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440 Pediatrics in Review VoL 15 No. 11 November 1994

Antibiotics: Mechanisms of ActionKathleen A. Woodin, MD* and Susan H. Morrison, MDt

Medical practice rests on the foundation of science. Clinicians are constantly making practical decisions and dealingwith immediate situations that demand solutions. Time should be taken to focus on those scientific principles that

underlie our diagnostic and therapeutic maneuvers. This section of Pediatrics in Review presents selected topics thatare relevant to practice from the areas of physiology, pharmacology, biochemistry, and other disciplines; clarification

of these will augment the pediatrician ‘s understanding of clinical procedures.

IntroductionUnlike physicians practicing in the1940s, who had only sulfonamidesand penicillin to treat infections,

practitioners now choose from abroad (and sometimes overwhelming)number of antibiotics. However,

trends in emerging antimicrobial re-sistance may force us to take a giantstep backward to that frightening sit-uation of the past of having bacteria

that are essentially “untreatable” byany of our available antibiotics.

This article is an overview of someof the microbiology, pharmacology,

and physiology critical to the rationaluse of antibiotics in today’s practice.It summarizes the basic mechanismsof action of some commonly usedantibiotics and briefly discusses theemergence of resistance to severalcommon pathogens.

Structures of BacteriaImportant to AntibioticActionThe outermost component of mostbacteria is the cell wall, a multilay-ered structure located external to thecytoplasmic membrane. The cell wallis composed of an inner layer of pep-tidoglycan, a complex interwoven lat-

tice of linear sugars (glycan) that are

cross-linked by peptide chains. Pep-

tidoglycan provides the rigid supportby which the cell maintains its char-acteristic shape.

Gram-positive and Gram-negativebacteria differ in their cell wall struc-tures (Figure). In Gram-positiveorganisms, the peptidoglycan layer isa thick (15 to 80 nm) multilayer andmay have a thin layer of teichoicacid outside the peptidoglycan. Incontrast, Gram-negative organismshave a thin (2 nm) single layer ofpeptidoglycan covered by a complex

outer membrane layer composed oflipopolysaccharides, lipoproteins, andphospholipids. The outer membrane

of Gram-negative bacteria containsporn proteins that act as channels to

transport small molecules such assugars, metals, vitamins, and antibiot-ics into the bacterial cell.

The cytoplasm of bacteria containsan inner nucleoid region composed ofsingle-stranded circular DNA andmatrix that contains ribosomes, nutri-ent granules, metabolites, and plas-mids. Plasmids are double-strandedcircular DNA molecules that can rep-licate independently of the bacterialchromosomes. Most plasmids are ex-trachromosomal, but some are inte-grated into the bacterial chromosome.

Plasmids occur in both Gram-nega-

tive and Gram-positive organismsand are an important source ofgenetic information that can conveyresistance to various antibiotics.

Selective Toxicity

An ideal antimicrobial agent wouldexhibit selective toxicity; that is, thedrug would be harmful to the infect-ing microorganism without harmingthe host. Because peptidoglycan ispresent in bacteria but not in humancells, it is an excellent target for anti-biotics. Similarly, antibiotics that af-fect protein synthesis take advantage

of the differences in size and chemi-cal composition of ribosomes frombacteria and eukaryotic organisms (ie,

those having a true nucleus sur-rounded by a nuclear membrane andmultiple chromosomes, as in humancells). Other metabolic steps that oc-cur in bacteria but not humans (eg,synthesis of folic acid for nucleo-tides) also can be inhibited selec-tively by antibiotics.

BactericIdal VersusBacterlostatlc Properties ofAntibioticsA favorable therapeutic outcome fol-lowing the administration of a spe-



WEAKEN CELL WALL BYINHIBITING CROSS-LINKING OFPEPTIDOGLYCAN

Pediatrics in Review VoL 15 No. Ii November 1994 441

Icific antibiotic depends on multiplefactors, including those related to thebacteria (eg, resistance mechanisms),the antibiotic (eg, mechanism of ac-tion, ability to penetrate to the in-fected site, and spectrum of activity),and the host defenses (eg, phagocyto-sis, opsonization, complement pro-duction). When host defenses aremaximally effective, the contributionof the antibiotic may be less impor-tant. For example, a bacteriostatic

agent (eg, chloramphenicol, erythro-mycin, clindamycin, tetracycline) thatslows or inhibits protein synthesis

may be adequate when combinedwith the host’s ability to opsonizeand phagocytize bacteria. In contrast,

a patient whose host defenses are im-paired may require a bactericidalagent (eg, penicillin, cephalosporin,aminoglycoside) that actually will kill

or lyse the bacteria. Bactericidalagents (Table 1) generally are used to

treat bacterial endocarditis, meningi-tis, and osteomyelitis as well as anybacterial infections in neutropenic

patients.

Antibiotic SusceptibilityIf the concentration of an antibioticrequired to inhibit or kill the organ-ism can be achieved safely in the af-

fected tissue or fluid, a micro-organism is considered sensitive to aparticular antibiotic. However, if the

concentration required is greater thanwhat can be achieved safely, the mi-croorganism is considered to be resis-

tant to that antibiotic. Most in vitrosensitivity tests are standardized on

the basis of drug concentrations thatcan be achieved safely in plasma andmay not take into account increased

drug concentrations that may occur atspecific sites (eg, bladder) or any lo-

cal conditions that may affect the ac-

tivity of the antimicrobial agent.

Mechanisms of Action ofAntibioticsFor many antibiotics, the mechanismof action is not understood fully.However, it is known that antibiotics

can act in the following ways: 1) in-hibit cell wall synthesis, 2) alter thepermeability of the cell membrane,

3) inhibit protein synthesis, and4) inhibit nucleic acid synthesis(Table 1).

Penicillins and Cephalosporins

Penicillins and cephalosporins (beta-

lactam antibiotics) are among themost widely prescribed antibiotics be-cause of their safety profiles. The ba-sic structure of penicillin consists ofa five-member thiazolidine ring con-nected to a beta-lactam ring to which

a side chain is attached. In contrast,the cephalosporins have a six-mem-bered hydrothiazine ring connected tothe beta-lactam ring. An intact beta-lactam ring structure is an essentialrequirement for the biologic and anti-bacterial activity of both penicillinsand cephalosporins. New derivativesof the basic penicillin nuclei continueto be produced; each has unique ad-vantages. Modification of the variousside chains on these structures affectsthe specific antibacterial spectrum aswell as the pharmacokinetic profile ofthese drugs.

Beta-lactam antibiotics kill suscep-tible bacteria by interfering with cellwall synthesis. They are bactericidal,but only kill organisms undergoingactive cell wall synthesis. The bio-synthesis of peptidoglycan in the cellwall occurs in three stages and in-volves about 30 different enzymes.

Beta-lactam antibiotics inhibit trans-peptidases, the enzymes that catalyzethe final cross-linking step of pepti-

doglycan synthesis.There also are receptors called

penicillin binding proteins (PBPs) inthe bacterial cell membrane and cellwall for the beta-lactam antibiotics.Each bacterium has several types of

PBPs that vary in their affinity fordifferent penicillins and cephalospo-rins. Some PBPs are transpeptidasesresponsible for peptidoglycan cross-

linking and necessary for bacterialshape; the function of others is

unknown. Inhibition of PBPs causesabnormal cell shape, division, andeventual lysis. Altering the PBPs is

one mechanism by which bacteriacan develop resistance to penicillin.This resistance may be intrinsic be-

cause of structural differences inPBPs or a previously sensitive strainmay acquire resistance following amutation of PBPs. Resistance ofStreptococcus pneumoniae to penicil-lin and cephalosporins, which hasbeen reported around the world aswell as in the United States, is due toalterations in PBPs (Table 2).

Activation of cell wall autolyticenzymes (ie, autolysins) is anotherfactor that is important in the degra-

dation of the cell wall. The relation-ship between the inhibition of PBPactivity and the activation of autoly-sis is unclear and very complex. Tol-

erance to penicillin occurs when theorganism is inhibited but not killedby an antibiotic that usually is bacte-ricidal. For example, the growth of

certain tolerant strains of Staphylo-coccus aureus can be arrested bybeta-lactam antibiotics, but autolyticenzymes are not activated.

Production of beta-lactamases, en-zymes that can cleave the beta-lactam

ring, is an important mechanism forthe inactivation of beta-lactam antibi-otics and development of resistanceby many bacteria (eg, S aureus, Neis-seria gonorrhoeae, Pseudomonas sp,Bacteroides fragilis, and some enteric




IT. I

MECHANISM DRUGS ACT1ON�

Weaken bacterial cell wall and cause cell death. Inhibit cross-linking of peptidoglycan Penicillins, cephalosporins Bactericidal

. Activate autolytic enzymes (ie, autolysins)

. Inhibit other steps in peptidoglycan synthesis Vancomycin Bactericidal

Increase cell membrane permeability. Cause leakage of cell contents Polymyxin NA

Inhibit protein synthesis. Bind to 505 ribosome subunit Chloramphenicol Bacteriostatic

Erythromycin Bacteriostatic

Clarithromycin BacteriostaticClindamycin Bacteriostatic

. Bind to 305 ribosome subunit Aminoglycosides BactericidalTetracyclines Bacteriostatic

Inhibit nucleic acid synthesis. Inhibit nucleotide synthesis Sulfonamides, trimethoprim Bacteriostatic

. Inhibit DNA-dependent RNA polymerase Rifampin Bactericidal

. Inhibit DNA supercoiling and DNA synthesis Quinolones Bactericidal

*Note: Bacteriostatic agents may be bactericidal against some organisms at high concentrations.

DRUGS FOR WHICH RESISTANCEORGANISM HAS BEEN REPORTED RECOMMENDATiONS

Streptococcus pneumoniae #{149}Penicillin #{149}Conduct oxacillin disk susceptibility onIntermediate-level resistance is all isolates

increasing #{149}If resistant, check MICs to penicillin,

High-level resistance has been cefotaxime, ceftriaxone, vancomyin,reported in various areas or othersworldwide and is increasing #{149}If sensitive, susceptible to all beta-

in the United States lactams

Clusters of cases may occur (eg, #{149}If meningitis, treat with vancomycinchildcare contacts) PLUS third-generation cephalosporin

#{149}Cephalosporins OR chloramphenicol OR imipenemTreatment failures have prompted pending susceptibility testing

susceptibility testing

Enterococcus fecalis #{149}Ampicillin #{149}If invasive disease, check MICs and treatEnterococcus faecium #{149}Vancomyin with ampicillin PLUS vancomycin

Resistant strains have been PLUS aminoglycoside (gentamicin)

identified pending susceptibility testing

Neisseria gonorrhoeae #{149}Penicillinase-producing strains #{149}Penicillin or doxycycline are not

common recommended empiric therapies#{149}Tetracycline #{149}Monitor fluoroquinolone susceptibility

High-level plasmid-mediated pattern and clinical responseresistance reported #{149}Third-generation cephalosporins (eg,

#{149}Fluoroquinolones ceftriaxone) still seem effectiveDecreased susceptibility reported



Pediatrics in Review VoL iS No. ii November 1994 443

Gram-negative bacilli). The informa-tion for producing beta-lactamasescan be coded in chromosomes or ona plasmid. The beta-lactamases canbe constitutive (produced all thetime) or inducible (only produced atcertain times).

In the case of inducible resistance,the organism initially will be suscep-tible to a certain antibiotic, but aftera short period of therapy, the organ-

ism will become resistant because ofthe beta-lactamases that have beeninduced. Frequently, this is signaledby only limited improvement or clini-cal deterioration of the patient afteran initial improvement. Inducible

beta-lactamase production is a partic-ular problem with some Gram-negative bacteria (eg, Pseudomonas,

Enterobacter, Citrobacter, Acineto-bacter, Serratia sp) treated with

broad-spectrum cephalosporins.Beta-lactamase production by bac-

teria can be inhibited by the additionof certain chemical structures that aresimilar in structure to penicillin (eg,clavulanic acid, sulbactam). The in-hibitors bind strongly to the beta-lac-

tamases and prevent the subsequent

inactivation of the penicillin nucleus.Penicillins have good activity

against Gram-positive bacteria and

oral anaerobes and variable activityagainst Gram-negative bacilli. Theyare the treatment of choice for syphi-lis, leptospirosis, or Listeria infec-tions. Penicillins generally areclassified according to their spectrum

of activity as determined by changesin their side chains relative to peni-cillin: penicillinase-resistant penicillin(eg, methicillin, nafcillin, oxacillin,cloxacillin, and dicloxacillin); amino-penicillins (ampicillin, amoxicillin);antipseudomonal penicillins (eg, car-benicillin, ticarcillin, and azlocillin);and extended-spectrum penicillins

(eg, mezlocillin, piperacillin).

The cephalosporins are dividedinto “generations” based on their an-

timicrobial activity. First-generationcephalosporins (eg, cephalexin, cefa-droxil, and cefazolin) have good ac-tivity against Gram-positive bacteria,including penicillinase-producing S

aureus, group A beta-hemolyticstreptococci, group B streptococci,and S pneumoniae, and modest activ-ity against some Gram-negative or-ganisms. The second-generation

cephalosporins (eg, cefaclor, cefurox-ime, cefuroxime axetil, cefprozil, cef-amandole, cefoxitin, and cefotetan)retain activity against Gram-positiveorganisms but have more activityagainst Gram-negative organisms, in-

cluding most strains of Haemophilusinfluenzae and some strains of entericbacteria. The third-generation cepha-

losporins (eg, cefixime, cefoperazone,cefotaxime, cefpodoxime proxetil,ceftazidime, ceftizoxime, and ceftriax-one) are more active against Gram-negative organisms (includingEnterobacteriaceae and beta-lactamase-producing strains of H infiuenzae,

Moraxella catarrhalLi, and N gonor-

rhoeae), but they are less active thanfirst-generation cephalosporins againstGram-positive organisms. Ceftazidimeis active against Pseudomonas sp andhas superior central nervous system

penetration compared with aminoglyco-sides. Ceftriaxone has a prolongedhalf-life that allows for once-a-daydosing. None of the cephalosporins is

effective against anaerobes, entero-cocci, or L monocytogenes.

Because of the structural similaritybetween penicillin and first- and sec-ond-generation cephalosporins, pa-tients may manifest cross-reactivitywhen a member of the other class isadministered. Immunologic studiesdemonstrate a 20% cross-reactivity;more recent clinical studies indicate afrequency as low as 1%. Cross-reac-tivity between penicillins and cepha-losporins generally occurs in about

8% of patients who have a history ofan allergic reaction to penicillin. Al-though side chains do not seem to bea factor in allergic reactions to peni-cillins, they may be important incephalosporin allergy. The patientwho is allergic to cephalosporins mayhave an allergy to the beta-lactamring, the bulky side chain, or both.The risk of allergic reaction with thenewer third-generation cephalosporins

is not known.

WEAKEN CELL WALL BYINHIBITING PEPFIDOGLYCANSYNTHESIS

Vancomycin

Vancomycin is a complex and unu-sual tricyclic glycopeptide that inhib-its cell synthesis in sensitive bacteriaby binding tightly to precursor sub-units of the cell wall and preventing

Itheir incorporation into the growingpeptidoglycan. The drug is rapidlybactericidal for dividing microor-ganisms. Because vancomycin maybe only bacteriostatic for some en-terococci, an aminoglycoside is

added to vancomycin therapy in se-rious infections known to be causedby this organism (eg, infective en-docarditis).

Early preparations of vancomycincontained impurities that probablycontributed significantly to the toxic-ity associated with its early use; thisno longer is a problem. In recentyears, there has been renewed interestin the use of vancomycin for several

reasons. First, it is structurally unre-lated to other antibiotics, so it is use-ful in the patient who is allergic topenicillin and cephalosporins. Sec-ond, it is active primarily againstGram-positive bacteria and forms themainstay of therapy for the treatmentof infections caused by methicillin-resistant S aureus (MRSA), coagu-lase-negative staphylococci that areresistant to other penicillins, and S

pneumoniae strains that are resistantto penicillin and cephalosporins (Ta-

ble 2). Vancomycin is an importantantibiotic for use in immunocom-promised patients who have evi-

dence of catheter-related infections.Because oral vancomycin is ab-sorbed poorly, high concentrationsoccur in the stool. Thus, it can beused as a more expensive alternativeto metronidazole for the treatment of

Clostridium difficile infections; me-tronidazole is not approved by theFood and Drug Administration for

use in children.Reports of vancomycin-resistant

strains of enterococci and S aureushave caused extreme concern in the

medical community. Prudent use ofthis drug is essential to minimize thedevelopment of further resistance.Measurement of serum levels of van-

comycin is recommended to avoidpotential ototoxicity and nephrotoxic-ity. The incidence of both toxicitiesis increased when vancomycin is ad-ministered simultaneously with anaminoglycoside.

INCREASE CELL PERMEABILITY

Polymyxin B

Polymyxin B is a basic peptide elab-orated by various strains of Bacillus



Gram-positive and Gram-negative bacteria differ in their cell

wall structures; the peptidoglycan layer is thick in Gram-positive

organisms and thin in Gram-negative organisms.

444 Pediatrics in Review Vol. 15 No. 11 November 1994

sp. It is a surface-active agent con-taming both lipophilic and lipophobicgroups within the molecule that inter-act strongly with phospholipids anddisrupt the integrity of cell mem-branes. The permeability of the bac-terial membrane changes immediatelyafter contact with the drug. Poly-myxin B is prescribed primarily forophthalmic, otic, or topical use incombination with a variety of othercompounds (eg, bacitracin, neomycin,hydrocortisone).

INHIBIT PROTEIN SYNTHESIS

Ribosomes are the site of proteinsynthesis in both bacterial and eukar-yotic cells, but bacterial and eukar-

yotic ribosomes differ in both sizeand chemical composition. Bacterialribosomes are 70S in size (with 50S

and 30S subunits) compared with80S (with 60S and 40S subunits) ineukaryotic cells. Thus, antibiotics that

phenicol usually is caused by aplasmid acquired by conjugation.

Other plasmids may transfer resis-tance to multiple antibiotics (eg,chloramphenicol, tetracycline, andbeta-lactams). Once acetylated, chor-amphenicol cannot attach to thebacterial ribosome.

Use of chloramphenicol must belimited to infections for which thebenefits of the drug outweigh the riskof the potential toxicities (eg, reversi-ble, dose-related bone marrow sup-pression, potentially fatal idiosyn-cratic aplastic anemia, and “gray

baby” syndrome). When antimicro-bials that have equivalent activity butare potentially less toxic are availa-ble, they should be used. In addition,it is necessary to monitor serum lev-els when treating a patient with chlo-ramphenicol.

Chloramphenicol is a broad-spec-trum antibiotic that is active against

Resistance to erythromycin can oc-

cur by at least three plasmid-medi-ated mechanisms: failure of the drugto penetrate the cell, modification ofthe target sites on the 505 ribosomeso that the drug fails to bind, andproduction of an esterase by the bac-teria to hydrolyze the drug.

Gram-positive bacteria accumulate

about 100 times more erythromycinthan do Gram-negative organisms.Although erythromycin generally isclassified as a bacteriostatic agent, it

can have bactericidal activity againsta small number of rapidly dividing

bacteria, especially in an alkalineenvironment.

In patients who have penicillin al-

lergy, erythromycin is an effective al-ternative agent against Gram-positivebacteria such as group A strepto-

cocci, S pneumoniae, and S aureus.However, the emergence of resistantstrains must be monitored. Erythro-

mycin also has good antimicrobialactivity against Bordetella pertussis,

Borrelia sp, Campylobacter sp, Chla-

mydia trachomatis, C pneumoniae(TWAR strain), Mycoplasma pneu-moniae, and Legionella pneumophila.

Clanthromycin

affect protein synthesis can have aselective effect on sensitive bacteriawithout affecting human cells.

Chloramphenicol

Chloramphenicol, a nitrobenzenemoiety, penetrates bacterial cells byfacilitated diffusion and binds reversi-

bly to the bacterial 505 ribosomal sub-unit. This drug (like tetracycline’seffect on the 305 ribosome subunit)blocks the binding of the aminoacyltransfer RNA (tRNA) to the acceptor

site on the ribosome. Chlorampheni-col has less of an effect on proteinsynthesis in eukaryotic cells than inbacterial cells. Chloramphenicol isprimarily a bacteriostatic agent, but itmay be bactericidal to certain species

(eg, H influenzae, S pneumoniae, Nmeningiditis).

Mechanisms of resistance to chlor-amphenicol include production of anacetyltransferase by the bacteria thatinactivates chloramphenicol and in-

ability of chloramphenicol to enterselected bacteria. Resistance of

Gram-negative bacteria to chloram-

many Gram-positive and -negativebacteria as well as against rickettsiae.

In particular, it is effective againstmost anaerobic bacteria, including B

fragilis, and the majority of Salmo-nella sp and H influenzae strains. Itis a recommended alternative therapyfor infections caused by Brucella and

Pasteurella sp as well as for RockyMountain spotted fever. Chloram-phenicol has been effective in some S

pneumoniae infections resistant topenicillins and cephalosporins.

Erythromycin

Erythromycin has a macrolide struc-

ture composed of a large 13-carbonring to which two sugars are attachedby glycosidic linkages. Erythromycinand other macrolides inhibit proteinsynthesis by reversibly binding to the50S ribosome subunit of sensitivemicroorganisms. It blocks the translo-

cation step in protein synthesis bypreventing the release of the tRNAfrom the acceptor to the donor siteon the ribosome after the peptide

bond is formed.

Clarithromycin, recently approved forpediatric use, differs chemically fromerythromycin by having a methylsubstitution on the macrolide ring. Itsspectrum of activity is similar to thatof erythromycin except for enhancedH influenzae activity (including beta-lactamase-producing strains), and itslonger half-life allows for twice-a-day

dosing. Clarithromycin and its activemetabolite penetrate well into bodyfluids and tissues (eg, lung tissue,tonsils), resulting in intracellular andtissue concentrations that are higherthan serum concentrations. Gastroin-

testinal side effects occur less fre-quently in patients receiving

clarithromycin (8% to 16%) than inthose treated with erythromycin (20%to 40%). Because it reaches excellentlevels in serum, alveoli, macrophages,

and lung tissue, other important uses

of clarithromycin will be in the ther-apy of Mycobacterium avium and Cpnewnoniae (TWAR) infections.

Clindamycin

Clindamycin, a derivative of anamino acid attached to a sulfur-con-



In patients who have penicillin allergy, erythromycin is an

effective alternative agent.

Pediatrics in Review VoL 15 No. ii November 1994 445

I� �taming sugar, has replaced its parentdrug lincomycin in clinical use. Clin-damycin inhibits protein synthesis byreversibly binding to the 505 ribo-some subunit of sensitive microrgan-isms. Although bactericidal for someorganisms, clindamycin generally isbacteriostatic. Mechanisms of resis-tance are similar to those outlined for

erythromycin.Clindamycin is active against

pneumococci and group A strepto-

cocci. It has excellent activity againstS aureus and many anaerobic bacte-ria, particularly B fragilis. Clinda-mycin is an important antibiotic forthe treatment of intra-abdominal orpelvic infections and as an alterna-tive therapy in patients who are al-lergic to penicillin. Bacterial strainsthat are resistant to clindamycin gen-erally are resistant to erythromycin.

Clindamycin penetrates well intomost body fluids, including sputum,pleural fluid, and bone. However, it

should not be used for central nerv-ous system infections because of itspoor penetration into cerebrospinalfluid.

the inner cytoplasmic membrane can

be reduced by acidic or anaerobic

conditions, such as those present inan abscess. Inactivation by microbial

enzymes is an important cause of the

acquired resistance to aminoglyco-sides that occurs frequently. The ge-netic information for these enzymes

is acquired primarily by conjugationand the transfer of DNA as plasmidsor resistance factors. Such plasmidsare widespread and may disseminateresistance to other antibiotics simulta-neously. Amikacin may be less vul-

nerable to these inactivating enzymesthan kanamycin, gentimicin, and to-bramycin because of protective mo-

lecular side chains.

The antibacterial activity of ami-noglycosides is directed primarilyagainst aerobic Gram-negative bacilli;there is little activity against anaer-

obes or Gram-positive bacteria.Streptomycin has been used in the

outer membrane of bacteria. Then itis transported into the inner cytoplas-mic membranes where it is boundmainly to the 30S subunits of thebacterial ribosomes. The tetracyclinesinhibit protein synthesis by blockingaminoacyl tRNA from entering theacceptor site on the mRNA ribosome

complex. Tetracycline’s selective ac-tion on bacterial cells is based on itsgreatly increased uptake in suscepti-

ble bacterial cells compared with

human cells; the host cells lack theactive transport system present inbacteria.

Resistance to the tetracyclines fre-quently is mediated by plasmids andis an inducible trait; that is, the bac-teria become resistant following ex-posure to the drug. A number oftransferable resistance determinantsfor tetracycline have been identified.Microrganisms that develop resis-tance to one tetracycline usually are

Aminoglycosides

The aminoglycosides (eg, amikacin,gentamicin, tobramycin, and strepto-mycin) contain amino sugars linkedto an aminocyclitol ring by glyco-sidic bonds. Aminoglycosides diffusethrough channels formed by porinproteins in the outer membrane of

Gram-negative bacteria and into theperiplasmic space (Figure). There theaminoglycosides bind irreversibly topolysomes, especially the 305 riboso-mal subunits, and prevent proteinsynthesis by inhibiting the ‘ ‘initiation

complex.” In addition, aminoglyco-sides cause misreading of the mes-senger RNA (mRNA) template,which results in the incorporation ofincorrect amino acids into the grow-ing protein chain. As a result, themembrane is damaged and the bacte-ria die. Unlike the other inhibitors ofmicrobial protein synthesis, the ami-noglycosides are bactericidal rather

than bacteriostatic.Bacteria may be resistant to the

antimicrobial activity of aminoglyco-sides if the drug fails to penetrate thecell, has a low affinity for the bacte-rial ribosome, or is inactivated bymicrobial enzymes. Transport across

multiple drug therapy of resistantpulmonary tuberculosis or dissemi-nated mycobacterial disease. Genta-micin has been used in combinationwith other antibiotics for its synergis-

tic effects against certain bacteria (eg,with penicillin against enterococci,with nafcillin against S aureus, withpenicillin against group B strepto-

cocci, with ampicillin against L mono-

cytogenes, and with other drugseffective against Pseudomonas sp).The clinical usefulness of aminogly-

cosides is limited by the potential forototoxicity and nephrotoxicity, poorcentral nervous system penetration,and the need for monitoring serumlevels.

Tetracycline

The structure of tetracycline consists

of four cyclic rings with differentsubstituents in three regions; the lat-ter substitutions result in differentpharmacologic properties but similarantibacterial activity. Initially, the tet-

racycline moiety passively diffusesthrough the porn proteins in the

resistant to the congeners as well.High-level plasmid resistance to tetra-

cycline has increased nationallyamong strains of N gonorrhoeae;

consequently, monotherapy with tet-racycline or doxycycline no longer isrecommended to treat a patient whohas both gonorrhea and chiamydialinfections (Table 2).

The tetracyclines have bacterio-static activity against a variety ofGram-positive and Gram-negative

bacteria. Tetracyclines are a recom-mended treatment for early Lymedisease, Rocky Mountain spotted

fever, and infections caused by M

pneumoniae, C trachomatis (includ-ing pelvic inflammatory disease), and

C pneumoniae (TWAR strain).Because of its increased lipophilic

properties, doxycycline attains highercentral nervous system concentrationsthan other tetracyclines, which maybe important in the treatment of earlyLyme disease. Tetracyclines are notgiven routinely to children youngerthan 9 years of age because of toxic-ity to teeth and bones. However, cx-



The clinical usefulness of aminoglycosides is limited by the

potential for ototoxicity and nephrotoxicity, poor central nervous

system penetration, and the need for monitoring serum levels.


I Iceptions have been made to treatyounger children who have RockyMountain spotted fever.

INHIBIT NUCLEIC ACIDSYNTHESIS

Sulfonamides

Sulfonamide is a generic name for

the derivatives of para-aminobenzene-sulfonamide. Sulfonamides are struc-tural analogs and competitive inhibi-tors of the bacterial enzyme dihydrop-teroate synthase, which is responsible

for incorporating para-aminobenzoic

acid (PABA) into dihydropteroicacid, the precursor of folic acid. Thisresults in a decreased pool of bacte-rial nucleotides, which are the build-ing blocks for DNA synthesis.Mammalian cells are not affected by

this mechanism because they requirepreformed folic acid from their diet.

Sulfonamides are bacteriostaticagents; thus, the final eradication ofthe infection depends on the cellularand humoral defense mechanisms ofthe host.

Sulfonamides have a wide range ofantimicrobial activity against Gram-positive and Gram-negative bacteria.They were the first effective chemo-

therapeutic agents used to cure bacte-rial diseases (eg, puerperal sepsis andmeningococcal infections). Sulfona-

mides frequently are used as chemo-prophylaxis and also are recom-mended for the treatment of Toxo-

plasma infections.

Tnmethoprim

Trimethoprim, an antimetabolite thataffects folic acid synthesis, is a

highly selective inhibitor of dihydro-folate reductase in lower organisms.It prevents the reduction of dihydro-folate to tetrahydrofolate, anothercritical precursor in purine synthesis.By combining trimethoprim with sul-

famethoxazole (TMP-SMZ), two se-quential steps of purine synthesis are

disrupted synergistically and less re-sistance develops. TMP-SMZ is usedwidely for the treatment of urinarytract infections, respiratory infections,

sinusitus, otitis media, and gastroin-testinal infections (eg, salmonellosis,shigellosis, traveler’s diarrhea). TMP-SMZ also is the drug of choice forthe treatment and prophylaxis ofPneumocystis carinii infections.

Rifampin

Rifampin inhibits DNA-dependentRNA polymerase at the B subunit ofthis enzyme, which prevents chain in-

itiation but not elongation in RNAsynthesis. Rifampin is bactericidal forboth intracellular and extracellular

microorganisms. Resistant strains ofbacteria have altered RNA polymer-ase that is not inhibited by rifampin.

Microorganisms may develop resis-tance to rifampin rapidly in vitro as a

one-step mutation; this also occurs invivo. For this reason, rifampin shouldnot be administered alone, except forshort-term chemoprophylaxis (eg, in-fections caused by N meningiditis orH influenzae type b). Rifampin is

used in combination with otheragents to treat tuberculosis and per-sistent group A streptococcal or

staphylococcal infections.

Quinolones

Nalidixic acid has been available forthe treatment of urinary tract infec-tions for decades, but it has limitedusefulness because bacterial resis-tance develops rapidly. Newer syn-

thetic fluoroquinolones (eg, norfiox-acm, ciprofloxacin, enoxacin, fleroxa-cm, lomefloxacin, and ofloxacin)

have broad-spectrum antimicrobialactivity and are a therapeutic ad-vance. Their use in pediatrics has

been limited by the potential risk ofarthropathy that has been documentedin several species of immature ani-

mals.The quinolones bind to the A sub-

units of DNA gyrase, which are re-sponsible for cutting DNA strands,thus preventing supercoiling, unravel-ing the DNA, and halting DNA repli-

cation. Most quinolones are not asactive against Gram-positive bacteriaas they are against Gram-negativebacteria; they are only effectiveagainst streptococci and enterococciat levels that can be reached in the

urine.The emergence of resistance to

fluoroquinolones has been problem-atic for MRSA, methicillin-sensitiveS aureus, P aeruginosa, and someSerratia infections. Decreased suscep-tibility of N gonorrhoeae to fluoro-

quinolones recently has been reported(Table 2). It is believed that wide-

spread and often indiscriminate useof fluoroquinolones has contributedto this resistance problem. However,

when used in selected patients, thequinolones can be life-saving, may

allow the patient to avoid or shortenhospitalization, and can be very cost-

effective.Fluoroquinolones have been used

to treat patients who have pyelone-phritis or recurrent urinary tract in-

fections, prostatitis, gonorrhea (singledose) and chlamydia (7-day course)infections, malignant external otitis,osteomyelitis caused by Gram-nega-tive bacteria, respiratory infectionsincluding exacerbations of cystic fi-

brosis, and gastrointestinal infections(eg, Shigella, Salmonella, Campylo-

bacter infections and traveler’s diar-

rhea).Quinolones are not approved by

the Food and Drug Administrationfor use in patients younger than 18years of age or in pregnant or nurs-ing women. Children who have cys-tic fibrosis and are younger than 18years old have been treated withquinolones without adverse effectsbecause the benefits were believed tooutweigh the risks.

ImplicationsUnderstanding the many differentmechanisms of action for availableantibiotics may help practitionersmake better clinical decisions regard-ing the use of antibiotics. Althoughthe increasing emergence of antibi-otic-resistant pathogens is alarming,there are steps that each physiciancan take to slow this trend (Table 3).



Pediatrics in Review VoL 15 No. ii November 1994 447

IAdmittedly, some of these recom-mendations are not easy or popular.However, the alternative may be theemergence of resistant bacteria thatcannot be treated with any of ourmany antibiotics.

SUGGESTED READINGGeneralBrooks OF, Butel JS, Ornston LN, Ct al.

Medical Microbiology. Norwalk, Conn:

Appleton and Lange; 1991Craft JC, Siepman N. Overview of the safety

profile of clarithromycin suspension in

pediatric patients. Pediatr Infect Dis J.1993;12:S142-.S147

Oilman AG, Rail 1’W, Nies AS, et al. ThePharmacological Basis of Therapeutics.

New York, NY: Pergamon Press; 1990

Kucers A, Bennett N. The Use of Antibiotics,

4th ed. Philadelphia, Penn: JB Lippincott

Company; 1987Mulligan Mi, Cobbs CO. Bacteriostatic versus

bactericidal activity. Infect Dis Clin North

Am. 1989;3:389-397Petz LD. Immunological reactions between

penicillins and cephalosporins: a review. JInfect Dis. 1978;137(suppl):S74-S79

Reese RE, Betts RF. Handbook of Antibiotics,

2nd ed. Boston, Mass: Little Brown and

Company; 1993Rodriequez Wi, Wiedermann VL. Role of

newer oral cephalosporins, fluoroquinolones

and macrolides in the treatment of pediatric

infections. In: Aronoff SC, ed. Advances in

Pediatric Infectious Diseases, vol 9. St.

Louis, Mo: CV Mosby; 1994:125-151

AntIbiotic-resistant Pathogens

Breiman RF, Butler JC, Tenover FC, ElliottJA, Facklam RR. Emergence of drug-resistant pneumococcal infections in the US.

JAMA. 1994;271:1831-1835Centers for Disease Control. Decreased

susceptibility of Neisseria gonorrhoeae to

fluoroquinolones: Ohio and Hawaii, 1992-1994. MMWR. 1994;43:325-327

Leggiadro RJ. Penicillin and cephalosporin-

resistant Streptococcus pneumoniae: an

emerging microbial threat. Pediatrics. 1994;93:500-503

Sloas MM, Barrett FF, Chesney PJ, et at.

Cephalosporin treatment failure in penicillin-

and cephalosporin-resistant Streptococcus

pneumoniae meningitis. Pediatr Infect Dis J.

1992;! 1:662-666Smith AL. Antibiotic resistance in pediatric

pathogens. Infect Dis Clin North Am. 1992;

6:177-195

Table 3. What Practftloners Can Do To Umft theEmergence of Antibiotlcreslstant Pathogens

#{149}Wash hands thoroughly to avoid spreading resistant organisms to otherpatients.

#{149}Stop and think. Is this a bacterial disease and is an antibiotic needed?#{149}Educate your patients that viral illnesses do not respond to antibiotics.#{149}Always use the narrowest-spectrum antibiotic possible.#{149}Try to limit the empiric use of broad-spectrum agents.

#{149}Stay informed about your hospital’s antibiotic resistance patterns.#{149}Recognize that hospitaiwide antibiotic control programs may be

implemented in some cases to limit access to certain antibiotics.

ASSiSOJU Professor of Pediatrics, Divisions

of Pediatric Infectious Diseases and General

Pediatrics, University of Rochester, Rochester,

NY.

Private Practice, Pediatric Infectious

Diseases and Allergy, Bellevile, NJ.



DOI: 10.1542/pir.15-11-440 1994;15;440-447 Pediatr. Rev.

Kathleen A. Woodin and Susan H. Morrison BACK TO BASICS: Antibiotics: Mechanisms of Action

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