PRINCIPLES OF TREATMENT OF INFECTION AND ANTIMICROBIAL THERAPY

Multiple factors influence the ability of bacteria to
cause infection and disease. One of the most commonly neglected yet
important concepts to understand is the fact that a diverse flora is
associated with the normal skin, mucous membranes, and the respiratory,
urogenital, and gastrointestinal mucosa from birth until death. The

human
body harbors numerous bacteria, with the composition of this flora
remaining relatively stable within body regions during a person’s
lifetime. In some instances, the flora may aid the host by competing
for microenvironments with other pathogenic bacteria, but in other
circumstances, if given the opportunity, these bacteria may be the
actual cause of disease. The main influences determining the
composition of the natural flora of the human body are pH, temperature,
redox potential, and oxygen, water, and nutrient levels.

The most important normal flora to be considered in
orthopaedic surgical infections are skin flora. The variety of
microenvironments provided by skin allows for the wide diversity of
dermal flora. Different bacteria characterize the following four
regions: (1) the axilla, perineum, and toe webs; (2) hand, face, and trunk; (3) upper arms and legs; and (4)
fingernails and toenails. Sites with more potential for occlusion, such
as the axilla or perineum, harbor more bacteria than open areas like
the arm or trunk. It is believed that the increased moisture,
temperature, and skin surface lipids allow for the higher numbers of
organisms. These more occluded regions may also have higher levels of
gram-negative bacteria.

Bacterial virulence, defined as the pathogenicity of a
microorganism, is affected by such factors as the number of infecting
organisms, route of entry into the body, and virulence factors that
bacteria have evolved to invade, cause disease, and evade the host’s
defenses. Virulence can be measured experimentally by determining the
dosage of bacteria required to cause death or disease in a given
subject. These calculations refer to the inoculum required to cause
death or symptoms in at least 50% of the population, the so-called
lethal dose (LD50) or effective dose (ED50) respectively.

Virulence factors may be specific to each bacterial
species or may be found in a broad range of organisms. One such factor
is the presence of pili or fimbria that allow bacterial adherence to
host cells or aid the bacteria in escaping host defenses. The pili of Streptococcus pyogenes and Escherichia coli allow the organisms to attach to the mucosa, whereas the pili of Neisseria gonorrhoeae also function as an inhibitor of phagocytosis.

Bacterial cell surface receptors also play a part in the disease process. S. aureus, Yersinieae, and S. pyogenes isolated from patients suffering from septic arthritis possess a cell surface collagen receptor (48). Rickettsia sp and Mycobacterium tuberculosis invade host cells and, as obligate or facultative intracellular pathogens, avoid the host immune response.

Capsule formation has long been recognized as a
bacterial protective mechanism. These capsules act to interfere with
opsonization by immunoglobulins, phagocytosis, and intracellular
killing of the bacteria. There are numerous bacteria that produce such
capsules including Streptococcus pneumoniae, E. coli, Bacteroides, Salmonella, and Haemophilus influenzae. Protein A, expressed by S. aureus, is antiphagocytic and binds to the Fc portion of IgG, preventing complement binding and opsonization. Protein M of S. pyogenes inhibits phagocytosis.

Endotoxin is most commonly produced by gram-negative
organisms. It is a naturally occurring bacterial outer-cell membrane
component that has systemic effects on the host, causing a generalized
sepsis that can progress to shock. Exotoxins are specifically produced
for release by bacteria, generally exerting their effects over a
limited site of action or on particular cell types or receptors. There
are multiple classes of exotoxins, including neurotoxins, cytotoxins,
and enterotoxins.

The classic neurotoxin is that of C. tetani
that affects only the inhibitory neurons in the central nervous system
(CNS). The result is unopposed firing of motor neurons, leading to
violent muscle contractions and a spastic paralysis known as tetanus. S. aureus
produces a leukocidin that destroys polymorphonuclear cells as well as
an α-toxin that functions to cause lysis of monocytes and platelets,
resulting in the formation of pus and abscesses.

Other bacteria secrete enzymes as a virulence factor.

Pseudomonas aeruginosa secretes elastase, collagenase, and lecithinase, as well as an exoprotease that cleaves and inactivates immunoglobulins. S. pyogenes produces the clot-lysing enzyme streptokinase, as well as the enzymes streptolysin O and S. IgA protease, produced by S. pneumoniae, N. gonorrhoeae, and H. influenzae, destroys the secretory immunoglobulins.

A specific virulence factor related to the pathogenesis
of prosthetic joint infections involves adhesion of the organism to the
biomaterial. The implant elicits a host response that results in the
coating of the prosthetic material and potential pathogen in a layer of
proteins including fibronectin, vitronectin, collagen, and fibrinogen.
This “extracellular slime” acts to bind the organism and foreign body
together. The adhesion of S. aureus to
bioprosthetic materials is also mediated by adhesin molecules belonging
to the microbial surface components recognizing adhesive matrix
molecules (MSCRAMM) family of microbial cell surface proteins. The
organism further encases itself in glycocalyx that probably includes
glycerol techoic acid. This extracellular slime isolates bacteria from
the immune surveillance of the host. Furthermore, the glycocalyx
stimulates monocytes to produce prostaglandin E₂, which acts
to inhibit T lymphocyte proliferation, B-lymphocyte blastogenesis, and
immunoglobulin production. It interferes with white cell chemotaxis and
degranulation, as well as immunoglobulin opsonization, and inhibits
antimicrobial therapy from locally reaching effective levels to exert
their actions.

Innate immunity is based on the normal physical and
physiologic barriers of the human body, as well as the inflammatory
reactions that begin once these barriers are compromised. This
nonspecific immune system protects from all invasion nondiscriminately.

The acquired immune system is composed of humoral and
cell-mediated responses. Unlike innate immunity, the acquired immune
system exhibits specificity, diversity, memory, and self and non-self
recognition. A discussion of the mechanism of this specific immunity is
beyond the scope of this chapter; it is important, however, to
understand the factors that may affect the ability of the body to mount
an adequate immune response.

The actions and decisions the surgeon makes in treating
a patient play a tremendous role in the development and subsequent
progression of infection. When treating a patient with an open wound
after trauma or infection, be certain to irrigate the wound adequately,
removing the greatest load of bacteria and foreign debris possible. At
the same time, debride the wound well, and remove all nonviable tissue,
making certain that the remaining tissue has an adequate blood supply.
In the case of open fractures, the use of prophylactic antibiotics with
early irrigation and debridement can minimize the risk of an infection
that may jeopardize healing. The length of surgery may also influence
the incidence of infection. In addition, orthopaedic techniques, such
as reaming, can disrupt local blood supply and alter host–cell, humoral
factor, and antibiotic penetration to the site.

In addition, foreign materials like
polymethylmethacrylate cement (PMMA) can contribute to the potential
for infection. PMMA significantly increases the likelihood for
infections with S. epidermidis and S. aureus. In vitro
studies have shown the toxicity of PMMA monomer on the bactericidal
serum factors, terminal complement components, phagocytosis, lymphocyte
function, and intracellular killing by polymorphonuclear cells. PMMA
monomers may reach toxic concentrations surrounding implanted
prostheses. When closing the wound, it is important to eliminate dead
space, have satisfactory drainage of hematomas, and provide adequate
soft-tissue coverage.

Preparation of the skin for surgery can play a role in
the incidence of infection, because infection may occur whenever the
protective barrier of the skin is broken. Proper preparation of the
skin before incision can decrease the risk of contamination
significantly (7).

The purpose of preoperative skin preparation is to
remove the soil and transient flora found on skin, to reduce resident
microbial counts to subpathogenic levels in a short period of time with
the least amount of tissue irritation, and to inhibit the rapid rebound
growth of microorganisms. Although the normal flora of the skin and
hair can never be eradicated, the total number of organisms can be
markedly reduced through the use of agents such as iodine iodophors,
alcohol, hexachlorophene, and chlorhexidine. These preparation agents
have excellent activity against gram-positive bacteria and good
activity against gram-negative bacteria and fungi, reducing microbial
activity 100-fold within minutes. It must be kept in mind that the
sebaceous glands and hair follicles of normal skin where bacteria
reside and multiply can never be sterilized because of the poor
penetration of these agents.

The transient skin flora is easier to remove than the
resident flora that may be attached or absorbed into the epidermal
layers. Studies have measured that approximately 20% of resident skin
flora is not removed by standard preparation techniques. A recent study
comparing clean and sterile prep kits showed no difference between the
efficacy of either kit, a fact that has significant financial
implications for medical centers. The cost of prep kits assembled in
the hospital is significantly less than that of disposable kits
provided by vendors. When necessary, perform hair removal in the
operating room. Studies have shown that shaving of the operative site
the night before surgery can produce conditions optimal for the
reproduction of bacteria, increasing the risk of infection (43).

Despite the use of ultra-clean air, airborne bacteria in
the operating room environment remain a source for contamination.
Bacteria may enter the wound directly or indirectly through gloves or
instruments that may become contaminated during skin preparation and
patient draping. These bacteria are believed to be mostly gram-positive
and shed by personnel in the room, particularly during periods of
increased activity. Conventional operating rooms may have as many as 10
to 15 bacteria per cubic foot. Lidwell reported the development of
infection following 1.5% of total hip arthroplasties performed in
conventional operating rooms and only 0.6% of procedures performed in
ultra-clean air operating rooms. Sir John Charnley advocated the use of
rapid air-change systems, along with multiple instrument trays in
orthopaedic operating rooms. Studies have found the number of airborne
bacteria can be reduced by approximately 50% in such ultra-clean air
rooms, and perhaps again by 50% with the use of body exhaust suits.
Other studies have shown no benefits to the use of ultra-clean air, and
one series examining the use of horizontal laminar flow actually
revealed an increase in the rate of infection in total knee
arthroplasty (6,41,45,51,56).

Rates of infection have been found to be directly
related to airborne bacterial levels. Standards have been recommended
for ultra-clean air operating rooms: fewer than 10 colony-forming units
per cubic meter (CFU/m³) within 30 cm of the wound and 20 CFU/m³ at the level of the operating table within the remaining clean-air enclosure (6,45).

A recent study examined the airborne bacterial counts during skin preparation and patient draping. Airborne

bacterial counts were found to be 4.4 times higher during prepping and
draping of the extremity with an unscrubbed, ungowned leg holder, and
2.4 times higher with a scrubbed and gowned leg holder as compared with
intraoperative levels. Another study examined the levels of bacterial
contamination in two layers of latex gloves during operative
procedures. It was found that the outer glove used exclusively for
draping is the most significantly contaminated, and that changing this
outer glove at appropriate times during surgery greatly minimizes the
rates of contamination (34).
The use of ultraviolet light in operating rooms has also been shown to
decrease the incidence of wound infection by reducing airborne bacteria.

The issue of administration of prophylactic antibiotics
is another important decision for the treating surgeon. The incidence
of infection in clean surgery should be less than 2%. For clean surgery
that involves the implantation of foreign material, grafts,
polymethylmethacrylate cement, or prosthetic devices, prophylaxis is
well accepted and justified, because this practice provides benefits
that outweigh the expected risks. Prophylactic antibiotics should also
be used in cases of major devascularization, impaired host defenses, or
suspected wound contamination.

Ideally, any prophylactic antibiotic given to a patient
should be bactericidal, have low toxicity and good tissue penetration,
be low in cost, and effective against the most commonly suspected
infecting agents. S. aureus and S. epidermidis
are the most common pathogens involved in at least half of prosthetic
joint infections and 70% to 90% of wound infections in clean surgery.
Gram-negative bacilli are involved to a much lesser extent.
First-generation cephalosporins have been favored in this country for a
variety of reasons. They are nontoxic, inexpensive, and effective
against the potential infective organisms. The administration of
antimicrobial agents for a short duration (24 to 48 hours)
postoperatively is effective in preventing infection (44).

Intravenous cefazolin, given as 1 g within 2 hours of
entering the operating room has been shown to be effective in this
capacity. Ideally, the infusion should be completed 30 minutes before
surgery to ensure adequate antibiotic levels at the time of skin
incision. An additional 1-g dose should be administered if the duration
of surgery is longer than 4 hours. Cefazolin 500 mg every 8 hours can
be continued for 24 hours postoperatively.

In institutions with a high incidence of methicillin-resistant S. aureus
or coagulase-negative staphylococcus, vancomycin alone or in
combination with another agent, such as gentamicin, has been shown to
be effective. Patients with a history of severe allergic reaction
(urticaria, angioedema, anaphylaxis) to a penicillin or cephalosporin
should receive 1 g of vancomycin 2 hours before incision and every 12
hours thereafter for 24 hours. Recent studies investigating
prophylactic use of the glycopeptide antibiotic teicoplanin against
methicillin-resistant staphylococcus species in patients unable to
tolerate vancomycin have shown it to be as efficacious as any other
regimen (31,37,44,57,59).

Alternatively, the prophylactic use of antibiotics in
cemented arthroplasty as well as antibiotic-impregnated polymethyl
methacrylate beads has been shown to be effective in reducing the risk
of infection. Josefsson et al. (22) followed a
prospective randomized group of 1688 consecutive total hip
arthroplasties comparing the use of gentamicin-impregnated bone cement
with systemic antibiotics. They found a decreased risk of deep
infection in those patients with antibiotic-impregnated cement, but
this effect was limited to the first year after operation.

Espehaug et al. (12)
retrospectively looked at 10,905 total hip arthroplasties performed in
Norway from 1987 to 1995. They compared patients who had received no
prophylactic antibiotics, systemic antibiotic prophylaxis only, cement
antibiotic prophylaxis only, and both systemic and cement antibiotic
prophylaxis. The lowest rate of revision arthroplasty was found among
those patients who had received both systemic and cement antibiotic
prophylaxis. Those receiving only systemic antibiotic prophylaxis had a
revision rate 4.3 times higher, those with only antibiotic bone cement
6.3 times higher, and those with no prophylaxis having a rate of
revision surgery 11.3 times higher (6,8,12,19,51,52).

Antibiotic-impregnated cement beads have been used extensively in the management of open fractures and chronic osteomyelitis (42).
These beads have been found to be cheaper than systemic antibiotics yet
provide the same efficacy. They are able to keep local antibiotic
concentration at levels that would be toxic systemically (29). Keating et al. (23) showed a decrease from 16% to 4% in infection rates among open tibia fractures. Cho et al. (10)
followed 54 patients with chronic osteomyelitis of the long bones
treated with local antibiotics and bone grafting an average of 4 years,
finding that 55% of these patients were completely free of infection.

The use of antibiotic prophylaxis in arthroplasty
patients who undergo dental procedures is controversial. A recent
survey has shown that a majority of orthopaedists (n = 44) and dentists
(n = 36) believe that patients with prosthetic joints should receive
prophylactic antibiotics before dental procedures (81% and 66%,
respectively) (47). Three approaches have been outlined in the literature.

The first approach does not recommend prophylactic
antibiotic use based on the cost, the adverse effects from antibiotic
agents, the potential for the emergence of antibiotic resistance, and
the lack of a clear cause-and-effect relationship. Others suggest
routine prophylaxis before dental and other procedures known to cause
transient bacteremia for at least 2 years after arthroplasty. Yet
others

recommend the use of prophylaxis only in those patients with conditions that predispose for infection (27,53).

Ainscow and Denham (1) reported
on 1,000 patients who had undergone 1,112 joint replacements and were
followed an average of 6 years. Their arthroplastic procedures were
performed between 1966 and 1980. The patients in this series were never
advised to take antibiotic prophylaxis before dental or surgical
procedures. Of these 1,000 patients, only three were found to have
developed prosthetic joint infections, and two of these patients
suffered from rheumatoid arthritis. Waldman et al. (54)
retrospectively looked at 3,490 patients who had had total knee
arthroplasty between 1982 and 1993. Of these patients, 62 developed
late infections of the prosthetic joint. Of these cases, seven were
strongly associated with prior dental procedures, representing 11% of
these late infections. The study concluded that the majority of
infections after dental procedures occurred in those patients with
systemic illnesses such as rheumatoid arthritis and diabetes mellitus.

When prophylaxis is used for dental procedures, an oral
first-generation cephalosporin is an appropriate choice because its
antimicrobial spectrum includes most organisms found in the oral
cavity. Cephalexin 1 to 2 g 1 hour before the procedure and 0.5 to 1 g
at 4 to 6 hours is recommended. Alternatively, 3 g of amoxicillin 1
hour before the procedure and 1.5 g 6 hours after the initial dose is
effective as well. Patients with allergy to penicillin should receive
600 mg of clindamycin 1 hour before the procedure and 6 hours later or
erythromycin 0.5 to 1 g 1 hour before the procedure and 0.5 g 4 to 6
hours after the first dose.

Antibiotic irrigation is commonly used in orthopaedic
procedures, although its true value has never been established. In
vitro systems have shown that colony counts of S. aureus, S. epidermidis, E. coli, and Pseudomonas
sp can be reduced 12% to 56% with saline irrigation alone. Several
studies have shown a decrease in colony counts in wounds and a decrease
in infection rates for general surgical procedures with the use of
antibiotic devices. It has been shown, however, that the use of power
irrigation increases the removal of bacteria by a factor of at least
100 over bulb-syringe irrigation of the same volume, regardless of the
solution used (2,5).

Topical antibiotics used in irrigation should have a
wide spectrum of activity and have low toxicity. The addition of
polymyxin, bacitracin, neomycin, or a combination of these agents is
most effective for this purpose (19).

Penicillins are bactericidal and act by inhibiting bacterial cell wall synthesis (Fig. 132.1).
These cell walls are composed of murein (peptidoglycan) and are
essential for the normal growth and development of bacteria.
Peptidoglycan is a heteropolymeric component of the cell wall that
provides rigid mechanical stability by virtue of its highly
cross-linked latticework structure. In gram-positive bacteria, the
thickness of this cell wall may be as much as 100 molecules, compared
with a thickness of only 1 or 2 molecules

in gram-negative organisms. Synthesis involves an N-acetylglucosamine-N-acetylmuramic
acid (GlcNAc-MurNAc) disaccharide unit that is attached to a
bactoprenyl lipid carrier molecule in the cytoplasmic membrane.
Autolytic enzymes open sites in the existing cell wall where the new
disaccharide units will be placed.

Once these molecules are donated by the lipid carrier
and oriented, transpeptidase enzymes cross-link the peptide of the new
GlcNAc-MurNAc moiety with that of another. The key targets of the
penicillins in this process are the transpeptidases. By binding tightly
to the active site of these enzymes, they inhibit the cross-linking of
the cell wall components and reduce the overall tensile strength these
cells need to resist osmotic lysis.

The enzymes that bind to penicillins are collectively
referred to as penicillin-binding proteins (PBP), because their initial
identification was based on their ability to bind with more complex and
varied forms of penicillin. The PBP are a diverse group of
transpeptidases and carboxypeptidases that are involved in various
aspect of cell wall synthesis, and as such, each β-lactam antibiotic
may have different affinities for selected PBP. Once the formation of
the bacterial cell wall is inhibited, two normally expressed classes of
autolysins seem to be responsible for the cidal action of β-lactam
antibiotics.

The natural penicillins, penicillin G (benzylpenicillin)
and penicillin V (the phenoxymethyl derivative), are very similar in
their antimicrobial spectrum for aerobic gram-positive organisms (Table 132.4 and Table 132.5).
They remain the agents of choice in gonococcal and streptococcal
arthritis and soft-tissue infections. Penicillin G is five to 10 times
more active than penicillin V against gonococcus sensitive to
penicillin. The sole virtue of penicillin V in comparison to penicillin
G is its stability in an acid environment. Therefore, it is better
suited for absorption from the gastrointestinal tract. On an equivalent
oral dose, penicillin V may yield plasma concentrations two to five
times greater than those provided by penicillin G. Once absorbed, both
penicillin G and penicillin V are widely distributed in the body and
excreted by the kidneys.

Intramuscular injection of penicillin G yields peak
plasma concentrations within 15 to 30 minutes, but this value declines
rapidly because of its short half-life (30 minutes). Many attempts have
been made to maintain the concentration of penicillin G doses given
parenterally. Probenicid has been found to block renal tubule secretion
of penicillin, but it is rarely used in this capacity. Instead,
repository preparations of penicillin may be used, the two favored
compounds being procaine penicillin G and benzathine penicillin G.
These preparations allow for slow release of antibiotic from the site
of injection, while maintaining bactericidal blood concentrations over
an extended period of time.

Newer penicillins grew from discoveries regarding the medium in which Penicillium
mold was grown, and the realization that changing the side chain moiety
could yield a wide variety of new properties. Investigators soon found
a highly reactive precursor of penicillin, 6-aminopenicillanic acid,
could be obtained by treating penicillin with an amidase. At that
point, an almost infinite number of synthetically generated organic
acids could then be fused with 6-aminopenicillanic acid to produce the
semisynthetic penicillins.

Three major goals propelled the investigation of novel
penicillin antibiotics. First, there was the need for a more
acid-stable penicillin that was orally available. Second, penicillin G
and V were effective against gram-positive aerobes but effective only
against a handful of gram-negative bacteria. Finally, the issue of
penicillin-resistant strains of bacteria had already begun to become a
matter of great concern.

The semisythentic aminopenicillins (ampicillin,
amoxicillin, and bacampicillin) were developed to extend the spectrum.
These antibiotics are effective against many gram-negative bacteria but
are only about one-half as effective against gram-positive bacteria as
is penicillin G. Their amino group allows them to traverse the charged
outer membrane of gram-negative bacteria easily and reach bactericidal
concentrations. They are also acid stable and readily bioavailable
through oral dosing. Their main limitation is that they are readily
hydrolyzed by β-lactamase enzymes and are not effective against P. aeruginosa. The aminopenicillins are effective against non-β-lactamase—producing strains of E. coli, H. influenzae, Proteus, Salmonella, and Shigella.

The carboxypenicillins, ureidopenicillins, and piperazine penicillins were all developed to treat infections of P. aeruginosa.
The carboxypenicillins carbenicillin and ticarcillin were the first
antipseudomonal agents developed. They are ineffective against
gram-positive organisms but

have excellent activity against enteric rods and Pseudomonas.
Piperazine penicillins, such as piperacillin, and the
ureidopenicillins, such as mezlocillin and azlocillin, are even more
effective against enteric bacteria and Pseudomonas,
as a result of their high affinity for gram-negative PBP.
Unfortunately, all of the antipseudomonal penicillins are sensitive to
β-lactamase, are generally more toxic than their predecessors, and must
be provided parenterally.

Bacterial resistance to penicillins can be mediated
through a variety of means: Chromosomal changes in the affinity of PBP
for penicillins, reduced antibiotic uptake, and decreased activities of
bacterial autolysins are all possible

mechanisms.
The most commonly encountered resistance to penicillins, however, is
based on the enzymatic destruction and inactivation of the β-lactam
ring. Different microorganisms elaborate a number of distinct
β-lactamases, although most bacteria are capable of producing only one
form of the enzyme. The substrate specificities of these enzymes are
relatively narrow, and they can often be described as either
penicillinases or cephalosporinases. Other “broad-spectrum” enzymes may
also be found that are capable of hydrolyzing a variety of β-lactam
antibiotics.

In general, gram-positive bacteria produce large amounts
of β-lactamase, secreting it extracellularly. In staphylococcus, the
information for penicillinase is encoded on a plasmid that can be
readily transferred by bacteriophage to other bacteria. In
gram-negative bacteria, β-lactamases are found in much lower
concentrations; their

location
in the periplasmic space, however, between the inner and outer cell
membranes makes them ideally located for maximal protection of the
microbe. In gram-negative organisms, β-lactamases are encoded in either
a plasmid or the chromosome, allowing it to be transferred by
conjugation with another bacterium as well. Whereas the staphylococcal
enzyme is inducible by substrates, the gram-negative β-lactamases may
be inducible or constitutive (35).

The β-lactamase—resistant penicillins include
methicillin, nafcillin, and the isoxazolyl penicillins (oxacillin,
cloxacillin, and dicloxacillin). These penicillins are more toxic and
have less activity than penicillin G against gram-positive cocci, but
it is their ability to resist hydrolysis by the β-lactamases produced
by staphylococci that allows them to remain the drug of choice in most
staphylococcal disease.

Clinical microbiology laboratories do not typically use
the term “methicillin-resistant Staphylococcus.” Most often, the
laboratory will test staphylococci with an oxacillin-impregnated disk,
reporting the organism as “resistant to oxacillin.” Oxacillin is the
commonly used class-disk for all penicillinase-resistant penicillins.
Although it is not specifically stated, this use indicates a resistance
of the organism to all other penicillinase-resistant penicillins
including methicillin, dicloxacillin, nafcillin, and cloxacillin. These
resistant organisms are also usually resistant to all available
cephalosporins (17).

The cephalosporins and related cephamycins constitute
the largest group of β-lactam antibiotics. The cephalosporins are
semisynthetic penicillin derivatives of 7-aminocephalosporanic acid,
consisting of a β-lactam ring coupled with a six-membered
dihydrothiazine ring (compared with the five-membered ring of
penicillins). In contrast to penicillins, cephalosporins can have up to
three side chains attached to the nucleus of the molecule. The R1 group
is attached to the same site as the R group of penicillin and
determines the antibacterial properties of the molecule. The R2 group
determines the metabolic and pharmacokinetic properties of the
molecule, and the R3 group acts to increase the resistance of
cephalosporins to the action of β-lactamase.

The cephalosporins have been divided into three major
groups, referred to as generations, depending on their efficacy against
gram-negative bacteria. Some of the more recently developed
cephalosporins are referred to as “fourth generation,” but this
classification has yet to achieve widespread acceptance.

The first-generation cephalosporins are effective primarily against gram-positive bacteria including pneumococci, streptococci, C. perfringens, Corynebacterium diphtheriae, S. epidermidis, and methicillin-sensitive S. aureus. The relevant spectrum of activity against gram-negative bacteria for these first-generation cephalosporins is limited to E. coli, Klebsiella, and Proteus mirabilis. It is important to note that most of the orally available cephalosporins are from this first-generation group (17,21,24) (Table 132.6).

Second-generation cephalosporins show more activity
against gram-negative bacteria, whereas they have comparable to
slightly less efficacy against gram-positive organisms compared with
first-generation cephalosporins. Second-generation cephalosporins are
not generally recommended for treatment of infections caused by
gram-positive organisms because they are more expensive, often need to
be given parenterally, and offer no real advantage over
first-generation cephalosporins. Cefuroxime is highly effective against
β-lactamase—producing strains of H. influenza and N. meningitidis,
two major causes of meningitis in children and young adults. Other
second-generation cephalosporins such as cefotetan and cefoxitin can
provide good coverage against N. gonorrhoeae, including β-lactamase—producing strains, as well as enteric rods such as E. coli, Klebsiella, and Proteus. Second-generation cephalosporins are not effective against P. aeruginosa.

Third-generation cephalosporins are highly resistant to
the actions of β-lactamase because of their unusually large R groups.
Although these antibiotics have an excellent spectrum of coverage for
gram-negative bacteria, they have very poor efficacy against
gram-positive bacteria. Third-generation cephalosporins are highly
effective against β-lactamase—producing strains of N. gonorrhoeae, N. meningitidis, H. influenzae, M. catarrhalis, and most enteric bacteria including Citrobacter strains, E. coli, Klebsiella, Morganella, Proteus, Providencia, Salmonella, and Shigella. Their excellent coverage is believed to be

a result of the strong affinity for gram-negative PBP and resistance to
β-lactamase. Of the third-generation cephalosporins, ceftazidime has
the strongest activity against P. aeruginosa.

Newer cephalosporins, such as cefepime and cefpirome,
exhibit activity against gram-negative bacteria similar to that of the
third-generation cephalosporins while having the efficacy of
first-generation cephalosporins in their activity against certain
gram-positive bacteria. This trait has prompted some clinicians to
refer to these antibiotics as fourth-generation cephalosporins, whereas
others view them as only extended-coverage third-generation
cephalosporins.

The carbapenems are synthetically derived antibiotics
from thienamycin. Although thienamycin is not suitable for human use,
its formimidoyl derivative imipenem has been shown to be the broadest
spectrum β-lactam antibiotic available. Imipenem is resistant to most
β-lactamases, can penetrate well into gram-negative bacteria, and is
also active against anaerobes. Thus, it is active against
β-lactamase—producing strains of Acinetobacter, Listeria, N. gonorrhoeae, N. meningitidis, P. aeruginosa, S. pneumoniae, gram-negative rods, and a number of strict anaerobes. Although it does not act as a cidal agent against Enterococcus faecalis, imipenem can act as a static agent against this organism.

Imipenem is inactivated by dihydropeptidase-1, which is
located on the brush border of proximal renal tubules. Cilastatin, a
specific inhibitor of dihydropeptidase-1 is given in a 1:1 ratio with
imipenem to block inactivation and decrease the risk of renal tubular
necrosis. Do not administer imipenem-cilastatin to individuals with CNS
lesions (such as strokes or head injuries), a history of convulsions,
or renal insufficiency. Reports have indicated that as many as 12% to
32% of these patients may develop convulsions as a consequence of this
treatment. Because of this propensity to cause seizures and its high
cost, imipenem is generally reserved for gravely ill patients with
multiple-pathogen nosocomial infections. Meropenem is a newly approved
carbapenem with a similar spectrum of activity as imipenem. It does not
require dosing of cilastatin and carries a lower risk of seizures (17,21).

Monobactams, as their name indicates, are composed
solely of a single ring. The first such antibiotic created was
aztreonam. In contrast to imipenem, aztreonam is a narrow-spectrum
antibiotic, having good activity against only N. gonorrhoeae, N. meningitidis, P. aeruginosa,
and most gram-negative enteric bacteria. Aztreonam is resistant to
gram-negative β-lactamase but is readily inactivated by plasmid-encoded
β-lactamase. The spectrum of aztreonam can be broadened with the
addition of a penicillin with gram-positive activity, such as nafcillin
or cloxicillin, or alternatively with an aminoglycoside. It also
appears that patients with allergy to penicillin show no such reaction
to aztreonam (17,21).

The aminoglycosides include gentamicin, amikacin,
tobramycin, and kanamycin. They exert their action by binding to the
30s ribosomal subunit in bacteria, disrupting the conformation of mRNA,
and forcing erroneous tRNA binding to the codon. At high
concentrations, aminoglycosides can bind to both the ribosomes and
mRNA, disrupting protein translation beyond initiation as well as
permanently altering the ribosome, rendering it functionally useless.

The aminoglycosides have a broad spectrum but are
limited by several factors. First, because they require active protein
production in the bacteria to exert their effect, they cannot be used
with agents that reversibly interfere with protein synthesis. It is for
this reason that aminoglycosides are not bactericidal in the presence
of chloramphenicol. Second, the rate of bacterial killing by an
aminoglycoside increases with the drug concentration, with the limiting
factor being the rate at which the antibiotic enters bacterial cells.
Third, aminoglycosides are effective only under aerobic conditions,
thus they are ineffective against obligate anaerobic bacteria. Fourth,
aminoglycosides are ineffective in areas of high acid or salt
concentrations. Fifth, because of their poor penetration into the host
cells, they offer little activity against intracellular bacteria.
Finally, aminoglycosides are relatively toxic with a limited
therapeutic window. High trough levels of aminoglycosides are
classically associated with ototoxicity and nephrotoxicity.

The use of aminoglycosides is primarily for aerobic
gram-negative rods. By administering aminoglycosides with a β-lactam,
the antibiotics work synergistically to reduce the dosage, increase the
therapeutic margin, and broaden the spectrum of the aminoglycosides.
Through this combination therapy, clinicians can avoid the toxicities
associated with this antibiotic.

Resistance to aminoglycosides can be due to two major
mechanisms. In order to create sufficient concentrations in bacteria,
the aminoglycosides must be transported intracellularly by means of a
specific carrier protein. Bacteria that generate lower levels or weakly
binding transport protein are innately resistant to aminoglycosides.
Another mechanism that confers resistance to bacteria is the presence
of a number of enzymes that deactivate the antibiotic by means of
acetylation, phosphorylation, or adenylation. These chemical
modifications do not allow the aminoglycoside molecule to interact with
bacterial ribosomes to exert their bactericidal activity (35).

Aminoglycoside antibiotics are associated with
nephrotoxicity, and their dosage must be adjusted on the basis of the
patient’s baseline renal function. Ototoxicity is another adverse
effect of the antibiotic, manifesting mainly as vestibular dysfunction
owing to the destruction of hair cells by prolonged drug trough levels
in excess of 10 mg/ml. Loss of hearing can occur as well, and it is
occasionally extensive and irreversible (17,21).

Bacitracin is a cell wall synthesis inhibitor that is
fairly toxic when administered systemically. The bactericidal action of
bacitracin works by blocking the dephosphorylation of the bactoprenyl
carrier molecule after it has donated its GlcNAc-MurNAc disaccharide to
the growing peptidoglycan chain. As a result, no bactoprenyl phosphate
is left available to receive to new disaccharide monomeric subunits to
be incorporated into the existing murein, halting cell wall synthesis.

Bacitracin is an extremely toxic compound when
administered parenterally, and therefore, it is restricted to topical
and oral use. It can be found in topical creams for use in treating eye
and skin infections caused by staphylococci and streptococci, as well
as oral preparations for the treatment of pseudomembranous colitis
caused by Clostridium difficile. Its use in this capacity is possible because of its poor absorption from oral intake.

Bacitracin is markedly nephrotoxic if absorbed,
producing proteinuria, hematuria, and nitrogen retention. Its systemic
use has been virtually abandoned. Topical application rarely causes
hypersensitivity reactions or systemic toxicity.

Chloramphenicol is a bacteriostatic antibiotic that
interferes with the action of peptidyl transferase, inhibiting the
formation of a peptide bond and arresting peptide chain elongation.
Because of its bacteriostatic nature, it is generally not administered
in combination with a bactericidal antibiotic. Chloramphenicol’s
ability to penetrate host cells is at the same time a great advantage
and a drawback. Its accumulation in the host cell’s cytoplasm allows
the antibiotic to be used against intracellular organisms. At the same
time, these cytoplasmic concentrations interfere with ribosomal protein
synthesis, depressing bone marrow activity and causing a pancytopenia.

In infants, ineffective hepatic clearance of the
medication leads to toxic levels, and leads to the condition known as
gray-baby syndrome, with vomiting, flaccidity, hypothermia, gray color,
shock, and collapse. One idiosyncratic reaction to the medication is
the development of an aplastic anemia. It is not related to dosage or
length of use,

but
the odds of developing this condition are increased by extended use of
the medication. It is for these reasons that clinicians in the United
States have limited its use.

The antibiotic remains an effective treatment for infections caused by H. influenzae and Rickettsia
sp. Resistance to chloramphenicol is mostly limited to enteric
bacteria. Three modes of resistance have been described in these
organisms. The mechanism most commonly found is a gene coding for an
enzyme that is able to acetylate both chloramphenicol and tetracylines,
thereby inactivating them. The second method of resistance involves the
ability of certain bacteria to limit their permeability to the
antibiotic. The final resistance factor discovered is a mutation in the
50s subunit of the bacterial ribosome that results in poor recognition
of the antibiotic by its target (35).

Other adverse reactions to chloramphenicol include GI
upset with nausea, vomiting, and diarrhea. Chloramphenicol may also
prolong the half-lives of many drugs including phenytoin, tolbutamide,
chlorpropamide, and warfarin. This effect is attributed to the
inhibition of liver microsomal enzymes by the antibiotic.

The fluoroquinolones are a group of synthetic quinolones
developed with broad-spectrum effectiveness against most gram-negative
and some gram-positive bacteria. Their proposed mechanism of action is
through binding to the α-subunit of bacterial DNA gyrase (topoisomerase
II), inhibiting the process of DNA supercoiling, a necessary step in
the replication of DNA. The fluoroquinolones can be used to treat
infections in most parts of the body including the urinary tract and to
treat gonorrhea, bacterial diarrhea, and infections of the skin, bones,
and joints as well. They are generally effective against N. gonorrhoeae and S. aureus, and they are usually effective against P. aeruginosa.

The most prominent adverse effects of the
fluoroquinolones are nausea, vomiting, and diarrhea. Occasionally,
headache, dizziness, insomnia, abnormal liver function tests, or skin
rash may develop. Concomitant administration of theophylline and
fluoroquinolones can lead to elevation of theophylline levels with
increased risk of toxic effects, especially seizures (Table 132.9).
Fluoroquinolones have been shown in animal models to damage immature
cartilage, but no study has documented this finding in the human
pediatric population.

The glycopeptide antibiotics vancomycin and teicoplanin
have become extremely important tools against methicillin-resistant
staphylococci. These antibiotics are macromolecules, consisting of
seven amino acids at their core, with all glycopeptides sharing a
homology of five of these amino acids. Because of their size, the
glycopeptide antibiotics cannot effectively penetrate the outer
membrane of the gram-negative bacteria and therefore can have no effect
on these organisms. Their inability to penetrate the cytoplasmic
membrane of gram-positive bacteria restricts their activities to the
metabolic processes of the microbe occurring outside this membrane.

Each glycopeptide antibiotic possesses a ring-like
configuration, with a central cleft binding tightly to its target. The
active sites of vancomycin and teicoplanin have been shown to recognize
tripeptides with a stereochemical configuration of L-D-D. This
configuration can be found only within the MurNAc pentapeptide, where
an L-amino acid can be found at position 3 with two terminal
D-alanines. When vancomycin is administered to susceptible
gram-positive bacteria, it first attaches to all available L-D-D
residues in the cell wall.

Once these sites are saturated, the glycopeptide
antibiotic attaches to the L-D-D of GlcNAc-MurNAc moeities that are
attached to the bactoprenyl transferring lipid. Once in this position,
the glycopeptide acts as a steric hindrance, blocking peptidoglycan
transglycosidase from transferring the disaccharide unit to the
peptidoglycan growth point. Moreover, the attachment of vancomycin to
the acyl-D-alanine-D-alanine of non-cross-linked dipeptides already
incorporated in the cell wall interferes with their ability to be
cross-linked.

Vancomycin and teicoplanin are used to treat severe infections caused by C. difficile, multiply resistant S. aureus, coagulase-negative staphylococci, and penicillinase-producing strains of S. pneumoniae and S. pyogenes.
A glycopeptide antibiotic can also be used in combination with an
aminoglycoside to treat infections caused by highly resistant E. faecalis.

Adverse reactions are rare with vancomycin use. Although
the use of vancomycin has occasionally been associated with ototoxicity
and nephrotoxicity, the highly purified preparations of vancomycin that
are now commercially available are generally considered safe for most
patients and make these toxicities mild. Vancomycin is an irritant to
tissue, and patients may develop phlebitis at the site of injection as
well as a nonimmune-mediated histamine release referred to as the “red
man syndrome.” This reaction can largely be prevented by the
administration of antihistamine and slow infusion. Vancomycin is
excreted through the kidneys, and in patients with altered renal
function, peak and trough blood levels of the antibiotic should be
checked to avoid any of the previously mentioned toxicities.

Resistance to glycopeptide antibiotics has been found mainly among Enterococcus
sp primarily owing to the production of a membrane-bound protein known
as VanA. VanA is a D-alanine-D-alanine ligase that synthesizes other
mixed dipeptides, replacing the D-alanine-D-alanine within MurNAc.
These VanA-containing enterococci no longer express the L-D-D target
for the binding of glycopeptide antibiotics and are therefore rendered
resistant to

its actions. VanA has been found to be transferred to other bacteria via conjugation. Less commonly, Entercoccus
sp express VanB or VanC proteins whose modes of action are most likely
similar to that of VanA but have not been found to be transferred by
conjugation (17,21,35,37,57,59).

The lincosamides include the antibiotics clindamycin and
lincomycin. The difference between these two antibiotics is the
presence at position 7 of a chlorine group on clindamycin that is a
hydroxyl group on lincomycin. This difference allows clindamycin to be
more easily absorbed orally and more active against anaerobic bacteria.
The lincosamides have the same receptor on the 50s subunit of the
bacterial ribosome as chloramphenicol. Lincosamides, however, are able
to cause a more rapid dissociation of the ribosome into its constituent
50s and 30s subunits.

The spectrum of action for clindamycin is similar to

that of penicillin G and erythromycin, but it is used primarily in the treatment of infections caused by the strict anaerobe B. fragilis, especially in patients with known reactions to penicillin. It is sometimes used to treat abscesses or sepsis caused by other Bacteroides sp, Actinobacillus, Actinomyces, Capnocytophaga, Clostridium, Flavobacterium, Fusobacterium, or Peptostreptococcus. Most of these bacteria are anaerobic or microaerophilic.

Clindamycin can also be used for deep staphylococcal
infections, and in combination with gentamicin to treat complicated
pelvic inflammatory disease. Although the development of
pseudomembranous colitis is seen with prolonged use of any antibiotic,
it is most commonly associated with clindamycin. Clindamycin
effectively eradicates the normal flora of the colon, leaving it prone
for superinfection by C. difficile. The newly dominant C. difficile elaborates a potent exotoxin responsible for the colitis. The colitis can be treated with either metronidazole or vancomycin.

Resistance to clindamycin is seen in organisms that also
exhibit resistance to macrolide antibiotic. The resistance appears
linked to the same mechanisms that alter the bacterial 50s ribosomal
subunit and produce resistance to the macrolides (17,35).

Macrolide antibiotics are large, cyclic molecules that
contain a lactone ring. Until recently, erythromycin was the only
macrolide antibiotic available. The increasing incidence of resistant
strains has led to the development of the newer macrolides azithromycin
and clarithromycin. These antibiotics are bacteriostatic at low
concentration and bactericidal at high concentration. Macrolides bind
to ribosomes, allowing the initiation and formation of a short peptide
sequence, but inhibit the process of translocation and elongation soon
thereafter. This blocked complex becomes unstable, and eventually the
ribosomal fragments are released from the mRNA strand.

The popularity of the macrolides is based on their
spectrum of action similar to that of penicillin G, resistance to
β-lactamase, oral availability, and absence of major toxicity. Most
adverse reactions are related to disturbances of the gastrointestinal
tract. Erythromycin is used in treating Legionnaires’ disease,
diptheria, pertussis, and atypical pneumonia cause by Mycoplasma or Chlamydia.
The newer macrolides have broadened the spectrum of this class of
antibiotics. Azithromycin has also been shown to be effective against Borrelia burgdorferi, the causative agent of Lyme disease; H. influenzae; and Toxoplasma gondii. Clarithromycin is unusual in its effectiveness against Mycobacterium avium-intracellulare and several of the atypical mycobacteria.

Resistance to macrolides is conferred by genetic changes
of the 50s ribosomal subunit in the bacteria resulting in an inability
of these subunits to recognize the antibiotic (35).

Adverse effects of macrolide antibiotics given orally
include anorexia, nausea, vomiting, and diarrhea. Erythromycin can also
produce acute cholestatic hepatitis (fever, jaundice, impaired liver
function), probably as a hypersensitivity reaction. Other allergic
reactions include fever, eosinophilia, and rashes. Erthyromycins can
also inhibit cytochrome P450 and increase the effects of
anticoagulants, digoxin, cyclosporine, and antihistamines.

Polymyxin antibiotics are large polypeptide antibiotics
that contain fatty acids, multiple positive charges, and a long alkyl
side chain. These properties allow polymyxins to act as cationic
detergents, binding avidly to lipopolysaccharide and
phosphotidylethanolamine in gram-negative outer membranes but poorly to
phosphatidylcholine, a constituent of human cell membranes. Therefore,
polymyxins are effective against gram-negative bacteria.

Two polymyxins are available in the United States,
polymyxin B and polymyxin E. Because of their toxicity, polymyxins are
not the drug of choice in the treatment of any bacterial infection.
Instead they can be used as a second-line drug to treat severe or
life-threatening infections caused by P. aeruginosa or other gram-negative rods when such infections have not responded to standard therapies.

Local reactions and hypersensitivity to topical
administration are rare. Systemic levels of polymyxins can cause
paresthesias, dizziness, and lack of coordination, which disappear when
the drug has been excreted. Very high blood levels (greater than 30
mg/ml) can cause respiratory paralysis. Polymyxins may also cause
proteinuria and hematuria.

Rifampin is a transcriptional inhibitor that binds to
the β-subunit of DNA-dependent RNA polymerase in bacteria. It allows
the creation of the first phosphodiesterase bond to form in the RNA but
then blocks any subsequent bond formation, and effectively terminates
chain initiation in RNA synthesis. Resistance to rifampin is based on a
mutation of the gene coding for the β-subunit of the bacterial
DNA-dependent RNA polymerase that will not allow for proper binding of
rifampin. Because of the high rate of spontaneous mutations that create
resistance to rifampin, its use has been limited to (1) long-term treatment of tuberculosis and leprosy, (2) prophylaxis for those exposed to patients with meningitis due to H. influenzae type b or N. meningitidis, and (3) combination therapy with vancomycin, nafcillin, and ciprofloxacin in the treatment of endocarditis or osteomyelitis caused by S. aureus or S. epidermidis.

Rifampin imparts a harmless orange color to urine,
sweat, tears, and contact lenses of which patients should be warned.
Occasional adverse reactions include rashes, thrombocytopenia,
nephritis, and impairment of liver

function.
Rifampin induces the cytochrome P450 system of the liver and increases
the elimination of anticoagulants and contraceptives. Likewise,
administration of rifampin with ketoconazole, cyclosporine, or
chloramphenicol results in significantly lower serum levels of these
medications.

Tetracyclines are broad-spectrum bacteriostatic agents
that are capable of penetrating well into host cells. They are most
effective against rapidly multiplying bacteria. This group of
antibiotics include tetracycline, doxycycline, demeclocycline, and
minocycline. The tetracyclines exert their action by binding to the 30s
bacterial ribosomal subunit and inhibiting the correct positioning of
the incoming tRNA, thereby inhibiting peptide elongation. The earlier
tetracylines were not well absorbed from the intestinal tract and, as a
result killed much of the normal flora, resulting in colitis. However,
with the development of the more lipophilic semisynthetic tetracyclines
doxycycline and minocycline, intestinal absorption has increased and
reduced the incidence of colitis.

Nausea, vomiting, and diarrhea are the most common
reasons for discontinuing tetracycline. These symptoms can usually be
controlled by administering the antibiotic with food. Use in children
under the age of 12 can impair bone development and stain developing
teeth. Tetracyclines can probably impair hepatic function and may also
result in liver necrosis, especially in pregnant patients. Renal
tubular acidosis and other renal injuries resulting in nitrogen
retention have been attributed to the administration of outdated
tetracycline preparations. Intravenous injection of tetracycline can
lead to venous thrombosis, whereas intramuscular injection produces
painful local irritation and should be avoided. Administration of
systemic tetracycline, especially demeclocycline, can induce
sensitivity to sunlight or ultraviolet light, particularly in
fair-skinned individuals. Dizziness, vertigo, nausea, and vomiting have
been particularly noted in patients receiving minocycline.

Tetracyclines are used primarily in the treatment of infections caused by intracellular organisms such as Chlamydia, Rickettsia, and pneumonia caused by M. pneumoniae.
Resistance to tetracyclines is based on a plasmid-encoded active efflux
system. Although tetracycline entry into the cell is not altered, an
active system for pumping the antibiotic out of the bacteria is
established (35).

Metronidazole is a nitroimidazole antiprotozoal drug
that also has striking bactericidal effects against most anaerobes,
including Bacteroides and clostridia. It
exerts its antibacterial effect through the formation of short-lived,
highly cytotoxic intermediates that develop in anaerobic conditions. It
is well absorbed when taken orally, metabolized by the liver, and may
accumulate in patients with hepatic insufficiency. Metronidazole is
considered for use in anaerobic and protozoal infections, and
antibiotic-associated enterocolitis. Adverse effects of the medication
include nausea, diarrhea, stomatitis, and peripheral neuropathy with
prolonged use. Advise patients to avoid alcohol ingestion because of
metronidazole’s disulfiram-like effect.

Trimethoprim and sulfamethoxazole (TMP/SMX) act at
different points in the chemical pathway that produces dihydrofolic
acid for bacterial cells. Dihydrofolic acid acts as a reducing agent in
bacteria and is necessary for normal cellular processes. Because of
their actions on the same pathway, TMP/SMX act synergistically against
susceptible bacteria as well as some parasites. Resistance to TMP/SMX
develops when enzymes in the dihydrofolic acid pathway mutate and no
longer bind these medications as avidly. Because of the use of two
medications on the same chemical pathway, however, the development of
resistant strains is somewhat hampered (35).

Sulfonamides can cause a wide variety of untoward
effects owing partly to allergy and partly to direct effects. The most
common adverse effects include fever, skin rashes, photosensitivity,
urticaria, nausea, vomiting, and diarrhea. Other effects include
stomatitis, conjunctivitis, arthritis, hepatitis, exfoliative
dermatitis, polyarteritis nodosa, Stevens-Johnson syndrome, and
psychosis. Sulfonamides can produce anemia (hemolytic or aplastic),
granulocytopenia, thrombocytopenia, or leukemoid reactions. These are
rare except in certain high-risk patients. Sulfonamides cause hemolytic
anemia in patients with glucose-6-phosphate dehydrogenase deficiency,
and sulfonamides taken near the end of pregnancy increase the risk of
kernicterus in the newborn infant.

Trimethoprim produces the predictable adverse effects of
an antifolate drug, especially megaloblastic anemia, leukopenia, and
granulocytopenia. These effects can be prevented by the simultaneous
administration of folinic acid.

Isoniazid (INH) is a bactericidal antibiotic that
interferes with the synthesis of mycolic acid, an essential component
of the cell wall complex of Mycobacterium tuberculosis.
When used as prophylaxis for tuberculosis, it can be given as
monotherapy. With the rise of multidrug-resistant TB, however, INH must
be given in combination with other antimycobacterial drugs. Another
antimycobacterial drug ethionamide is closely related to INH and has
the same mode of action.

The most common side effects of INH use, seen in 10% to
20% percent of patients, are on the peripheral nervous system and CNS.
These are related to a relative pyridoxine deficiency and include
peripheral neuritis, insomnia, restlessness, muscle twitching, urinary
retention, and even convulsions or psychotic episodes. Most of these
complications can be avoided by the administration of pyridoxine
(vitamin B₆). Isoniazid has been associated with
hepatotoxicity with abnormal liver function tests, clinical jaundice,
and multilobular necrosis.

Pyrazinamide is a relative of nicotinamide and strongly
inhibits the growth of tubercle bacilli and other mycobacteria.
Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed throughout the body. Tubercle bacilli develop
resistance to pyrazinamide fairly readily, but there is no
cross-resistance with INH or other antimycobacterial drugs. The major
adverse effects of pyrazinamide include hepatotoxicity (in 1% to 5% of
patients), nausea, vomiting, drug fever, and hyperuricemia.

The use of rifampin for bacterial infections has been
discussed earlier. It is also used as a front-line chemotherapeutic
agent against mycobacterial infections.

Ethambutol is a bactericidal antibiotic that inhibits
the synthesis of cellular metabolites by an unknown mechanism. In
combination with other medication, it is used in the short-term
treatment of tuberculosis. Ethambutol may cause reduced visual acuity,
optic neuritis, and perhaps retinal damage in about 0.8% of patients
but rarely in patients with normal renal function.

Cycloserine acts as an analog of D-alanine-D-alanine,
and inhibits the formation of peptidoglycan cross-links by acting as a
competitive inhibitor of the transpeptidase enzymes. Cycloserine is
indicated primarily as a second-line agent in the treatment of
tuberculosis. Its use has been associated with convulsions, other
serious CNS dysfunction, and psychotic reactions.

Streptomycin is identical in action to the
aminoglycosides previously discussed and possesses the same adverse
effects. Most tubercle bacilli are inhibited by streptomycin, but the
drug can exert its effects only on extracellular bacteria because only
10% of the antibiotic can penetrate cells that harbor the intracellular
pathogen.

Dapsone is a sulfone antibiotic with an identical mode
of action and adverse effects as the sulfonamides. For many years,
dapsone was the treatment of choice against Mycobacterium leprae.
With the rise of dapsone resistance among leprosy bacilli during the
past few years, standard treatment of leprosy now combines dapsone with
other antimycobacterial drugs.

Amphotericin B and nystatin are polyene antibiotics.
They are selectively toxic to fungi because of their ability to
preferentially bind ergosterol. This binding disorganizes the lipid
bilayer, and fungal metabolites leak out of the damaged cell. In
addition to their ability to bind ergosterol, the polyenes can bind to
cholesterol in the human cell membrane. It is for this reason that
amphotericin B is toxic when used IV, and high-dose therapy may damage
renal basement membranes. This is not a problem with nystatin, because
it is not given intravenously. Regardless of its toxic effects,
amphotericin remains the drug of choice in the treatment of systemic
aspergillosis, blastomycosis, candidiasis, coccidiomycosis,
cryptococcosis, histoplasmosis, mucormycosis, and sporotrichosis.
Nystatin is used in the treatment of cutaneous and mucocutaneous
Candida infections. Because nystatin is not absorbed well from the gut,
it is often used in the treatment of gastrointestinal candidiasis.

Intravenous injection of amphotericin B usually produces
chills, fever, vomiting, and headache. The severity of these reactions
may be diminished by reducing the dosage temporarily; administering
aspirin, phenothiazines, antihistamines, or corticosteroids; or
stopping injections for several days. Therapeutically active amounts of
amphotericin B commonly impair renal and hepatocellular function, and
produce anemia.

The azole antibiotics are fungistatic and exert their
antifungal effect by blocking the synthesis of ergosterol through the
inhibition of the cytochrome P-450 enzyme lanosterol-14-demethylase.
When the available ergesterol for cell growth is depleted and there is
no additional supply of ergesterol produced, fungal growth ceases. The
azole antifungals can be used topically in the treatment of
dermatophyte infections, chronic mucocutaneous candidiasis,

candidiasis in immunodepressed individuals, chromoblastomycosis, paracoccidiomycosis, and cutaneous or lymphatic sporotrichosis.

Adverse effects of the azole antifungal drugs include
vomiting, nausea, diarrhea, rashes, and sometimes impairment of hepatic
function. Fluconazole and ketoconazole inhibit cytochrome P450 and may
increase serum concentrations of phenytoin, cyclosporine, oral
hypoglycemic drugs, and anticoagulants.

Flucytosine is the only nucleoside analog used in the
treatment of fungal infections. In fungal cells, flucytosine is
enzymatically converted to fluorouracil, and acts to terminate RNA
replication, and thus protein synthesis. Flucytosine can be used as a
single agent to treat Candida infections of the urinary tract, and is
used in combination with amphotericin B in the treatment of systemic
candidiasis or cryptococcosis. As much as 15% of fungal isolates,
however, rapidly develop resistance to flucytosine when it is used as a
single agent. In addition, flucytosine may be toxic in some patients,
with prolonged serum levels causing bone marrow depression with
leukopenia or thrombocytopenia, hair loss, and abnormal liver function.

Griseofulvin is a fungistatic antibiotic produced by Penicillium
and is used to treat dermatophyte infections that are not responsive to
topical antibiotics. It may also be administered orally to eradicate
infections that are localized in the stratum corneum. It is believed
that griseofulvin acts as a colchicine-like agent, interfering with
cellular microtubule assembly and inhibiting fungal mitosis. Although
griseofulcin is effective against dermatophytes, it has limited
effectiveness for the treatment of tinea versicolor or tinea nigra. It
is well tolerated, with headache being the most commonly reported
adverse reaction.

Naftifine and terbinafine are two members of the newer
allylamine class of antifungal agents available. They are used mostly
to treat dermatophyte infections, such as athlete’s foot and ringworm.
These antibiotics are fungicidal and work through allosteric inhibition
of squalene epoxidase, leading to an accumulation of high levels of
squalene and inhibition of ergosterol synthesis (39).