Antibacterial Drugs
Drugs for Treating Bacterial Infections
When bacteria overcome the cutaneous
or mucosal barriers and penetrate body
tissues, a bacterial infection is present.
Frequently the body succeeds in removing
the invaders, without outward signs
of disease, by mounting an immune response.
If bacteria multiply faster than
the body’s defenses can destroy them,
infectious disease develops with inflammatory
signs, e.g., purulent wound infection
or urinary tract infection. Appropriate
treatment employs substances
that injure bacteria and thereby prevent
their further multiplication, without
harming cells of the host organism (1).
Apropos nomenclature: antibiotics
are produced by microorganisms (fungi,
bacteria) and are directed “against life”
at any phylogenetic level (prokaryotes,
eukaryotes). Chemotherapeutic agents
originate from chemical synthesis. This
distinction has been lost in current usage.
Specific damage to bacteria is particularly
practicable when a substance
interferes with a metabolic process that
occurs in bacterial but not in host cells.
Clearly this applies to inhibitors of cell
wall synthesis, because human and animal
cells lack a cell wall. The points of
attack of antibacterial agents are schematically
illustrated in a grossly simplified
bacterial cell, as depicted in (2).
In the following sections, polymyxins
and tyrothricin are not considered
further. These polypeptide antibiotics
enhance cell membrane permeability.
Due to their poor tolerability, they are
prescribed in humans only for topical
use.
The effect of antibacterial drugs can
be observed in vitro (3). Bacteria multiply
in a growth medium under control
conditions. If the medium contains an
antibacterial drug, two results can be
discerned: 1. bacteria are killed—bactericidal
effect; 2. bacteria survive, but do
not multiply—bacteriostatic effect. Although
variations may occur under
therapeutic conditions, different drugs
can be classified according to their respective
primary mode of action (color
tone in 2 and 3).
When bacterial growth remains unaffected
by an antibacterial drug, bacterial
resistance is present. This may occur
because of certain metabolic characteristics
that confer a natural insensitivity
to the drug on a particular strain of
bacteria (natural resistance). Depending
on whether a drug affects only a few or
numerous types of bacteria, the terms
narrow-spectrum (e.g., penicillin G) or
broad-spectrum (e.g., tetracyclines)
antibiotic are applied. Naturally susceptible
bacterial strains can be transformed
under the influence of antibacterial
drugs into resistant ones (acquired
resistance), when a random genetic alteration
(mutation) gives rise to a resistant
bacterium. Under the influence of
the drug, the susceptible bacteria die
off, whereas the mutant multiplies unimpeded.
The more frequently a given
drug is applied, the more probable the
emergence of resistant strains (e.g., hospital
strains with multiple resistance)!
Resistance can also be acquired
when DNA responsible for nonsusceptibility
(so-called resistance plasmid) is
passed on from other resistant bacteria
by conjugation or transduction.
Inhibitors of Cell Wall Synthesis
In most bacteria, a cell wall surrounds
the cell like a rigid shell that protects
against noxious outside influences and
prevents rupture of the plasma membrane
from a high internal osmotic
pressure. The structural stability of the
cell wall is due mainly to the murein
(peptidoglycan) lattice. This consists of
basic building blocks linked together to
form a large macromolecule. Each basic
unit contains the two linked aminosugars
N-acetylglucosamine and N-acetylmuramyl
acid; the latter bears a peptide
chain. The building blocks are synthesized
in the bacterium, transported outward
through the cell membrane, and
assembled as illustrated schematically.
The enzyme transpeptidase cross-links
the peptide chains of adjacent aminosugar
chains.
Inhibitors of cell wall synthesis
are suitable antibacterial agents, because
animal and human cells lack a cell
wall. They exert a bactericidal action on
growing or multiplying germs. Members
of this class include !-lactam antibiotics
such as the penicillins and cephalosporins,
in addition to bacitracin and
vancomycin.
Penicillins (A). The parent substance
of this group is penicillin G (benzylpenicillin).
It is obtained from cultures
of mold fungi, originally from Penicillium
notatum. Penicillin G contains
the basic structure common to all penicillins,
6-amino-penicillanic acid (p.
271, 6-APA), comprised of a thiazolidine
and a 4-membered !-lactam ring. 6-
APA itself lacks antibacterial activity.
Penicillins disrupt cell wall synthesis by
inhibiting transpeptidase. When bacteria
are in their growth and replication
phase, penicillins are bactericidal; due
to cell wall defects, the bacteria swell
and burst.
Penicillins are generally well tolerated;
with penicillin G, the daily dose
can range from approx. 0.6 g i.m. (= 106
international units, 1 Mega I.U.) to 60 g
by infusion. The most important adverse
effects are due to hypersensitivity
(incidence up to 5%), with manifestations
ranging from skin eruptions to
anaphylactic shock (in less than 0.05% of
patients). Known penicillin allergy is a
contraindication for these drugs. Because
of an increased risk of sensitization,
penicillins must not be used locally.
Neurotoxic effects, mostly convulsions
due to GABA antagonism, may occur
if the brain is exposed to extremely
high concentrations, e.g., after rapid i.v.
injection of a large dose or intrathecal
injection.
Penicillin G undergoes rapid renal
elimination mainly in unchanged form
(plasma t1/2 ~ 0.5 h). The duration of
the effect can be prolonged by:
1. Use of higher doses, enabling plasma
levels to remain above the minimally
effective antibacterial concentration;
2. Combination with probenecid. Renal
elimination of penicillin occurs
chiefly via the anion (acid)-secretory
system of the proximal tubule (-COOH
of 6-APA). The acid probenecid (p. 316)
competes for this route and thus retards
penicillin elimination;
3. Intramuscular administration in
depot form. In its anionic form (-COO-)
penicillin G forms poorly water-soluble
salts with substances containing a positively
charged amino group (procaine,
p. 208; clemizole, an antihistamine;
benzathine, dicationic). Depending on
the substance, release of penicillin from
the depot occurs over a variable interval.
Although very well tolerated, penicillin
G has disadvantages (A) that limit
its therapeutic usefulness: (1) It is inactivated
by gastric acid, which cleaves
the !-lactam ring, necessitating parenteral
administration. (2) The !-lactam
ring can also be opened by bacterial enzymes
(!-lactamases); in particular,
penicillinase, which can be produced by
staphylococcal strains, renders them resistant
to penicillin G. (3) The antibacterial
spectrum is narrow; although it encompasses
many gram-positive bacteria,
gram-negative cocci, and spirochetes,
many gram-negative pathogens
are unaffected.
Derivatives with a different substituent
on 6-APA possess advantages
(B): (1) Acid resistance permits oral administration,
provided that enteral absorption
is possible. All derivatives
shown in (B) can be given orally. Penicillin
V (phenoxymethylpenicillin) exhibits
antibacterial properties similar to
those of penicillin G. (2) Due to their
penicillinase resistance, isoxazolylpenicillins
(oxacillin dicloxacillin, flucloxacillin)
are suitable for the (oral) treatment
of infections caused by penicillinaseproducing
staphylococci. (3) Extended
activity spectrum: The aminopenicillin
amoxicillin is active against many gramnegative
organisms, e.g., coli bacteria or
Salmonella typhi. It can be protected
from destruction by penicillinase by
combination with inhibitors of penicillinase
(clavulanic acid, sulbactam, tazobactam).
The structurally close congener ampicillin
(no 4-hydroxy group) has a similar
activity spectrum. However, because
it is poorly absorbed (<50%) and therefore
causes more extensive damage to
the gut microbial flora (side effect: diarrhea),
it should be given only by injection.
A still broader spectrum (including
Pseudomonas bacteria) is shown by carboxypenicillins
(carbenicillin, ticarcillin)
and acylaminopenicillins (mezclocillin,
azlocillin, piperacillin). These substances
are neither acid stable nor penicillinase
resistant.
Cephalosporins (C). These !-lactam
antibiotics are also fungal products
and have bactericidal activity due to inhibition
of transpeptidase. Their
shared basic structure is 7-aminocephalosporanic
acid, as exemplified by
cephalexin (gray rectangle). Cephalosporins
are acid stable, but many are
poorly absorbed. Because they must be
given parenterally, most—including
those with high activity—are used only
in clinical settings. A few, e.g., cephalexin,
are suitable for oral use. Cephalosporins
are penicillinase-resistant, but
cephalosporinase-forming organisms
do exist. Some derivatives are, however,
also resistant to this !-lactamase.
Cephalosporins are broad-spectrum
antibacterials. Newer derivatives (e.g.,
cefotaxime, cefmenoxin, cefoperazone,
ceftriaxone, ceftazidime, moxalactam)
are also effective against pathogens resistant
to various other antibacterials.
Cephalosporins are mostly well tolerated.
All can cause allergic reactions, some
also renal injury, alcohol intolerance,
and bleeding (vitamin K antagonism).
Other inhibitors of cell wall synthesis.
Bacitracin and vancomycin
interfere with the transport of peptidoglycans
through the cytoplasmic
membrane and are active only against
gram-positive bacteria. Bacitracin is a
polypeptide mixture, markedly nephrotoxic
and used only topically. Vancomycin
is a glycopeptide and the drug of
choice for the (oral) treatment of bowel
inflammations occurring as a complication
of antibiotic therapy (pseudomembranous
enterocolitis caused by Clostridium
difficile). It is not absorbed.
Inhibitors of Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a co-enzyme
in the synthesis of purine bases
and thymidine. These are constituents
of DNA and RNA and required for cell
growth and replication. Lack of THF
leads to inhibition of cell proliferation.
Formation of THF from dihydrofolate
(DHF) is catalyzed by the enzyme dihydrofolate
reductase. DHF is made from
folic acid, a vitamin that cannot be synthesized
in the body, but must be taken
up from exogenous sources. Most bacteria
do not have a requirement for folate,
because they are capable of synthesizing
folate, more precisely DHF, from
precursors. Selective interference with
bacterial biosynthesis of THF can be
achieved with sulfonamides and trimethoprim.
Sulfonamides structurally resemble
p-aminobenzoic acid (PABA), a precursor
in bacterial DHF synthesis. As
false substrates, sulfonamides competitively
inhibit utilization of PABA, hence
DHF synthesis. Because most bacteria
cannot take up exogenous folate, they
are depleted of DHF. Sulfonamides thus
possess bacteriostatic activity against a
broad spectrum of pathogens. Sulfonamides
are produced by chemical synthesis.
The basic structure is shown in
(A). Residue R determines the pharmacokinetic
properties of a given sulfonamide.
Most sulfonamides are well absorbed
via the enteral route. They are
metabolized to varying degrees and
eliminated through the kidney. Rates of
elimination, hence duration of effect,
may vary widely. Some members are
poorly absorbed from the gut and are
thus suitable for the treatment of bacterial
bowel infections. Adverse effects
may include, among others, allergic reactions,
sometimes with severe skin
damage, displacement of other plasma
protein-bound drugs or bilirubin in neonates
(danger of kernicterus, hence contraindication
for the last weeks of gestation
and in the neonate). Because of the
frequent emergence of resistant bacteria,
sulfonamides are now rarely used.
Introduced in 1935, they were the first
broad-spectrum chemotherapeutics.
Trimethoprim inhibits bacterial
DHF reductase, the human enzyme being
significantly less sensitive than the
bacterial one (rarely bone marrow depression).
A 2,4-diaminopyrimidine, trimethoprim,
has bacteriostatic activity
against a broad spectrum of pathogens.
It is used mostly as a component of cotrimoxazole.
Co-trimoxazole is a combination of
trimethoprim and the sulfonamide sulfamethoxazole.
Since THF synthesis is
inhibited at two successive steps, the
antibacterial effect of co-trimoxazole is
better than that of the individual components.
Resistant pathogens are infrequent;
a bactericidal effect may occur.
Adverse effects correspond to those of
the components.
Although initially developed as an
antirheumatic agent (p. 320), sulfasalazine
(salazosulfapyridine) is used mainly
in the treatment of inflammatory
bowel disease (ulcerative colitis and
terminal ileitis or Crohn’s disease). Gut
bacteria split this compound into the
sulfonamide sulfapyridine and mesalamine
(5-aminosalicylic acid). The latter
is probably the anti-inflammatory agent
(inhibition of synthesis of chemotactic
signals for granulocytes, and of H2O2
formation in mucosa), but must be
present on the gut mucosa in high concentrations.
Coupling to the sulfonamide
prevents premature absorption
in upper small bowel segments. The
cleaved-off sulfonamide can be absorbed
and may produce typical adverse
effects (see above).
Dapsone (p. 280) has several therapeutic
uses: besides treatment of leprosy,
it is used for prevention/prophylaxis
of malaria, toxoplasmosis, and actinomycosis.
Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves as a
template for the synthesis of nucleic acids.
Ribonucleic acid (RNA) executes
protein synthesis and thus permits cell
growth. Synthesis of new DNA is a prerequisite
for cell division. Substances
that inhibit reading of genetic information
at the DNA template damage the
regulatory center of cell metabolism.
The substances listed below are useful
as antibacterial drugs because they do
not affect human cells.
Gyrase inhibitors. The enzyme gyrase
(topoisomerase II) permits the orderly
accommodation of a ~1000 μmlong
bacterial chromosome in a bacterial
cell of ~1 μm. Within the chromosomal
strand, double-stranded DNA has a
double helical configuration. The former,
in turn, is arranged in loops that
are shortened by supercoiling. The gyrase
catalyzes this operation, as illustrated,
by opening, underwinding, and
closing the DNA double strand such that
the full loop need not be rotated.
Derivatives of 4-quinolone-3-carboxylic
acid (green portion of ofloxacin
formula) are inhibitors of bacterial gyrases.
They appear to prevent specifically
the resealing of opened strands and
thereby act bactericidally. These agents
are absorbed after oral ingestion. The
older drug, nalidixic acid, affects exclusively
gram-negative bacteria and attains
effective concentrations only in
urine; it is used as a urinary tract antiseptic.
Norfloxacin has a broader spectrum.
Ofloxacin, ciprofloxacin, and
enoxacin, and others, also yield systemically
effective concentrations and are
used for infections of internal organs.
Besides gastrointestinal problems
and allergy, adverse effects particularly
involve the CNS (confusion, hallucinations,
seizures). Since they can damage
epiphyseal chondrocytes and joint cartilages
in laboratory animals, gyrase inhibitors
should not be used during pregnancy,
lactation, and periods of growth.
Azomycin (nitroimidazole) derivatives,
such as metronidazole, damage
DNA by complex formation or strand
breakage. This occurs in obligate anaerobes,
i.e., bacteria growing under O2
exclusion. Under these conditions, conversion
to reactive metabolites that attack
DNA takes place (e.g., the hydroxylamine
shown). The effect is bactericidal.
A similar mechanism is involved in the
antiprotozoal action on Trichomonas vaginalis
(causative agent of vaginitis and
urethritis) and Entamoeba histolytica
(causative agent of large bowel inflammation,
amebic dysentery, and hepatic
abscesses). Metronidazole is well absorbed
via the enteral route; it is also
given i.v. or topically (vaginal insert).
Because metronidazole is considered
potentially mutagenic, carcinogenic,
and teratogenic in the human, it should
not be used longer than 10 d, if possible,
and be avoided during pregnancy and
lactation. Timidazole may be considered
equivalent to metronidazole.
Rifampin inhibits the bacterial enzyme
that catalyzes DNA template-directed
RNA transcription, i.e., DNA-dependent
RNA polymerase. Rifampin acts
bactericidally against mycobacteria (M.
tuberculosis, M. leprae), as well as many
gram-positive and gram-negative bacteria.
It is well absorbed after oral ingestion.
Because resistance may develop
with frequent usage, it is restricted to
the treatment of tuberculosis and leprosy
(p. 280).
Rifampin is contraindicated in the
first trimester of gestation and during
lactation.
Rifabutin resembles rifampin but
may be effective in infections resistant
to the latter.
Inhibitors of Protein Synthesis
Protein synthesis means translation
into a peptide chain of a genetic message
first copied (transcribed) into m-
RNA (p. 274). Amino acid (AA) assembly
occurs at the ribosome. Delivery of amino
acids to m-RNA involves different
transfer RNA molecules (t-RNA), each of
which binds a specific AA. Each t-RNA
bears an “anticodon” nucleobase triplet
that is complementary to a particular
m-RNA coding unit (codon, consisting of
3 nucleobases.
Incorporation of an AA normally involves
the following steps (A):
1. The ribosome “focuses” two codons
on m-RNA; one (at the left) has
bound its t-RNA-AA complex, the AA
having already been added to the peptide
chain; the other (at the right) is
ready to receive the next t-RNA-AA
complex.
2. After the latter attaches, the AAs
of the two adjacent complexes are
linked by the action of the enzyme peptide
synthetase (peptidyltransferase).
Concurrently, AA and t-RNA of the left
complex disengage.
3. The left t-RNA dissociates from
m-RNA. The ribosome can advance
along the m-RNA strand and focus on
the next codon.
4. Consequently, the right t-RNAAA
complex shifts to the left, allowing
the next complex to be bound at the
right.
These individual steps are susceptible
to inhibition by antibiotics of different
groups. The examples shown originate
primarily from Streptomyces bacteria,
some of the aminoglycosides also
being derived from Micromonospora
bacteria.
1a. Tetracyclines inhibit the binding
of t-RNA-AA complexes. Their action
is bacteriostatic and affects a broad
spectrum of pathogens.
1b. Aminoglycosides induce the
binding of “wrong” t-RNA-AA complexes,
resulting in synthesis of false proteins.
Aminoglycosides are bactericidal.
Their activity spectrum encompasses
mainly gram-negative organisms.
Streptomycin and kanamycin are used
predominantly in the treatment of tuberculosis.
Note on spelling: -mycin designates
origin from Streptomyces species; -micin
(e.g., gentamicin) from Micromonospora
species.
2. Chloramphenicol inhibits peptide
synthetase. It has bacteriostatic activity
against a broad spectrum of
pathogens. The chemically simple molecule
is now produced synthetically.
3. Erythromycin suppresses advancement
of the ribosome. Its action is
predominantly bacteriostatic and directed
against gram-positve organisms.
For oral administration, the acid-labile
base (E) is dispensed as a salt (E. stearate)
or an ester (e.g., E. succinate).
Erythromycin is well tolerated. It is a
suitable substitute in penicillin allergy
or resistance. Azithromycin, clarithromycin,
and roxithromycin are derivatives
with greater acid stability and better
bioavailability. The compounds mentioned
are the most important members
of the macrolide antibiotic group, which
includes josamycin and spiramycin. An
unrelated action of erythromycin is its
mimicry of the gastrointestinal hormone
motiline (! interprandial bowel
motility).
Clindamycin has antibacterial activity
similar to that of erythromycin. It
exerts a bacteriostatic effect mainly on
gram-positive aerobic, as well as on anaerobic
pathogens. Clindamycin is a
semisynthetic chloro analogue of lincomycin,
which derives from a Streptomyces
species. Taken orally, clindamycin
is better absorbed than lincomycin,
has greater antibacterial efficacy and is
thus preferred. Both penetrate well into
bone tissue.
Tetracyclines are absorbed from
the gastrointestinal tract to differing degrees,
depending on the substance, absorption
being nearly complete for
doxycycline and minocycline. Intravenous
injection is rarely needed (rolitetracycline
is available only for i.v. administration).
The most common unwanted
effect is gastrointestinal upset
(nausea, vomiting, diarrhea, etc.) due to
(1) a direct mucosal irritant action of
these substances and (2) damage to the
natural bacterial gut flora (broad-spectrum
antibiotics) allowing colonization
by pathogenic organisms, including
Candida fungi. Concurrent ingestion of
antacids or milk would, however, be inappropriate
because tetracyclines form
insoluble complexes with plurivalent
cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting
in their inactivation; that is, absorbability,
antibacterial activity, and
local irritant action are abolished. The
ability to chelate Ca2+ accounts for the
propensity of tetracyclines to accumulate
in growing teeth and bones. As a result,
there occurs an irreversible yellowbrown
discoloration of teeth and a reversible
inhibition of bone growth. Because
of these adverse effects, tetracycline
should not be given after the second
month of pregnancy and not prescribed
to children aged 8 y and under. Other
adverse effects are increased photosensitivity
of the skin and hepatic damage,
mainly after i.v. administration.
The broad-spectrum antibiotic
chloramphenicol is completely absorbed
after oral ingestion. It undergoes
even distribution in the body and readily
crosses diffusion barriers such as the
blood-brain barrier. Despite these advantageous
properties, use of chloramphenicol
is rarely indicated (e.g., in CNS
infections) because of the danger of
bone marrow damage. Two types of bone
marrow depression can occur: (1) a
dose-dependent, toxic, reversible form
manifested during therapy and, (2) a
frequently fatal form that may occur after
a latency of weeks and is not dose
dependent. Due to high tissue penetrability,
the danger of bone marrow depression
must also be taken into account
after local use (e.g., eye drops).
Aminoglycoside antibiotics consist
of glycoside-linked amino-sugars
(cf. gentamicin C1α, a constituent of the
gentamicin mixture). They contain numerous
hydroxyl groups and amino
groups that can bind protons. Hence,
these compounds are highly polar,
poorly membrane permeable, and not
absorbed enterally. Neomycin and paromomycin
are given orally to eradicate
intestinal bacteria (prior to bowel surgery
or for reducing NH3 formation by
gut bacteria in hepatic coma). Aminoglycosides
for the treatment of serious
infections must be injected (e.g., gentamicin,
tobramycin, amikacin, netilmicin,
sisomycin). In addition, local inlays
of a gentamicin-releasing carrier can be
used in infections of bone or soft tissues.
Aminoglycosides gain access to the bacterial
interior by the use of bacterial
transport systems. In the kidney, they
enter the cells of the proximal tubules
via an uptake system for oligopeptides.
Tubular cells are susceptible to damage
(nephrotoxicity, mostly reversible). In
the inner ear, sensory cells of the vestibular
apparatus and Corti’s organ may be
injured (ototoxicity, in part irreversible).
Drugs for Treating Mycobacterial
Infections
Mycobacteria are responsible for two
diseases: tuberculosis, mostly caused by
M. tuberculosis, and leprosy due to M. leprae.
The therapeutic principle applicable
to both is combined treatment
with two or more drugs. Combination
therapy prevents the emergence of resistant
mycobacteria. Because the antibacterial
effects of the individual substances
are additive, correspondingly
smaller doses are sufficient. Therefore,
the risk of individual adverse effects is
lowered. Most drugs are active against
only one of the two diseases.
Antitubercular Drugs (1)
Drugs of choice are: isoniazid, rifampin,
ethambutol, along with streptomycin
and pyrazinamide. Less well tolerated,
second-line agents include: p-aminosalicylic
acid, cycloserine, viomycin, kanamycin,
amikacin, capreomycin, ethionamide.
Isoniazid is bactericidal against
growing M. tuberculosis. Its mechanism
of action remains unclear. (In the bacterium
it is converted to isonicotinic acid,
which is membrane impermeable,
hence likely to accumulate intracellularly.)
Isoniazid is rapidly absorbed after
oral administration. In the liver, it is inactivated
by acetylation, the rate of
which is genetically controlled and
shows a characteristic distribution in
different ethnic groups (fast vs. slow
acetylators). Notable adverse effects
are: peripheral neuropathy, optic neuritis
preventable by administration of
vitamin B6 (pyridoxine); hepatitis, jaundice.
Rifampin. Source, antibacterial activity,
and routes of administration are
described on p. 274. Albeit mostly well
tolerated, this drug may cause several
adverse effects including hepatic damage,
hypersensitivity with flu-like
symptoms, disconcerting but harmless
red/orange discoloration of body fluids,
and enzyme induction (failure of oral
contraceptives). Concerning rifabutin
see p. 274.
Ethambutol. The cause of its specific
antitubercular action is unknown.
Ethambutol is given orally. It is generally
well tolerated, but may cause dosedependent
damage to the optic nerve
with disturbances of vision (red/green
blindness, visual field defects).
Pyrazinamide exerts a bactericidal
action by an unknown mechanism. It is
given orally. Pyrazinamide may impair
liver function; hyperuricemia results
from inhibition of renal urate elimination.
Streptomycin must be given i.v. (pp.
278ff) like other aminoglycoside antibiotics.
It damages the inner ear and the
labyrinth. Its nephrotoxicity is comparatively
minor.
Antileprotic Drugs (2)
Rifampin is frequently given in combination
with one or both of the following
agents:
Dapsone is a sulfone that, like sulfonamides,
inhibits dihydrofolate synthesis
(p. 272). It is bactericidal against
susceptible strains of M. leprae. Dapsone
is given orally. The most frequent adverse
effect is methemoglobinemia with
accelerated erythrocyte degradation
(hemolysis).
Clofazimine is a dye with bactericidal
activity against M. leprae and antiinflammatory
properties. It is given
orally, but is incompletely absorbed. Because
of its high lipophilicity, it accumulates
in adipose and other tissues
and leaves the body only rather slowly
(t1/2 ~ 70 d). Red-brown skin pigmentation
is an unwanted effect, particularly
in fair-skinned patients.
Drugs for Treating Bacterial Infections
When bacteria overcome the cutaneous
or mucosal barriers and penetrate body
tissues, a bacterial infection is present.
Frequently the body succeeds in removing
the invaders, without outward signs
of disease, by mounting an immune response.
If bacteria multiply faster than
the body’s defenses can destroy them,
infectious disease develops with inflammatory
signs, e.g., purulent wound infection
or urinary tract infection. Appropriate
treatment employs substances
that injure bacteria and thereby prevent
their further multiplication, without
harming cells of the host organism (1).
Apropos nomenclature: antibiotics
are produced by microorganisms (fungi,
bacteria) and are directed “against life”
at any phylogenetic level (prokaryotes,
eukaryotes). Chemotherapeutic agents
originate from chemical synthesis. This
distinction has been lost in current usage.
Specific damage to bacteria is particularly
practicable when a substance
interferes with a metabolic process that
occurs in bacterial but not in host cells.
Clearly this applies to inhibitors of cell
wall synthesis, because human and animal
cells lack a cell wall. The points of
attack of antibacterial agents are schematically
illustrated in a grossly simplified
bacterial cell, as depicted in (2).
In the following sections, polymyxins
and tyrothricin are not considered
further. These polypeptide antibiotics
enhance cell membrane permeability.
Due to their poor tolerability, they are
prescribed in humans only for topical
use.
The effect of antibacterial drugs can
be observed in vitro (3). Bacteria multiply
in a growth medium under control
conditions. If the medium contains an
antibacterial drug, two results can be
discerned: 1. bacteria are killed—bactericidal
effect; 2. bacteria survive, but do
not multiply—bacteriostatic effect. Although
variations may occur under
therapeutic conditions, different drugs
can be classified according to their respective
primary mode of action (color
tone in 2 and 3).
When bacterial growth remains unaffected
by an antibacterial drug, bacterial
resistance is present. This may occur
because of certain metabolic characteristics
that confer a natural insensitivity
to the drug on a particular strain of
bacteria (natural resistance). Depending
on whether a drug affects only a few or
numerous types of bacteria, the terms
narrow-spectrum (e.g., penicillin G) or
broad-spectrum (e.g., tetracyclines)
antibiotic are applied. Naturally susceptible
bacterial strains can be transformed
under the influence of antibacterial
drugs into resistant ones (acquired
resistance), when a random genetic alteration
(mutation) gives rise to a resistant
bacterium. Under the influence of
the drug, the susceptible bacteria die
off, whereas the mutant multiplies unimpeded.
The more frequently a given
drug is applied, the more probable the
emergence of resistant strains (e.g., hospital
strains with multiple resistance)!
Resistance can also be acquired
when DNA responsible for nonsusceptibility
(so-called resistance plasmid) is
passed on from other resistant bacteria
by conjugation or transduction.
Inhibitors of Cell Wall Synthesis
In most bacteria, a cell wall surrounds
the cell like a rigid shell that protects
against noxious outside influences and
prevents rupture of the plasma membrane
from a high internal osmotic
pressure. The structural stability of the
cell wall is due mainly to the murein
(peptidoglycan) lattice. This consists of
basic building blocks linked together to
form a large macromolecule. Each basic
unit contains the two linked aminosugars
N-acetylglucosamine and N-acetylmuramyl
acid; the latter bears a peptide
chain. The building blocks are synthesized
in the bacterium, transported outward
through the cell membrane, and
assembled as illustrated schematically.
The enzyme transpeptidase cross-links
the peptide chains of adjacent aminosugar
chains.
Inhibitors of cell wall synthesis
are suitable antibacterial agents, because
animal and human cells lack a cell
wall. They exert a bactericidal action on
growing or multiplying germs. Members
of this class include !-lactam antibiotics
such as the penicillins and cephalosporins,
in addition to bacitracin and
vancomycin.
Penicillins (A). The parent substance
of this group is penicillin G (benzylpenicillin).
It is obtained from cultures
of mold fungi, originally from Penicillium
notatum. Penicillin G contains
the basic structure common to all penicillins,
6-amino-penicillanic acid (p.
271, 6-APA), comprised of a thiazolidine
and a 4-membered !-lactam ring. 6-
APA itself lacks antibacterial activity.
Penicillins disrupt cell wall synthesis by
inhibiting transpeptidase. When bacteria
are in their growth and replication
phase, penicillins are bactericidal; due
to cell wall defects, the bacteria swell
and burst.
Penicillins are generally well tolerated;
with penicillin G, the daily dose
can range from approx. 0.6 g i.m. (= 106
international units, 1 Mega I.U.) to 60 g
by infusion. The most important adverse
effects are due to hypersensitivity
(incidence up to 5%), with manifestations
ranging from skin eruptions to
anaphylactic shock (in less than 0.05% of
patients). Known penicillin allergy is a
contraindication for these drugs. Because
of an increased risk of sensitization,
penicillins must not be used locally.
Neurotoxic effects, mostly convulsions
due to GABA antagonism, may occur
if the brain is exposed to extremely
high concentrations, e.g., after rapid i.v.
injection of a large dose or intrathecal
injection.
Penicillin G undergoes rapid renal
elimination mainly in unchanged form
(plasma t1/2 ~ 0.5 h). The duration of
the effect can be prolonged by:
1. Use of higher doses, enabling plasma
levels to remain above the minimally
effective antibacterial concentration;
2. Combination with probenecid. Renal
elimination of penicillin occurs
chiefly via the anion (acid)-secretory
system of the proximal tubule (-COOH
of 6-APA). The acid probenecid (p. 316)
competes for this route and thus retards
penicillin elimination;
3. Intramuscular administration in
depot form. In its anionic form (-COO-)
penicillin G forms poorly water-soluble
salts with substances containing a positively
charged amino group (procaine,
p. 208; clemizole, an antihistamine;
benzathine, dicationic). Depending on
the substance, release of penicillin from
the depot occurs over a variable interval.
Although very well tolerated, penicillin
G has disadvantages (A) that limit
its therapeutic usefulness: (1) It is inactivated
by gastric acid, which cleaves
the !-lactam ring, necessitating parenteral
administration. (2) The !-lactam
ring can also be opened by bacterial enzymes
(!-lactamases); in particular,
penicillinase, which can be produced by
staphylococcal strains, renders them resistant
to penicillin G. (3) The antibacterial
spectrum is narrow; although it encompasses
many gram-positive bacteria,
gram-negative cocci, and spirochetes,
many gram-negative pathogens
are unaffected.
Derivatives with a different substituent
on 6-APA possess advantages
(B): (1) Acid resistance permits oral administration,
provided that enteral absorption
is possible. All derivatives
shown in (B) can be given orally. Penicillin
V (phenoxymethylpenicillin) exhibits
antibacterial properties similar to
those of penicillin G. (2) Due to their
penicillinase resistance, isoxazolylpenicillins
(oxacillin dicloxacillin, flucloxacillin)
are suitable for the (oral) treatment
of infections caused by penicillinaseproducing
staphylococci. (3) Extended
activity spectrum: The aminopenicillin
amoxicillin is active against many gramnegative
organisms, e.g., coli bacteria or
Salmonella typhi. It can be protected
from destruction by penicillinase by
combination with inhibitors of penicillinase
(clavulanic acid, sulbactam, tazobactam).
The structurally close congener ampicillin
(no 4-hydroxy group) has a similar
activity spectrum. However, because
it is poorly absorbed (<50%) and therefore
causes more extensive damage to
the gut microbial flora (side effect: diarrhea),
it should be given only by injection.
A still broader spectrum (including
Pseudomonas bacteria) is shown by carboxypenicillins
(carbenicillin, ticarcillin)
and acylaminopenicillins (mezclocillin,
azlocillin, piperacillin). These substances
are neither acid stable nor penicillinase
resistant.
Cephalosporins (C). These !-lactam
antibiotics are also fungal products
and have bactericidal activity due to inhibition
of transpeptidase. Their
shared basic structure is 7-aminocephalosporanic
acid, as exemplified by
cephalexin (gray rectangle). Cephalosporins
are acid stable, but many are
poorly absorbed. Because they must be
given parenterally, most—including
those with high activity—are used only
in clinical settings. A few, e.g., cephalexin,
are suitable for oral use. Cephalosporins
are penicillinase-resistant, but
cephalosporinase-forming organisms
do exist. Some derivatives are, however,
also resistant to this !-lactamase.
Cephalosporins are broad-spectrum
antibacterials. Newer derivatives (e.g.,
cefotaxime, cefmenoxin, cefoperazone,
ceftriaxone, ceftazidime, moxalactam)
are also effective against pathogens resistant
to various other antibacterials.
Cephalosporins are mostly well tolerated.
All can cause allergic reactions, some
also renal injury, alcohol intolerance,
and bleeding (vitamin K antagonism).
Other inhibitors of cell wall synthesis.
Bacitracin and vancomycin
interfere with the transport of peptidoglycans
through the cytoplasmic
membrane and are active only against
gram-positive bacteria. Bacitracin is a
polypeptide mixture, markedly nephrotoxic
and used only topically. Vancomycin
is a glycopeptide and the drug of
choice for the (oral) treatment of bowel
inflammations occurring as a complication
of antibiotic therapy (pseudomembranous
enterocolitis caused by Clostridium
difficile). It is not absorbed.
Inhibitors of Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a co-enzyme
in the synthesis of purine bases
and thymidine. These are constituents
of DNA and RNA and required for cell
growth and replication. Lack of THF
leads to inhibition of cell proliferation.
Formation of THF from dihydrofolate
(DHF) is catalyzed by the enzyme dihydrofolate
reductase. DHF is made from
folic acid, a vitamin that cannot be synthesized
in the body, but must be taken
up from exogenous sources. Most bacteria
do not have a requirement for folate,
because they are capable of synthesizing
folate, more precisely DHF, from
precursors. Selective interference with
bacterial biosynthesis of THF can be
achieved with sulfonamides and trimethoprim.
Sulfonamides structurally resemble
p-aminobenzoic acid (PABA), a precursor
in bacterial DHF synthesis. As
false substrates, sulfonamides competitively
inhibit utilization of PABA, hence
DHF synthesis. Because most bacteria
cannot take up exogenous folate, they
are depleted of DHF. Sulfonamides thus
possess bacteriostatic activity against a
broad spectrum of pathogens. Sulfonamides
are produced by chemical synthesis.
The basic structure is shown in
(A). Residue R determines the pharmacokinetic
properties of a given sulfonamide.
Most sulfonamides are well absorbed
via the enteral route. They are
metabolized to varying degrees and
eliminated through the kidney. Rates of
elimination, hence duration of effect,
may vary widely. Some members are
poorly absorbed from the gut and are
thus suitable for the treatment of bacterial
bowel infections. Adverse effects
may include, among others, allergic reactions,
sometimes with severe skin
damage, displacement of other plasma
protein-bound drugs or bilirubin in neonates
(danger of kernicterus, hence contraindication
for the last weeks of gestation
and in the neonate). Because of the
frequent emergence of resistant bacteria,
sulfonamides are now rarely used.
Introduced in 1935, they were the first
broad-spectrum chemotherapeutics.
Trimethoprim inhibits bacterial
DHF reductase, the human enzyme being
significantly less sensitive than the
bacterial one (rarely bone marrow depression).
A 2,4-diaminopyrimidine, trimethoprim,
has bacteriostatic activity
against a broad spectrum of pathogens.
It is used mostly as a component of cotrimoxazole.
Co-trimoxazole is a combination of
trimethoprim and the sulfonamide sulfamethoxazole.
Since THF synthesis is
inhibited at two successive steps, the
antibacterial effect of co-trimoxazole is
better than that of the individual components.
Resistant pathogens are infrequent;
a bactericidal effect may occur.
Adverse effects correspond to those of
the components.
Although initially developed as an
antirheumatic agent (p. 320), sulfasalazine
(salazosulfapyridine) is used mainly
in the treatment of inflammatory
bowel disease (ulcerative colitis and
terminal ileitis or Crohn’s disease). Gut
bacteria split this compound into the
sulfonamide sulfapyridine and mesalamine
(5-aminosalicylic acid). The latter
is probably the anti-inflammatory agent
(inhibition of synthesis of chemotactic
signals for granulocytes, and of H2O2
formation in mucosa), but must be
present on the gut mucosa in high concentrations.
Coupling to the sulfonamide
prevents premature absorption
in upper small bowel segments. The
cleaved-off sulfonamide can be absorbed
and may produce typical adverse
effects (see above).
Dapsone (p. 280) has several therapeutic
uses: besides treatment of leprosy,
it is used for prevention/prophylaxis
of malaria, toxoplasmosis, and actinomycosis.
Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves as a
template for the synthesis of nucleic acids.
Ribonucleic acid (RNA) executes
protein synthesis and thus permits cell
growth. Synthesis of new DNA is a prerequisite
for cell division. Substances
that inhibit reading of genetic information
at the DNA template damage the
regulatory center of cell metabolism.
The substances listed below are useful
as antibacterial drugs because they do
not affect human cells.
Gyrase inhibitors. The enzyme gyrase
(topoisomerase II) permits the orderly
accommodation of a ~1000 μmlong
bacterial chromosome in a bacterial
cell of ~1 μm. Within the chromosomal
strand, double-stranded DNA has a
double helical configuration. The former,
in turn, is arranged in loops that
are shortened by supercoiling. The gyrase
catalyzes this operation, as illustrated,
by opening, underwinding, and
closing the DNA double strand such that
the full loop need not be rotated.
Derivatives of 4-quinolone-3-carboxylic
acid (green portion of ofloxacin
formula) are inhibitors of bacterial gyrases.
They appear to prevent specifically
the resealing of opened strands and
thereby act bactericidally. These agents
are absorbed after oral ingestion. The
older drug, nalidixic acid, affects exclusively
gram-negative bacteria and attains
effective concentrations only in
urine; it is used as a urinary tract antiseptic.
Norfloxacin has a broader spectrum.
Ofloxacin, ciprofloxacin, and
enoxacin, and others, also yield systemically
effective concentrations and are
used for infections of internal organs.
Besides gastrointestinal problems
and allergy, adverse effects particularly
involve the CNS (confusion, hallucinations,
seizures). Since they can damage
epiphyseal chondrocytes and joint cartilages
in laboratory animals, gyrase inhibitors
should not be used during pregnancy,
lactation, and periods of growth.
Azomycin (nitroimidazole) derivatives,
such as metronidazole, damage
DNA by complex formation or strand
breakage. This occurs in obligate anaerobes,
i.e., bacteria growing under O2
exclusion. Under these conditions, conversion
to reactive metabolites that attack
DNA takes place (e.g., the hydroxylamine
shown). The effect is bactericidal.
A similar mechanism is involved in the
antiprotozoal action on Trichomonas vaginalis
(causative agent of vaginitis and
urethritis) and Entamoeba histolytica
(causative agent of large bowel inflammation,
amebic dysentery, and hepatic
abscesses). Metronidazole is well absorbed
via the enteral route; it is also
given i.v. or topically (vaginal insert).
Because metronidazole is considered
potentially mutagenic, carcinogenic,
and teratogenic in the human, it should
not be used longer than 10 d, if possible,
and be avoided during pregnancy and
lactation. Timidazole may be considered
equivalent to metronidazole.
Rifampin inhibits the bacterial enzyme
that catalyzes DNA template-directed
RNA transcription, i.e., DNA-dependent
RNA polymerase. Rifampin acts
bactericidally against mycobacteria (M.
tuberculosis, M. leprae), as well as many
gram-positive and gram-negative bacteria.
It is well absorbed after oral ingestion.
Because resistance may develop
with frequent usage, it is restricted to
the treatment of tuberculosis and leprosy
(p. 280).
Rifampin is contraindicated in the
first trimester of gestation and during
lactation.
Rifabutin resembles rifampin but
may be effective in infections resistant
to the latter.
Inhibitors of Protein Synthesis
Protein synthesis means translation
into a peptide chain of a genetic message
first copied (transcribed) into m-
RNA (p. 274). Amino acid (AA) assembly
occurs at the ribosome. Delivery of amino
acids to m-RNA involves different
transfer RNA molecules (t-RNA), each of
which binds a specific AA. Each t-RNA
bears an “anticodon” nucleobase triplet
that is complementary to a particular
m-RNA coding unit (codon, consisting of
3 nucleobases.
Incorporation of an AA normally involves
the following steps (A):
1. The ribosome “focuses” two codons
on m-RNA; one (at the left) has
bound its t-RNA-AA complex, the AA
having already been added to the peptide
chain; the other (at the right) is
ready to receive the next t-RNA-AA
complex.
2. After the latter attaches, the AAs
of the two adjacent complexes are
linked by the action of the enzyme peptide
synthetase (peptidyltransferase).
Concurrently, AA and t-RNA of the left
complex disengage.
3. The left t-RNA dissociates from
m-RNA. The ribosome can advance
along the m-RNA strand and focus on
the next codon.
4. Consequently, the right t-RNAAA
complex shifts to the left, allowing
the next complex to be bound at the
right.
These individual steps are susceptible
to inhibition by antibiotics of different
groups. The examples shown originate
primarily from Streptomyces bacteria,
some of the aminoglycosides also
being derived from Micromonospora
bacteria.
1a. Tetracyclines inhibit the binding
of t-RNA-AA complexes. Their action
is bacteriostatic and affects a broad
spectrum of pathogens.
1b. Aminoglycosides induce the
binding of “wrong” t-RNA-AA complexes,
resulting in synthesis of false proteins.
Aminoglycosides are bactericidal.
Their activity spectrum encompasses
mainly gram-negative organisms.
Streptomycin and kanamycin are used
predominantly in the treatment of tuberculosis.
Note on spelling: -mycin designates
origin from Streptomyces species; -micin
(e.g., gentamicin) from Micromonospora
species.
2. Chloramphenicol inhibits peptide
synthetase. It has bacteriostatic activity
against a broad spectrum of
pathogens. The chemically simple molecule
is now produced synthetically.
3. Erythromycin suppresses advancement
of the ribosome. Its action is
predominantly bacteriostatic and directed
against gram-positve organisms.
For oral administration, the acid-labile
base (E) is dispensed as a salt (E. stearate)
or an ester (e.g., E. succinate).
Erythromycin is well tolerated. It is a
suitable substitute in penicillin allergy
or resistance. Azithromycin, clarithromycin,
and roxithromycin are derivatives
with greater acid stability and better
bioavailability. The compounds mentioned
are the most important members
of the macrolide antibiotic group, which
includes josamycin and spiramycin. An
unrelated action of erythromycin is its
mimicry of the gastrointestinal hormone
motiline (! interprandial bowel
motility).
Clindamycin has antibacterial activity
similar to that of erythromycin. It
exerts a bacteriostatic effect mainly on
gram-positive aerobic, as well as on anaerobic
pathogens. Clindamycin is a
semisynthetic chloro analogue of lincomycin,
which derives from a Streptomyces
species. Taken orally, clindamycin
is better absorbed than lincomycin,
has greater antibacterial efficacy and is
thus preferred. Both penetrate well into
bone tissue.
Tetracyclines are absorbed from
the gastrointestinal tract to differing degrees,
depending on the substance, absorption
being nearly complete for
doxycycline and minocycline. Intravenous
injection is rarely needed (rolitetracycline
is available only for i.v. administration).
The most common unwanted
effect is gastrointestinal upset
(nausea, vomiting, diarrhea, etc.) due to
(1) a direct mucosal irritant action of
these substances and (2) damage to the
natural bacterial gut flora (broad-spectrum
antibiotics) allowing colonization
by pathogenic organisms, including
Candida fungi. Concurrent ingestion of
antacids or milk would, however, be inappropriate
because tetracyclines form
insoluble complexes with plurivalent
cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) resulting
in their inactivation; that is, absorbability,
antibacterial activity, and
local irritant action are abolished. The
ability to chelate Ca2+ accounts for the
propensity of tetracyclines to accumulate
in growing teeth and bones. As a result,
there occurs an irreversible yellowbrown
discoloration of teeth and a reversible
inhibition of bone growth. Because
of these adverse effects, tetracycline
should not be given after the second
month of pregnancy and not prescribed
to children aged 8 y and under. Other
adverse effects are increased photosensitivity
of the skin and hepatic damage,
mainly after i.v. administration.
The broad-spectrum antibiotic
chloramphenicol is completely absorbed
after oral ingestion. It undergoes
even distribution in the body and readily
crosses diffusion barriers such as the
blood-brain barrier. Despite these advantageous
properties, use of chloramphenicol
is rarely indicated (e.g., in CNS
infections) because of the danger of
bone marrow damage. Two types of bone
marrow depression can occur: (1) a
dose-dependent, toxic, reversible form
manifested during therapy and, (2) a
frequently fatal form that may occur after
a latency of weeks and is not dose
dependent. Due to high tissue penetrability,
the danger of bone marrow depression
must also be taken into account
after local use (e.g., eye drops).
Aminoglycoside antibiotics consist
of glycoside-linked amino-sugars
(cf. gentamicin C1α, a constituent of the
gentamicin mixture). They contain numerous
hydroxyl groups and amino
groups that can bind protons. Hence,
these compounds are highly polar,
poorly membrane permeable, and not
absorbed enterally. Neomycin and paromomycin
are given orally to eradicate
intestinal bacteria (prior to bowel surgery
or for reducing NH3 formation by
gut bacteria in hepatic coma). Aminoglycosides
for the treatment of serious
infections must be injected (e.g., gentamicin,
tobramycin, amikacin, netilmicin,
sisomycin). In addition, local inlays
of a gentamicin-releasing carrier can be
used in infections of bone or soft tissues.
Aminoglycosides gain access to the bacterial
interior by the use of bacterial
transport systems. In the kidney, they
enter the cells of the proximal tubules
via an uptake system for oligopeptides.
Tubular cells are susceptible to damage
(nephrotoxicity, mostly reversible). In
the inner ear, sensory cells of the vestibular
apparatus and Corti’s organ may be
injured (ototoxicity, in part irreversible).
Drugs for Treating Mycobacterial
Infections
Mycobacteria are responsible for two
diseases: tuberculosis, mostly caused by
M. tuberculosis, and leprosy due to M. leprae.
The therapeutic principle applicable
to both is combined treatment
with two or more drugs. Combination
therapy prevents the emergence of resistant
mycobacteria. Because the antibacterial
effects of the individual substances
are additive, correspondingly
smaller doses are sufficient. Therefore,
the risk of individual adverse effects is
lowered. Most drugs are active against
only one of the two diseases.
Antitubercular Drugs (1)
Drugs of choice are: isoniazid, rifampin,
ethambutol, along with streptomycin
and pyrazinamide. Less well tolerated,
second-line agents include: p-aminosalicylic
acid, cycloserine, viomycin, kanamycin,
amikacin, capreomycin, ethionamide.
Isoniazid is bactericidal against
growing M. tuberculosis. Its mechanism
of action remains unclear. (In the bacterium
it is converted to isonicotinic acid,
which is membrane impermeable,
hence likely to accumulate intracellularly.)
Isoniazid is rapidly absorbed after
oral administration. In the liver, it is inactivated
by acetylation, the rate of
which is genetically controlled and
shows a characteristic distribution in
different ethnic groups (fast vs. slow
acetylators). Notable adverse effects
are: peripheral neuropathy, optic neuritis
preventable by administration of
vitamin B6 (pyridoxine); hepatitis, jaundice.
Rifampin. Source, antibacterial activity,
and routes of administration are
described on p. 274. Albeit mostly well
tolerated, this drug may cause several
adverse effects including hepatic damage,
hypersensitivity with flu-like
symptoms, disconcerting but harmless
red/orange discoloration of body fluids,
and enzyme induction (failure of oral
contraceptives). Concerning rifabutin
see p. 274.
Ethambutol. The cause of its specific
antitubercular action is unknown.
Ethambutol is given orally. It is generally
well tolerated, but may cause dosedependent
damage to the optic nerve
with disturbances of vision (red/green
blindness, visual field defects).
Pyrazinamide exerts a bactericidal
action by an unknown mechanism. It is
given orally. Pyrazinamide may impair
liver function; hyperuricemia results
from inhibition of renal urate elimination.
Streptomycin must be given i.v. (pp.
278ff) like other aminoglycoside antibiotics.
It damages the inner ear and the
labyrinth. Its nephrotoxicity is comparatively
minor.
Antileprotic Drugs (2)
Rifampin is frequently given in combination
with one or both of the following
agents:
Dapsone is a sulfone that, like sulfonamides,
inhibits dihydrofolate synthesis
(p. 272). It is bactericidal against
susceptible strains of M. leprae. Dapsone
is given orally. The most frequent adverse
effect is methemoglobinemia with
accelerated erythrocyte degradation
(hemolysis).
Clofazimine is a dye with bactericidal
activity against M. leprae and antiinflammatory
properties. It is given
orally, but is incompletely absorbed. Because
of its high lipophilicity, it accumulates
in adipose and other tissues
and leaves the body only rather slowly
(t1/2 ~ 70 d). Red-brown skin pigmentation
is an unwanted effect, particularly
in fair-skinned patients.
