis after bowel surgery) Note that these

are both high-risk situations of short duration;

prolonged administration of drugs before surgery

would result in the areas concerned (mouth and

bowel) being colonised by drug-resistant

organisms with potentially disastrous results (see

below) Immunocompromised patients can benefit

from chemoprophylaxis, e.g prophylaxis of

Gram-negative septicaemia complicating neutropenia

with an oral quinolone or of Pneumocystis carinii

pneumonia with co-trimoxazole

• Suppression of existing infection before it causes

overt disease, e.g tuberculosis, malaria, animal

bites, trauma

• Prevention of acute exacerbations of a chronic

infection, e.g bronchitis, in cystic fibrosis

8 Rheumatic fever is caused by a large number of types of

Group A streptococci and immunity is type-specific.

Recurrent attacks are commonly due to infection with

different strains of these, all of which are sensitive to

penicillin and so chemoprophylaxis is effective Acute

glomerulonephritis is also due to group A streptococci But

only a few types cause it, so that natural immunity is more

likely to protect and, in fact, second attacks are rare.

Therefore, chemoprophylaxis is not used (see also p 239).

• Prevention of spread amongst contacts (in epidemics

and/or sporadic cases) Spread of influenza A can be partially prevented by amantadine; in an outbreak of meningococcal meningitis, or when there is a case in the family, rifampicin may be used; very young and fragile nonimmune child contacts of pertussis might benefit from erythromycin

Long-term prophylaxis of bacterial infection can

be achieved often by doses that are inadequate for therapy, although prophylaxis of infection asso-ciated with surgical procedures should always employ high doses to ensure eradication of the high bacterial numbers that may be introduced to normally sterile sites Details of the practice of chemoprophylaxis are given in the appropriate sections

Attempts to use drugs routinely in groups specially at risk to prevent infection by a range of organisms, e.g pneumonia in the unconscious or in patients with heart failure, in the newborn after prolonged labour, and in patients with long-term urinary catheters, have not only failed but have sometimes encouraged infections with less suscept-ible organisms Attempts routinely to prevent bacterial infection secondary to virus infections, e.g

in respiratory tract infections, measles, have not been sufficiently successful to outweigh the dis-advantages of drug allergy and infection with drug-resistant bacteria In these situations it is generally better to be alert for complications and then to treat them vigorously, than to try to prevent them

CHEMOPROPHYLAXIS IN SURGERY

The principles governing use of antimicrobials in this context are as follows

Chemoprophylaxis is justified:

— When the risk of infection is high because of the presence of large numbers of bacteria in the viscus which is being operated on, e.g the large bowel

— when the risk of infection is low but the consequences of infection would be disastrous, e.g infection of prosthetic joints or prosthetic heart valves, or of abnormal heart valves following the transient bacteraemia of dentistry

— when the risks of infection are low but

randomised controlled trials in large numbers

of patients have shown the benefits of

prophylaxis to outweigh the risks, e.g

single-dose antistaphylococcal prophylaxis for

uncomplicated hernia and breast surgery This

indication remains controversial

Antimicrobials should be selected with a

know-ledge of the likely pathogens at the sites of surgery

and their prevailing antimicrobial susceptibility

Antimicrobials should be given i.v., i.m or

occa-sionally rectally at the beginning of anaesthesia and

for no more than 48 h A single preoperative dose,

given at the time of induction of anaesthesia, has

been shown to give optimal cover for many

diff-erent operations Specific instances are:

1 Colorectal surgery, because there is a high risk of

infection with Escherichia coli, Clostridium spp,

streptococci and Bacteroides spp which inhabit

the gut (a cephalosporin plus metronidazole, or

benzylpenicillin plus gentamicin plus

metronidazole are commonly used)

2 Gastroduodenal surgery, because colonisation of

the stomach with gut organisms occurs

especially when acid secretion is low, e.g in

gastric malignancy, following use of a histamine

H2-receptor antagonist or following previous

gastric surgery (usually a cephalosporin will be

adequate)

3 Gynaecological surgery, because the vagina

contains Bacteroides spp and other anaerobes,

streptococci and coliforms (metronidazole and a

cephalosporin are often used)

4 Leg amputation, because there is a risk of gas

gangrene in an ischaemic limb and the mortality

is high (benzylpenicillin, or metronidazole for

the patient with allergy to penicillin)

5 Insertion of prosthetic joints Chemoprophylaxis is

justified because infection (Staphylococcus aureus,

coagulase-negative staphylococci and coliforms

are commonest) almost invariably means that

the artificial joint, valve or vessel must be

replaced (various regimens are used, with

inclusion of vancomycin when the local MRSA

prevalence is high) Single perioperative doses

of appropriate antibiotics with plasma

elimination half-lives of several hours (e.g cefotaxime) are adequate, but if short half-life agents are used (e.g flucloxacillin) several doses should be given during the first 24 hours

Problems with antimicrobial drugs

RESISTANCE

Microbial resistance to antimicrobials is a matter of great importance; if sensitive strains are supplanted

by resistant ones, then a valuable drug may become useless Just as:

Some are born great, some achieve greatness, and some have greatness thrust upon them.9

so microorganisms may be naturally Cborn') resistant, 'achieve' resistance by mutation or have resistance 'thrust upon them' by transfer of plasmids and other mobile genetic elements

Resistance may become more prevalent in a human population by spread of microorganisms containing resistance genes, and this may also occur

by dissemination of the resistance genes among different microbial species Because resistant strains are encouraged (selected) at the population level by use of antimicrobial agents, antibiotics are the only group of therapeutic agents which can alter the actual diseases suffered by untreated individuals Problems of antimicrobial resistance have bur-geoned during the past decade in most countries of the world Some resistant microbes are currently mainly restricted to patients in the hospital, e.g MRSA, vancomycin-resistant enterococci (VRE), and coliforms that produce 'extended spectrum (3-lactamases' Others more commonly infect patients

in the community, e.g penicillin-resistant Strepto-coccus pneumoniae and multiply-resistant My co-bacterium tuberculosis Evidence is accruing that

the outcomes of infections with antibiotic resistant bacteria are generally poorer than those with

9 Malvolio in Twelfth Night, Act 2 Scene 5, by William

Shakespeare (1564-1616).