Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 14) pptx

allergy, renal disease.Antibacterial drugs are here discussed in groups primarily by their site of antibacterial action and secondly by molecular structure, because members of each struc

Antibacterial drugs

SYNOPSIS

The range of antibacterial drugs is wide and

affords the clinician scope to select with

knowledge of the likely or proved pathogen(s)

and of factors relevant to the patient, e.g.

allergy, renal disease.Antibacterial drugs are

here discussed in groups primarily by their site

of antibacterial action and secondly by

molecular structure, because members of each

structural group are usually handled by the

body in a similar way and have the same range

lactams, the structure of which contains a

(3-lactam ring The major subdivisions are:

(a) penicillins whose official names usually include

or end in 'cillin'

(b) cephalosporins and cephamycins which are

recog-nised by the inclusion of 'cef' or 'ceph' in their

official names In the UK recently all these names

have been standardised to begin with 'cef'

Lesser categories of (3-lactams include

— carbapenems (e.g meropenem)

— monobactams (e.g aztreonam) and

— p-lactamase inhibitors (e.g clavulanic acid).Other inhibitors of cell wall synthesis includevancomycin and teicoplanin

INHIBITION OF PROTEIN SYNTHESIS

Aminoglycosid.es The names of those that arederived from streptomyces end in 'mycin', e.g

tobramycin Others include gentamicin (from monospora purpurea which is not a fungus, hence the

Micro-spelling as 'micin') and semisynthetic drugs, e.g.amikacin

Tetracyclines as the name suggests are four-ringedstructures and their names end in '-cycline'

Macrolides: e.g erythromycin Clindamycin, turally a lincosamide, has a similar action andoverlapping antibacterial activity

struc-Other drugs that act by inhibiting protein

syn-thesis include quinupristin-dalfopristin, linezolid,chloramphenicol and sodium fusidate

INHIBITION OF NUCLEIC ACID SYNTHESIS

Sulphonamides Usually their names contain'sulpha' or 'sulfa' These drugs, and trimethoprim,

12A N T I B A C T E R I A L D R U G S

with which they may be combined, inhibit synthesis

of nucleic acid precursors

Quinolones are structurally related to nalidixic

acid; the names of the most recently introduced

members of the group end in '-oxacin', e.g

cipro-floxacin They act by preventing DNA replication

Azoles all contain an azole ring and the names

end in '-azole', e.g metronidazole They act by the

production of short-lived intermediate compounds

which are toxic to DNA of sensitive organisms

Rifampicin inhibits bacterial DNA-dependent RNA

polymerase

Antimicrobials that are restricted to certain

speci-fic uses, i.e tuberculosis, urinary tract infections,

are described with the treatment of these conditions

Benzylpenicillin (1942) is produced by growing one

of the penicillium moulds in deep tanks In 1957 the

penicillin nucleus (6-amino-penicillanic acid) was

synthesised and it became possible to add various

side-chains and so to make semisynthetic

penicil-lins with different properties It is important to

recognise that not all penicillins have the same

antibacterial spectrum and that it is necessary to

choose between a number of penicillins just as it is

between antimicrobials of different structural

groups, as is shown below

A general account of the penicillins follows and

then of the individual drugs in so far as they differ

Mode of action Penicillins act by inhibiting the

enzymes (Penicillin Binding Proteins, PBPs)

in-volved in the crosslinking of the peptidoglycan

layer of the cell wall which protects the bacterium

from its environment; incapable of withstanding

the osmotic gradient between its interior and itsenvironment the cell swells and ruptures Penicillinsare thus bactericidal and are effective only againstmultiplying organisms because resting organismsare not making new cell wall The main defence ofbacteria against penicillins is to produce enzymes,(Mactamases, which open the (3-lactam ring andterminate their activity Other mechanisms thathave been described include modifications to PBPs

to render them unable to bind pMactams, reducedpermeability of the outer cell membrane of Gram-negative bacteria, and possession of pumps in theouter membrane which remove |3-lactam moleculesthat manage to enter Some particularly resistantbacteria may possess several mechanisms that act inconcert The remarkable safety and high therapeu-tic index of the penicillins is due to the fact thathuman cells, while bounded by a cell membrane,lack a cell wall They exhibit time-dependentbacterial killing (see p 203)

Narrow spectrum

(natural penicillins) Antistaphylococcal penicillins ((3-lactamase resistant)

Broad spectrum Mecillinam Monobactam (active only

against Gram-negative bacteria)

Antipseudomonal

Carboxypenidllin Ureidopenicillin

Penicillin-p-lactamase inhibitor combinations Carbapenems

benzylpenicillin, phenoxymethylpenicillin cloxacillin, flucloxacillin ampicillin, amoxicillin, bacampicillin.

pivmecillinam aztreonam'

ticarcillin piperacillin co-amoxiclav, piperacillin-tazobactam, ticarcillin-clavulanate meropenem, imipenem-cilastatin

Pharmacokinetics Benzylpenicillin is destroyed bygastric acid and is unsuitable for oral use Others,e.g phenoxymethylpenicillin, resist acid and areabsorbed in the upper small bowel The plasma t1/,

of penicillins is usually < 2 h They are distributedmainly in the body water and enter well into the

1 While not strictly a penicillin, it has a similar spectrum of action including some antipseudomonal activity.

P - L A C T A M S _12

CSF if the meninges are inflamed Penicillins are

organic acids and their rapid clearance from plasma

is due to secretion into renal tubular fluid by the

anion transport mechanism in the kidney Renal

clearance therefore greatly exceeds the glomerular

filtration rate (127 ml/min) The excretion of

penicillin can be usefully delayed by concurrently

giving probenecid which competes successfully for

the transport mechanism Dosage of penicillins

may should be reduced for patients with severely

impaired renal function

Adverse effects The main hazard with the

penicil-lins is allergic reactions These include itching, rashes

(eczematous or urticarial), fever and angioedema

Rarely (about 1 in 10 000) there is anaphylactic

shock which can be fatal (about 1 in 50 000-100 000

treatment courses) Allergies are least likely when

penicillins are given orally and most likely with

local application Metabolic opening of the f5-lactam

ring creates a highly reactive penicilloyl group

which polymerises and binds with tissue proteins

to form the major antigenic determinant The

anaphylactic reaction involves specific IgE

anti-bodies which can be detected in the plasma of

susceptible persons

There is cross-allergy between all the various

forms of penicillin, probably due in part to their

common structure, and in part to the degradation

products common to them all Partial cross-allergy

exists between penicillins and cephalosporins (a

maximum of 10%) which is of particular concern

when the reaction to either group of antimicrobials

has been angioedema or anaphylactic shock

Carba-penems (meropenem and imipenem-cilastatin) and

the monobactam aztreonam apparently have a

much lower risk of cross-reactivity

When attempting to predict whether a patient

will have an allergic reaction, a reliable history of a

previous adverse response to penicillin is valuable

Immediate-type reactions such as urticaria,

angio-oedema and anaphylactic shock can be taken to

indicate allergy, but interpretation of

maculopapu-lar rashes is more difficult Since an alternative drug

can usually be found, a penicillin is best avoided

if there is suspicion of allergy, although the

condi-tion is undoubtedly overdiagnosed and may be

transient (see below)

When the history of allergy is not clear-cut and it

is necessary to prescribe a penicillin, the presence

of IgE antibodies in serum is a useful indicator ofreactions mediated by these antibodies, i.e imme-diate (type 1) reactions Additionally, an intradermaltest for allergy may be performed using standardamounts of a mixture of a major determinant (meta-bolite) (benzylpenicilloyl polylysine) and minordeterminants (such as benzylpenicillin), of theallergic reaction; appearance of a flare and wealreaction indicates a positive response The fact thatonly about 10% of patients with a history of 'peni-cillin allergy' respond suggests that many who are

so labelled are not, or are no longer, allergic topenicillin

Other (nonallergic) adverse effects include rrhoea due to alteration in normal intestinal flora

dia-which may progress to Clostridium difficile-associated

diarrhoea Neutropenia is a risk if penicillins (orother (3-lactam antibiotics) are used in high doseand usually for a period of longer than 10 days.Rarely the penicillins cause anaemia, sometimeshaemolytic, and thrombocytopenia or interstitialnephritis Penicillins are presented as their sodium

or potassium salts which are inevitably taken insignificant amounts if high dose of antimicrobial

is used Physicians should be aware of this expected source of sodium or potassium, especially

un-in patients with renal or cardiac disease Extremelyhigh plasma penicillin concentrations cause convul-sions Co-amoxiclav and flucloxacillin given in highdoses for prolonged periods in the elderly maycause hepatic toxicity

NARROW SPECTRUM PENICILLINS Benzylpenicillin (penicillin G)

Benzylpenicillin (i l / 2 0.5 h) is used when highplasma concentrations are required The short

t1,/ means that reasonably spaced doses have to

be large to maintain a therapeutic concentration.Fortunately, the unusually large therapeutic ratio

of penicillin allows the resulting fluctuations to

be tolerable.2 Benzylpenicillin is eliminated by the

2 Is it surprise at the answer that reduces most classes of students to silence when asked the trough:peak ratio for

a drug given 6-hourly with a t 1 ^ of 0.5 h? (answer: 2 12 = 4096).

12A N T I B A C T E R I A L D R U G S

kidney, with about 80% being actively secreted by

the renal tubule and this can be blocked by

probe-necid, e.g to reduce the frequency of injection

for small children or for single dose therapy as in

gonorrhoea

Uses (see Table 11.1, p 211) Benzylpenicillin is

highly active against Streptococcus pneumoniae and

the Lancefield group A, (3-haemolytic streptococcus

(Streptococcus pyogenes) Viridans streptococci are

usually sensitive unless the patient has recently

received penicillin Enterococcus faecalis is less

sus-ceptible and, especially for endocarditis, penicillin

should be combined with an aminoglycoside,

usually gentamicin This combination is synergistic

unless the enterococcus is highly resistant to the

aminoglycoside; such strains are becoming more

frequent in hospital patients and present major

difficulties in therapy Benzylpenicillin used to be

active against most strains of Staphylococcus aureus,

but now over 90% are resistant in hospital and

domiciliary practice Benzylpenicillin is the drug

of choice for infections due to Neisseria meningitidis

(meningococcal meningitis and septicaemia),

Baci-llus anthracis (anthrax), Clostridium perfringens (gas

gangrene) and tetani (tetanus), Con/nebacterium

diphtheriae (diphtheria), Treponema pallidum (syphilis),

Leptospira spp (leptospirosis) and Actinomyces

israelii (actinomycosis) It is also the drug of choice

for Borrelia burgdorferi (Lyme disease) in children.

The sensitivity of Neisseria gonorrhoeae varies in

different parts of the world and, in some, resistance

is rife

Adverse effects are in general uncommon, apart

from allergy (above) It is salutary to reflect that

the first clinically useful true antibiotic (1942) is

still in use and is also amongst the least toxic Only

in patients with bacterial endocarditis, where the

requirement for high doses can co-exist with reduced

clearance due to immune complex

glomeruloneph-ritis, does a risk of dose related toxicity (convulsions)

arise

Preparations and dosage for injection

Benzyl-penicillin may be given i.m or i.v (by bolus

injection or by continuous infusion) For a sensitive

infection, benzylpenicillin3 600 mg 6-hourly is

enough This is obviously inconvenient in

domi-ciliary practice where a mixture of benzylpenicillinand one of its long-acting variants may be preferred(see below)

For relatively insensitive infections and wheresensitive organisms are sequestered within avasculartissue (e.g infective endocarditis) 7.2 g are givendaily i.v in divided doses When an infection iscontrolled, a change may be made to the oral routeusing phenoxymethylpenicillin, or amoxicillinwhich is more reliably absorbed in adults

Procaine penicillin, given i.m only, is a stable salt

and liberates benzylpenicillin over 12-24 h, ing to the dose administered Usually this is 360 mg12-24-hourly There is no general agreement on itsplace in therapy, and it is no longer available in

accord-a number of countries It is best to use penicillin in the most severe infections, especially

benzyl-at the outset, as procaine penicillin will not givetherapeutic blood concentrations for some hoursafter injection and peak concentrations are muchlower

Preparations and dosage for oral use methylpenicillin (penicillin V), is resistant to gastricacid and so reaches the small intestine intactwhere it is moderately well absorbed, sometimeserratically in adults It is less active than benzyl-

Phenoxy-penicillin against Neisseria gonorrhoeae and tidis, and so is unsuitable for use in gonorrhoea

meningi-and meningococcal meningitis It is a satisfactory

substitute for benzylpenicillin against Streptococcus pneumoniae and Streptococcus pyogenes, especially

after the acute infection has been brought underinitial control by intravenous therapy The dose is

500 mg 6-hourly

All oral penicillins are best given on an emptystomach to avoid the absorption delay caused byfood

Antistaphylococcal penicillins

Certain bacteria produce (Mactamases which openthe (Mactam ring that is common to all penicillins,and thus terminate the antibacterial activity (3-lactamases vary in their activity against different(3-lactams, with side chains attached to the p-lactam

3 600 mg = 1 000 000 units, 1 mega-unit.

p - L A C T A M S _12

ring being responsible for most of these effects

by stearic hindrance of access of the drug to the

enzymes' active sites Drugs that resist the action of

staphylococcal p-lactamase do so by possession

of an acyl side-chain The drugs do have activity

against other bacteria for which penicillin is

indi-cated, but benzylpenicillin is substantially more

active against these organisms — up to 20 times

more so in the cases of pneumococci, (3-haemolytic

streptococci and Neisseria Hence, when infection is

mixed, it may be preferable to give benzylpenicillin

as well as a (3-lactamase-resistant drug in severe

cases

Examples of these agents include:

Fludoxacillin (t l / 2 1 h) is better absorbed and so

gives higher blood concentrations than does

cloxa-cillin It may cause cholestatic jaundice, particularly

when used for more than 2 weeks or to patients > 55

years

Cloxacillin (t l / 2 0.5 h) resists degradation by gastric

acid and is absorbed from the gut, but food

markedly interferes with absorption Recently it

has been withdrawn from the market in some

countries, including the UK

Methidllin and oxacillin: their use is now

con-fined to laboratory sensitivity tests Identification of

methicillin-resistant Staphylococcus aureus (MRSA)

in patients indicates the organisms are resistant to

flucloxacillin and cloxacillin, all other (3-lactam

anti-biotics and often to other antibacterial drugs, and

demands special infection-control measures

BROAD SPECTRUM PENICILLINS

The activity of these semisynthetic penicillins extends

beyond the Gram-positive and Gram-negative cocci

which are susceptible to benzylpenicillin, and

includes many Gram-negative bacilli They do

not resist (3-lactamases and their usefulness has

reduced markedly in recent years because of the

increased prevalence of organisms that produce

these enzymes

As a general rule these agents are rather less

active than benzylpenicillin against Gram-positive

cocci, but more active than the (3-lactamase-resistant

penicillins (above) They have useful activity against

Enterococcus faecalis and many strains of

Haemo-philus influenzae Enterobacteriaceae are variably

sen-sitive and laboratory testing for sensitivity is

important The differences between the members

of this group are pharmacological rather thanbacteriological

Amoxicillin (i l / 2 I h; previously known as

amoxy-cillin) is a structural analogue of ampicillin (below)and is better absorbed from the gut (especially afterfood), and for the same dose achieves approxi-mately double the plasma concentration Diarrhoea

is less frequent with amoxicillin than with cillin The oral dose is 250 mg 8-hourly; a parenteralform is available but offers no advantage overampicillin For oral use, however, amoxicillin ispreferred because of its greater bioavailability andfewer adverse effects

ampi-Co-amoxiclav (Augmentin) Clavulanic acid is a

p-lactam molecule which has little intrinsic bacterial activity but binds irreversibly to (3-lactamases.Thereby it competitively protects the penicillin,

anti-so potentiating it against bacteria which owe theirresistance to production of p-lactamases, i.e clavu-lanic acid acts as a 'suicide' inhibitor It is formulated

in tablets as its potassium salt (equivalent to 125 mg

of clavulanic acid) in combination with amoxicillin(250 or 500 mg), as co-amoxiclav, and is a satisfac-tory oral treatment for infections due to (3-lactamase-producing organisms, notably in the respiratory

or urogenital tracts It should be used when lactamase-producing amoxicillin resistant organismsare either suspected or proven by culture These

(3-include many strains of Staphylococcus aureus, many strains of Escherichia coll and an increasing number

of strains of Haemophilus influenzae It also has ful activity against [3-lactamase-producing Bacteroides

use-spp The t1/, is 1 h and the dose one tablet 8-hourly.Ampicillin (t1// 1 h) is acid-stable and is moderatelywell absorbed when swallowed The oral dose is

250 mg-1 g 6-8-hourly; or i.m or i.v 500 mg4-6-hourly Approximately one-third of a doseappears unchanged in the urine The drug isconcentrated in the bile

Adverse effects Ampicillin may cause diarrhoeabut the incidence (12%) is less with amoxicillin.Ampicillin and amoxicillin are the commonest

antibiotics to be associated with Clostridium difficile

diarrhoea, although this is related to the frequency

12A N T I B A C T E R I A L D R U G S

of their use rather than to their innate risk of

causing the disease (this is probably highest for

the injectable cephalosporins) Ampicillin and its

analogues have a peculiar capacity to cause a macular

rash resembling measles or rubella, usually

un-accompanied by other signs of allergy These rashes

are very common in patients with disease of the

lymphoid system, notably infectious mononudeosis

and lymphoid leukaemia A macular rash should

not be taken to imply allergy to other penicillins

which tend to cause a true urticarial reaction Patients

with renal failure and those taking allopurinol for

hyperuricaemia also seem more prone to ampicillin

rashes Cholestatic jaundice has been associated

with use of co-amoxiclav even up to 6 weeks after

cessation of the drug; the clavulanic acid may be

responsible

MECILLINAM

Pivmecillinam (i l / 2 I h) is an oral agent closely

related to the broad spectrum penicillins but with

differing antibacterial activity by virtue of having

a high affinity for penicillin binding protein It is

active against Gram-negative organisms including

p-lactamase-producing Enterobacteriaceae but is

inactive against Pseudomonas aeruginosa and its

relatives, and against Gram-positive organisms

Pivmecillinam is hydrolysed in vivo to the active

form mecillinam (which is poorly absorbed by

mouth) It has been used to treat urinary tract

infec-tion Diarrhoea and abdominal pain may occur

MONOBACTAM

Aztreonam (t l / 2 2 h) is the first member of this class

of (3-lactam antibiotic It is active against

Gram-negative organisms including Pseudomonas

aerugi-nosa, Haemophilus influenzae and Neisseria

meningi-tidis and gonorrhoeae Aztreonam is used to treat

septicaemia and complicated urinary tract

infec-tions, Gram-negative lower urinary tract infections

and gonorrhoea

Adverse effects include reactions at the site of

infusion, rashes, gastrointestinal upset, hepatitis,

thrombocytopenia and neutropenia It appears

to have a remarkably low risk of causing (3-lactam

allergy, and may be used with caution in some

destroy Pseudomonas aeruginosa and indole-positive Proteus spp.

Ticarcillin (t1// 1 h) is presented in combination withclavulanic acid (as Timentin), so to provide greateractivity against (3-lactamase-producing organisms

It is given by i.m or slow i.v injection or by rapidi.v infusion Note that ticarcillin is presented as itsdisodium salt and each 1 g delivers about 5.4 mmol

of sodium, which should be borne in mind whentreating patients with impaired cardiac or renalfunction Carboxypenicillins inactivate aminogly-cosides if both drugs are administered in the samesyringe or intravenous infusion system

Ureidopenicillins

These are adapted from the ampicillin molecule,with a side-chain derived from urea Their majoradvantages over the Carboxypenicillins are higher

efficacy against Pseudomonas aeruginosa and the fact

that as monosodium salts they deliver on averageabout 2 mmol of sodium per gram of antimicrobial(see above) and are thus safer where sodium over-load should particularly be avoided They aredegraded by many (3-lactamases Ureidopenicillinsmust be administered parenterally and are elimin-ated mainly in the urine Accumulation in patientswith poor renal function is less than with otherpenicillins as 25% is excreted in the bile An unusualfeature of their kinetics is that, as the dose isincreased, the plasma concentration rises dispropor-

tionately, i.e they exhibit saturation (zero-order) kinetics.

For pseudomonas septicaemia, a lin plus an aminoglycoside provides a synergisticeffect but the co-administration in the same fluidresults in inactivation of the aminoglycoside (aswith Carboxypenicillins, above)

ureidopenicil-Azlocillin (i l / 2 1 h), highly effective against monas aeruginosa infections, is less so than other

Pseudo-O T H E R P - L A C T A M A N T I B A C T E R I A L S 12

ureidopenicillins against other common

Gram-negative organisms and has recently been

with-drawn from the market in many countries

Piperacillin (tV2 1 h) has the same or slightly

greater activity as azlocillin against Pseudomonas

aeruginosa but is more effective against the common

Gram-negative organisms It is also available as

a combination with the p-lactamase inhibitor

tazo-bactam (as tazocin)

Cephalosporins

Cephalosporins were first obtained from a

filamen-tous fungus Cephalosporium cultured from the

sea near a Sardinian sewage outfall in 1945; their

molecular structure is closely related to that of

penicillin, and many semisynthetic forms have

been introduced They now comprise a group of

antibiotics having a wide range of activity and

low toxicity The term Cephalosporins will be used

here in a general sense although some are strictly

cephamycins, e.g cefoxitin and cefotetan

Mode of action is that of the (3-lactams, i.e.

Cephalosporins impair bacterial cell wall synthesis

and hence are bactericidal They exhibit

time-dependent bacterial killing (see p 203)

Addition of various side-chains on the

cephalo-sporin molecule confers variety in pharmacokinetic

and antibacterial activities The (3-lactam ring can be

protected by such structural manoeuvring, which

results in compounds with improved activity against

Gram-negative organisms; a common corollary is that

such agents lose some anti-Gram-positive activity

The Cephalosporins resist attack by (3-lactamases but

bacteria develop resistance to them by other means

Methicillin-resistant Staphylococcus aureus (MRSA)

should be considered resistant to all Cephalosporins

Pharmacokinetics Usually, Cephalosporins are

excreted unchanged in the urine, but some,

includ-ing cefotaxime, form a desacetyl metabolite which

possesses some antibacterial activity Many are

actively secreted by the renal tubule, a process

which can be blocked with probenecid As a rule,

the dose of Cephalosporins should be reduced in

patients with poor renal function Cephalosporins

in general have a t1// of 1-4 h although there are

exceptions (e.g ceftriaxone, t1/^, 8 h) Wide tion in the body allows treatment of infection atmost sites, including bone, soft tissue, muscle and(in some cases) CSF Data on individual Cephalo-sporins appear in Table 12.1

distribu-Classification and uses The Cephalosporins are

conventionally categorised by generations havingbroadly similar antibacterial and pharmacokineticproperties; newer agents have rendered this classi-fication less precise but it retains sufficient useful-ness to be presented in Table 12.1

Adverse effects Cephalosporins are well tolerated.

The most usual unwanted effects are allergic tions of the penicillin type There is cross-allergybetween penicillins and Cephalosporins involvingabout 7% of patients; if a patient has had a severe

reac-or immediate allergic reaction reac-or if serum reac-or skintesting for penicillin allergy is positive (see p 217),then a cephalosporin should not be used Pain may

be experienced at the sites of i.v or i.m injection

If Cephalosporins are continued for more than 2weeks, thrombocytopenia, haemolytic anaemia,neutropenia, interstitial nephritis or abnormal liverfunction tests may occur especially at high dosage;these reverse on stopping the drug The broadspectrum of activity of the third generation Cephalo-sporins may predispose to opportunist infection

with resistant bacteria or Candida albicans and to Clostridium difficile diarrhoea Ceftriaxone achieves

high concentrations in bile and, as the calciumsalt, may precipitate to cause symptoms resemblingcholelithiasis (biliary pseudolithiasis) Cefamandolemay cause prothrombin deficiency and a disulfiram-like reaction after ingestion of alcohol

Other (3-lactam antibacterials

CARBAPENEMS

Members of this group have the widest spectrum

of all currently available antimicrobials, being

1 1 1

3 1 2 1 8 4 2 2

Excretion

in urine (%)

90 86 86 88 88

90 80 75

80 60 88 90

56 (44 bile)

23 (77 bile) 65 80

Comment

May be used for staphylococcal infections but generally have been replaced by the newer cephalosporins.

All very similar Effective against the common respiratory pathogens

Streptococcus pneumoniae and Momxella catarrhalis but (excepting cefaclor) have poor activity against Haemophilus influenzae Also active against

Escherichia coli which, increasingly, is demonstrating resistance to

amoxicillin and trimethoprim May be used for uncomplicated upper and lower respiratory tract, urinary tract and soft tissue infections, and also as follow-on treatment once parenteral drugs have brought an infection under control.

More resistant to p-lactamases than the first-generation drugs and active

against Stopny/ococcus aureus, Streptococcus pyogenes, Streptococcus

pneumoniae, Neisseria spp., Haemophilus influenzae and many Enterobacteriaceae Cefoxitin also kills Boctero/des fragilis and is effective in

abdominal and pelvic infections.

Cefuroxime may be given for community-acquired pneumonia, commonly

due to Strep pneumoniae (not when causal organism is Mycoplasma

pneumoniae, Legionella or Ch/amyd/a).The oral form, cefuroxime axetil, is also

used for the range of infections listed for the first-generation oral cephalosporins (above)

More effective than the second-generation drugs against Gram-negative organisms whilst retaining useful activity against Gram-postive bacteria Cefotaxime, ceftizoxime and ceftriaxone are used for serious infections such as septicaemia, pneumonia, and for meningitis Ceftriaxone also used for gonorrhoea and Lyme disease.

Active against a range of Gram-positive and Gram-negative organisms

including Staphylococcus aureus (excepting cefixime), Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria spp., Haemophilus influenzae and

(excepting cefpodoxime) many Enterobacteriaceae Used to treat urinary, upper and lower respiratory tract infections.

bactericidal against most positive and

Gram-negative aerobic and anaerobic pathogenic bacteria

They are resistant to hydrolysis by most P-lactamases

Only occasional pseudomonas relatives are naturally

resistant, and acquired resistance is uncommon in

all species

Imipenem

Imipenem (i l / 2 1 h) is inactivated by metabolism in

the kidney to products that are potentially toxic

to renal tubules; combining imipenem with

cilastatin (as Primaxin), a specific inhibitor of

dihydropeptidase—the enzyme responsible for itsrenal metabolism—prevents both inactivation andtoxicity

Imipenem is used to treat septicaemia, cularly of renal origin, intra-abdominal infectionand nosocomial pneumonia In terms of imipenem,

parti-1-2 g/d is given by i.v infusion in 3-A doses; reduced

doses are recommended when renal function isimpaired

Adverse effects It may cause gastrointestinal upset

including nausea, blood disorders, allergic reactions,confusion and convulsions

A M I N O G L Y C O S I D E S 12

Meropenem (t l / 2 1 h) is similar to imipenem but is

stable to renal dihydropeptidase and can therefore

be given without cilastatin It penetrates into the CSF

and is not associated with nausea or convulsions

Other inhibitors of cell

wall synthesis

Vancomycin

Vancomycin (i l / 2 8h), a 'glycopeptide' or

'pepto-lide', acts on multiplying organisms by inhibiting

cell wall formation at a site different from the

(3-lactam antibacterials It is bactericidal against most

strains of clostridia (including Clostridium difficile),

almost all strains of Staphylococcus aureus (including

those that produce (Hactamase and

methicillin-resistant strains), coagulase-negative staphylococci,

viridans group streptococci and enterococci, i.e

several organisms that cause endocarditis

Vancomycin is poorly absorbed from the gut and

is given i.v for systemic infections, as there is no

satisfactory i.m preparation It distributes

effec-tively into body tissues and is eliminated by the

kidney

Uses Vancomycin is effective in cases of

antibiotic-associated pseudomembranous colitis (caused by

Clostridium difficile or, less commonly,

staphylo-cocci) in a dose of 125 mg 6-hourly by mouth

(although oral metronidazole is preferred, being as

effective and less costly) Combined with an

amino-glycoside, it may be given i.v for streptococcal

endocarditis in patients who are allergic to

benzyl-penicillin It may also be used for serious infection

with multiply-resistant staphylococci Dosing is

guided by plasma concentration monitoring

Adverse effects The main disadvantage to

vanco-mycin is auditory damage Tinnitus and deafness

may improve if the drug is stopped Nephrotoxicity

and allergic reactions also occur Rapid i.v infusion

may cause a maculopapular rash possibly due to

histamine release (the 'red person' syndrome)

Teicoplanin is structurally related to vancomycin

and is active against Gram-positive bacteria The

t1/^ of 50 h allows once daily i.v or i.m tration It is used for serious infection with Gram-positive bacteria including endocarditis, and forperitonitis in patients undergoing chronic ambula-tory peritoneal dialysis It is less likely to causeoto- or nephrotoxicity than vancomycin, but serummonitoring is required for severely ill patientsand those with changing renal function to assureadequate serum concentrations are being achieved

adminis-A rising prevalence of clinically-significant ance and decrease in susceptibility to vancomycinand teicoplanin has become a serious worry recentlywith the emergence of vancomycin-resistant entero-cocci (VRE) or glycopeptide-resistant enterococci

resist-(GRE) and vancomycin-intermediate resistant lococcus aureus (VISA or GISA) Only one naturally occurring strain of vancomycin resistant Staphylo- coccus aureus has been reported, but these will no

Staphy-doubt emerge in time and the appearance of biotics active against multiply resistant Gram-positive bacteria, e.g quinupristin-dalfopristin andlinezolid (see p 229), is welcome

anti-Cycloserine is used for drug-resistant tuberculosis

(see p 253)

Inhibition of protein synthesis

Aminoglycosides

In the purposeful search that followed the stration of the clinical efficacy of penicillin, strepto-

demon-mycin was obtained from Streptomyces griseus in

1944, cultured from a heavily manured field, andalso from a chicken's throat Aminoglycosidesresemble each other in their mode of action, andtheir pharmacokinetic, therapeutic and toxic proper-ties The main differences in usage reflect variation

in their range of antibacterial activity; resistance is variable

cross-Mode of action The aminoglycosides act insidethe cell by binding to the ribosomes in such a waythat incorrect amino acid sequences are entered into

12 A N T I B A C T E R I A L D R U G S

peptide chains The abnormal proteins which result

are fatal to the microbe, i.e aminoglycosides are

bactericidal and exhibit concentration-dependent

bacterial killing (see p 203)

Pharmacokinetics Aminoglycosides are

water-soluble and do not readily cross cell membranes

Poor absorption from the intestine necessitates their

administration i.v or i.m for systemic use and they

distribute mainly to the extracellular fluid; transfer

into the cerebrospinal fluid is poor even when the

meninges are inflamed Their t1// is 2-5 h

Aminoglycosides are eliminated unchanged

mainly by glomerular filtration, and attain high

concentrations in the urine Significant

accumula-tion occurs in the renal cortex unless there is severe

renal parenchymal disease Plasma concentration

should be measured regularly (and frequently in

renally-impaired patients) and it is good practice to

monitor approximately twice weekly even if renal

function is normal With prolonged therapy, e.g

endocarditis (gentamicin), monitoring must be

meticulous The dose should be reduced to

com-pensate for varying degrees of renal impairment,

including that of normal aging Numerous

success-ful legal actions by patients against doctors for

negligence in this area have resulted in large

compensation payments, especially for ototoxicity

Current practice is to administer

aminoglyco-sides as a single daily dose rather than as twice

or thrice daily doses Algorithms are available to

guide such dosing according to patients' weight

and renal function, and in this case only trough

con-centrations need to be assayed Single daily dose

therapy is probably less oto- and nephrotoxic than

divided dose regimens, and appears to be as

effec-tive The immediate high plasma concentrations

that result from single daily dosing are

advanta-geous, e.g for acutely ill septicaemic patients, as

aminoglycosides exhibit concentration-dependent

killing (see p 203)

Antibacterial activity Aminoglycosides are in

general active against staphylococci and aerobic

Gram-negative organisms including almost all the

Enterobacteriaceae; individual differences in activity

are given below Bacterial resistance to

aminoglyco-sides is an increasing but patchily-distributed

problem, notably by acquisition of plasmids (see

p 209) which carry genes coding for the formation

of drug-destroying enzymes Gentamicin resistance

is rare in community-acquired pathogens in manyhospitals in the UK

Uses include:

• Gram-negative baciUary infection, particularly

septicaemia, renal, pelvic and abdominal sepsis.Gentamicin remains the drug of choice buttobramycin may be preferred for infections caused

by Pseudomonas aeruginosa Amikacin has the

widest antibacterial spectrum of theaminoglycosides but is best reserved for infectioncaused by gentamicin-resistant organisms As long

as local resistance rates are low, an aminoglycosidemay be included in the initial best-guess regimenfor treatment of serious septicaemia before thecausative organism(s) is identified A potentiallyless toxic antibiotic may be substituted whenculture results are known (48-72 h), and toxicity isvery rare after such a short course

• Bacterial endocarditis An aminoglycoside, usually

gentamicin, should comprise part of theantimicrobial combination for enterococcal,streptococcal or staphylococcal infection of theheart valves, and for the therapy of clinicalendocarditis which fails to yield a positive bloodculture

• Other infections: tuberculosis, tularaemia, plague,

brucellosis

• Topical uses Neomycin and framycetin, whilst

too toxic for systemic use, are effective for topicaltreatment of infections of the conjunctiva orexternal ear They are sometimes used inantimicrobial combinations selectively todecontaminate the bowel of patients who are toreceive intense immunosuppressive therapy.Tobramycin is given by inhalation for therapy ofinfective exacerbations of cystic fibrosis

Sufficient systemic absorption may occur torecommend assay of serum concentrations insuch patients

Adverse effects Aminoglycoside toxicity is a riskwhen the dose administered is high or of longduration, and the risk is higher if renal clearance isinefficient (because of disease or age), other poten-tially nephrotoxic drugs are co-administered (e.g