You are on page 1of 4

Chapter 230

Antibiotics
Christopher C. Gasbarre, Steven K. Schmitt
& Kenneth J. Tomecki

BASIC PRINCIPLES
Mechanisms of Action
Antibiotics are largely classified by their chemical
structures and subsequent mechanisms of action.
Four major groups exist:
1. Those that inhibit formation of bacterial cell
walls, for example, the -lactams (penicillins,
cephalosporins, and carbapenems) and vancomycin; these are generally bacteriocidal.
2. Those that interfere with protein synthesis
by binding to either the 50S or 30S bacterial
ribosomal subunit may be bacteriostatic or
bacteriocidal. Reversible binding (tetracyclines, macrolides, lincosamides, and linezolid)
usually halts microbial growth, resulting in a
bacteriostatic effect. Irreversible bacteriocidal
binding occurs with aminoglycosides.
3. Those that interfere with bacterial nucleic
acid synthesis, for example, rifampin (inhibits
RNA polymerase), and quinolones (inhibit
bacterial topoisomerase). These agents are
typically bacteriocidal.
4. Those that interfere with key enzymes in folate
metabolism, for example, trimethoprim and
sulfonamides.

Bacteriocidal Versus
Bacteriostatic Agents
While antibiotics may be considered bactericidal
(producing cell death) or bacteriostatic (halting
cell growth or division), the distinction is based
on in vitro assays. In an immunocompetent host,
both modes of action can eliminate pathogens.
Other considerations such as absorption, tissue
distribution, and drug metabolism/elimination
often play a more important role in eradication of
infection. Additionally, some antibiotics are variably
bacteriotoxic and bacteriostatic depending on the
infective organism. There are few situations where
the distinction may be clinically relevant: bacterial
meningitis, infective endocarditis, osteomyelitis,
and infections occurring in neutropenic patients.

Finally, host factors such as immunocompromising


disease or therapy, and ability to debulk infections
by debridement or drainage, may also overshadow
in vitro susceptibility in treating infection.

Susceptibility Testing
Susceptibility testing, following isolation and
identification of an organism from an appropriate clinical specimen, helps to direct therapy. A
standard concentration of the bacteria is grown at
several concentrations of antibiotic. The minimum
inhibitory concentration (MIC) is defined as the lowest concentration at which growth is inhibited. An
isolate is considered susceptible if the MIC is below
the maximum concentration normally achieved in
patients serum following accepted dosing schedules. Susceptibility determinations are somewhat
relative and should be interpreted with caution. The
laboratory breakpoints may not recognize variation
in tissue antibiotic concentration or antibiotic activity (low pH, anaerobic environment, and protein
concentration) at the site of infection. In-vitro
determinations of MIC may fail to detect inducible
resistance among certain pathogens (e.g., inducible
clindamycin resistance among Staphylococci). However, susceptibility testing for most dermatologic
infections is reliable.

Resistance Mechanisms
Since the advent of antibiotics, microbes have
become increasingly resistant to available therapies. Approximately 70% of all infective bacteria
encountered in the hospital setting have developed
resistance to at least one of the antibiotics initially
used to treat them. In order for an antibiotic to
be effective, it must reach its target in an active
form, bind to the target, and inhibit the organisms
growth. Bacteria can evade the intended action if:
(1) the drug cannot reach its target, for example,
efflux pumps in the bacterial cell membrane can
remove antibiotics from the cell. Numerous antibiotics (-lactams, tetracyclines, fluoroquinolones,
and macrolides) are eliminated in this fashion. (2)
The drug is inactivated, as exemplified by resistance to -lactams by organisms able to produce
-lactamase. (3) The drug can no longer bind its
target. Numerous permutations of this mechanism
are known. One such example is natural mutation
of bacterial topoisomerases resulting in fluoroquinolone resistance.
There are many ways in which bacteria can

Copyright McGraw-Hill Companies, Inc. All rights reserved.

324 Chapter 230: Antibiotics

acquire resistance genes. Spontaneous mutations may be preferentially selected and passed
to progeny. More common is the intraspecies or
interspecies horizontal transfer of genetic material encoding resistance determinants. Horizontal
transfer mechanisms (plasmids, transposons,
transformation, conjugation, viral transduction)
typically result in higher levels of resistance than
spontaneous mutation, leading to incremental
changes in bacterial resistance patterns. There are
now many bacterial strains that have incorporated
resistance determinants for multiple antibiotics,
making treatment daunting. Multidrug resistance
typically occurs in areas of intensive antibiotic use.
Exact resistance rates for uncomplicated SSTIs are
unknown, but growing resistance patterns have
been reported with macrolide-resistant group A
Streptococcus isolates, community-acquired MRSA
isolates, and fluoroquinolone-resistant staphylococcal and streptococcal isolates. As resistance patterns emerge, appropriate culture and susceptibility
testing become more important.

Pharmacokinetics and
Pharmacodynamics
Pharmacokinetics refers to the absorption, distribution, and elimination of a drug.2 Peak and trough
serum concentrations after antimicrobial dosing are
examples of pharmacokinetic parameters. Pharmacodynamics describes the relationship between
pharmacokinetic measurements (drug concentrations) and antimicrobial effect (dose > MIC). For
some antibiotics, treatment efficacy is determined
predominantly by the amount of time between
doses during which tissue concentration of drug is
above the MIC, irrespective of the peak tissue level
of antibiotic. This is referred to as time-dependent
growth inhibition, and is true for most -lactam
antibiotics. Conversely, peak tissue levels of drug
following each dose typically predict eradication of
infection. Aminoglycosides and fluoroquinolones
exhibit such concentration-dependent growth inhibition. Such activity may also vary depending on
the organism and site of infection. Use of a drug at
an inappropriately low dose or wide dosing interval
can encourage the development of resistance.

Adjustments for Renal


Insufficiency
Many antibiotics excreted by the kidneys require
dosing adjustments for patients with renal insufficiency to ensure adequate dosing and avoid drug
toxicity (Table 230-1). Adjustments to either the
amount of drug or frequency of its administration
are based on creatinine clearance, which is most
easily approximated using the following calculation:
CCR = ideal weight (kg) (140 - age)
72 serum creatinine (mg/dL)
This formula applies to men; for women, multiply
by 0.85. Some antibiotics are removed by hemodialysis and require additional dosing.

Pregnancy and Lactation


Ideally, systemic antibiotics should be avoided
during pregnancy. However, for uncomplicated
SSTIs, penicillins, cephalosporins, and erythromycin,
as class B medications, are considered the safest
candidates for use. As class D medications, tetracyclines, fluoroquinolones, and trimethoprim-sulfamethoxazole are contraindicated during pregnancy
(Table 230-2). Most antibiotics are considered safe
for lactating (breastfeeding) women, but fluoroquinolones should be avoided due to possible development of arthropathies and cartilage defects.3
Infrequently used systemically in dermatologic
practice, metronidazole has carcinogenic and mutagenic risk. If used, current guidelines recommend
discontinuation of breastfeeding for 1224 hours to
allow for excretion of the drug.

Prophylaxis and
Perioperative Use
The prophylactic use of antibiotics in dermatology and dermatologic surgery is controversial.4,5
Published guidelines and existing studies inadequately address dermatologic procedures (such as
prolonged procedures and involvement of mucosal
sites), and a consensus does not exist. It is likely
that antibiotics are currently overused in this arena,
and several recent publications have proposed
guidelines relevant to dermatology. Prophylactic

Copyright McGraw-Hill Companies, Inc. All rights reserved.

Chapter 230:

antibiotic use may be considered for two purposes:


(1) prevention of endocarditis and/or prosthesis infection, and (2) prevention of surgical site infection.
The American Heart Association (AHA) published
its most recent guidelines regarding infective
endocarditis (IE) prophylaxis in 2007. Compared
to earlier recommendations, the latest guidelines
recommend prophylaxis only for those patients
with a high risk of a poor outcome from IE, rather
than a high lifetime risk of IE alone. Prophylaxis has
further been restricted to dental procedures, and
those involving the respiratory tract (nasal and oral
mucosa included) or infected tissue elsewhere. Conditions that warrant prophylaxis include prosthetic
valve, certain congenital cardiac anomalies, valve
disease in cardiac transplant patients, and a prior
history of IE.
Several studies have demonstrated that bacteremia rates for routine dermatologic surgery procedures involving properly cleansed and noninflamed
skin are near 3%. In comparison, tooth brushing
produces bacteremia rates between 24% and 40%.
Therefore, antibiotic use for prophylaxis against endocarditis is not indicated for routine surgical procedures on noninflamed and surgically prepared
skin. The data for procedures involving inflamed
skin, sites associated with a higher rate of bacteremia (such as mucosa, genitalia, and ear), and
prolonged procedures such as Mohs micrographic
surgery are less clear. Prophylaxis for high- and
moderate-risk patients in these situations varies by
institution and practitioner. Procedures that must
be performed on infected tissue probably warrant
antibiotic prophylaxis in the high- and moderaterisk group due to higher rates of bacteremia.
Data concerning the risk of infection of total joint
arthroplasty following dermatologic procedures
is sparse. Most infections of involving joint replacements occur in the immediate postoperative
period. Prophylaxis for low-risk patients whose
joint replacement is greater than 2 years old is not
recommended. Procedures in high-risk patients,
patients having joint prostheses less than 2 years
old, and procedures on patients with vascular grafts
or neurologic shunts present situations with no current recommendation guidelines.

Antibiotics 325

best classified between clean (class I) and cleancontaminated (class II) wounds. These wounds are
at low risk of infection, and prophylactic antibiotics
to prevent surgical site infection are not warranted.
This generally includes most Mohs micrographic
surgical procedures, which have reported infection rates of 2%-3%. However, the risk of infection
increases when Mohs procedures involve mucosal
sites, the ear, or involve delayed closures. In these
cases, prophylactic antibiotics may be warranted,
though dedicated studies to address this question
are lacking. There is much debate regarding the
use of antibiotic prophylaxis following medium to
deep facial laser resurfacing or chemical peels. Reported infection rates of these clean-contaminated
wounds are less than 10%. Furthermore, some
studies have demonstrated selection of pathogenic organisms and higher infection rates following prophylaxis in this setting. As such, antibiotic
prophylaxis for these procedures is probably not
warranted.
If the decision to administer antibiotic prophylaxis has been made, it is important to choose an
antibiotic that will achieve proper wound coagulum concentrations at the time of surgery and have
an adequate spectrum of activity against the most
common likely pathogens at that site. The AHA
recommends administration of antibiotic 3060
minutes prior to surgery to ensure proper concentrations in the wound coagulum. However, according to the latest AHA guidelines, the antibiotic can
be given up to 2 hours after the procedure if the
preoperative dose is not given. The most likely organisms to cause infection following dermatologic
procedures are staphylococcal and streptococcal
species. It is important to consider Gram-negative
organisms in sites near the waist, involving the ear,
or in diabetic patients. Viridans group Streptococci
and Peptostreptococci are the leading pathogens
following procedures involving the mouth. For
surgery involving glabrous skin, a cephalosporin
or dicloxacillin is used. Clindamycin or macrolides
are considerations for penicillin-allergic patients.
Amoxicillin is the agent of choice for oral mucosal
procedures.

While wound classification correlates well with


infection rate, most routine dermatologic procedures are difficult to categorize and are probably

Copyright McGraw-Hill Companies, Inc. All rights reserved.

326 Chapter 230: Antibiotics

Copyright McGraw-Hill Companies, Inc. All rights reserved.