Topic Resources
Antibacterial drugs are derived from bacteria or molds or are
synthesized de novo. Technically, “antibiotic” refers only to
antimicrobials derived from bacteria or molds but is often (including in
THE MANUAL) used synonymously with “antibacterial drug.”
Antibiotics have many mechanisms of action, including the following:
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Inhibiting cell wall synthesis
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Increasing cell membrane permeability
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Interfering with protein synthesis, nucleic acid metabolism, and other metabolic processes (eg, folic acid synthesis)
Antibiotics sometimes interact with other drugs, raising or
lowering serum levels of other drugs by increasing or decreasing their
metabolism or by various other mechanisms (see table Some Common Effects of Antibiotics on Other Drugs).
The most clinically important interactions involve drugs with a low
therapeutic ratio (ie, toxic levels are close to therapeutic levels).
Also, other drugs can increase or decrease levels of antibiotics.
Many antibiotics are chemically related and are thus grouped into
classes. Although drugs within each class share structural and
functional similarities, they often have different pharmacology and
spectra of activity.
Selection and Use of Antibiotics
Antibiotics should be used only if clinical or laboratory
evidence suggests bacterial infection. Use for viral illness or
undifferentiated fever is inappropriate in most cases; it exposes
patients to drug complications without any benefit and contributes to
bacterial resistance.
Certain bacterial infections (eg, abscesses, infections with
foreign bodies) require surgical intervention and do not respond to
antibiotics alone.
In general, clinicians should try to use antibiotics with the narrowest spectrum of activity and for the shortest duration.
Spectrum of activity
Cultures and antibiotic sensitivity testing are essential for
selecting a drug for serious infections. However, treatment must often
begin before culture results are available, necessitating selection
according to the most likely pathogens (empiric antibiotic selection).
Whether chosen according to culture results or not, drugs with
the narrowest spectrum of activity that can control the infection should
be used. For empiric treatment of serious infections that may involve
any one of several pathogens (eg, fever in neutropenic patients) or that
may be due to multiple pathogens (eg, polymicrobial anaerobic
infection), a broad spectrum of activity is desirable. The most likely
pathogens and their susceptibility to antibiotics vary according to
geographic location (within cities or even within a hospital) and can
change from month to month. Susceptibility data should be compiled into
antibiograms and used to direct empiric treatment whenever possible.
Antibiograms summarize regional facility–specific (or location–specific)
antibiotic susceptibility patterns of common pathogens to commonly used
antibiotics.
For serious infections, combinations of antibiotics are often
necessary because multiple species of bacteria may be present or because
combinations act synergistically against a single species of bacteria.
Synergism is usually defined as a more rapid and complete bactericidal
action from a combination of antibiotics than occurs with either
antibiotic alone. A common example is a cell wall–active antibiotic (eg,
a beta-lactam, vancomycin) plus an aminoglycoside.
Effectiveness
In vivo antibiotic effectiveness is affected by many factors, including
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Pharmacokinetics: The time course of antibiotic levels, which are affected by factors such as absorption, distribution (concentration in fluids and tissues, protein binding), rate of metabolism, and excretion
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Pharmacodynamics: The antimicrobial activity of local antibiotic concentrations on the target pathogen and that pathogen's response including resistance
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Presence of foreign materials
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Control of source of infection
Bactericidal drugs kill bacteria. Bacteriostatic drugs slow or
stop in vitro bacterial growth. These definitions are not absolute;
bacteriostatic drugs may kill some susceptible bacterial species, and
bactericidal drugs may only inhibit growth of some susceptible bacterial
species. More precise quantitative methods identify the minimum in
vitro concentration at which an antibiotic can inhibit growth (minimum
inhibitory concentration [MIC]) or kill (minimum bactericidal
concentration [MBC]). An antibiotic with bactericidal activity may
improve bacterial killing when host defenses are impaired locally at the
site of infection (eg, in meningitis or endocarditis) or systemically
(eg, in patients who are neutropenic or immunocompromised in other
ways). However, there are limited clinical data indicating that a
bactericidal drug should be selected over a bacteriostatic drug simply
on the basis of that classification. Drug selection for optimal efficacy
should be based on how the drug concentration varies over time in
relation to the MIC rather than whether the drug has bactericidal or
bacteriostatic activity.
Antibiotics can be grouped into 3 general categories (1) based on the pharmacokinetics that optimizes antimicrobial activity (pharmacodynamics):
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Concentration-dependent: The magnitude by which the peak concentration exceeds the MIC (typically expressed as the peak-to-MIC ratio) best correlates with antimicrobial activity
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Time-dependent: The duration of the dosing interval in which the antibiotic concentration exceeds the MIC (typically expressed as the percentage of time above MIC) best correlates with antimicrobial activity
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Exposure-dependent: The amount of drug given relative to the MIC (the amount of drug is the 24-hour area under the concentration-time curve [AUC24]; the AUC24-to-MIC ratio best correlates with antimicrobial activity)
Aminoglycosides, fluoroquinolones, and daptomycin
exhibit concentration-dependent bactericidal activity. Increasing their
concentrations from levels slightly above the MIC to levels far above
the MIC increases the rate and extent of their bactericidal activity. In
addition, if concentrations exceed the MIC even briefly,
aminoglycosides and fluoroquinolones have a post-antibiotic effect (PAE)
on residual bacteria; duration of PAE is also concentration-dependent.
If PAEs are long, drug levels can be below the MIC for extended periods
without loss of efficacy, allowing less frequent dosing. Consequently,
aminoglycosides and fluoroquinolones are usually most effective as
intermittent boluses that reach peak free serum levels ≥ 10 times the MIC of the bacteria; usually, trough levels are not important.
Beta-lactams, clarithromycin, and erythromycin
exhibit time-dependent bactericidal activity. Increasing their
concentration above the MIC does not increase their bactericidal
activity, and their in vivo killing is generally slow. In addition,
because there is no or very brief residual inhibition of bacterial
growth after concentrations fall below the MIC (ie, minimal
post-antibiotic effect), beta-lactams are most often effective when
serum levels of free drug (drug not bound to serum protein) exceed the
MIC for ≥ 50% of the time. Because ceftriaxone
has a long serum half-life (about 8 hours), free serum levels exceed
the MIC of very susceptible pathogens for the entire 24-hour dosing
interval. However, for beta-lactams that have serum half-lives of ≤ 2 hours, frequent dosing or continuous infusion is required to optimize the time above the MIC.
Most antimicrobials have exposure-dependent antibacterial activity best characterized by the AUC-to-MIC ratio. Vancomycin, tetracyclines, and clindamycin are examples.
Time vs concentration of a single dose of a theoretical antibiotic
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There are 3 pharmacokinetic/pharmacodynamic parameters related to antimicrobial efficacy:
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Effectiveness reference
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1. A PK/PD Approach to Antibiotic Therapy. RxKinetics. Accessed 3/26/20.
Route
For many antibiotics, oral administration results in therapeutic
blood levels nearly as rapidly as IV administration. However, IV
administration of orally available drugs is preferred in the following
circumstances:
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Oral antibiotics cannot be tolerated (eg, because of vomiting).
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Oral antibiotics are poorly absorbed (eg, because of malabsorption after intestinal surgery, impaired intestinal motility [eg, due to opioid use]).
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Patients are critically ill, possibly impairing gastrointestinal tract perfusion or making even the brief delay with oral administration detrimental.
Special populations
Doses and scheduling of antibiotics may need to be adjusted for the following:
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Patients with hepatic insufficiency (most commonly for cefoperazone, chloramphenicol, metronidazole, rifabutin, and rifampin)
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Obese patients
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Patients with cystic fibrosis
Pregnancy and breastfeeding affect choice of antibiotic. Penicillins, cephalosporins, and erythromycin
are among the safest antibiotics during pregnancy; tetracyclines are
contraindicated. Most antibiotics reach sufficient concentrations in
breast milk to affect a breastfed baby, sometimes contraindicating their
use in women who are breastfeeding.
Duration
Antibiotics should be continued until objective evidence of
systemic infection (eg, fever, symptoms, abnormal laboratory findings)
is absent for several days. For some infections (eg, endocarditis, tuberculosis, osteomyelitis, leprosy), antibiotics are continued for weeks or months to prevent relapse.
Complications
Complications of antibiotic therapy include superinfection by
nonsusceptible bacteria or fungi and cutaneous, renal, hematologic,
neurologic, and gastrointestinal adverse effects.
Adverse effects frequently require stopping the causative drug
and substituting another antibiotic to which the bacteria are
susceptible; sometimes, no alternatives exist.
Overview of Mechanisms of Antimicrobial Resistance
VIDEO
Antibiotic Resistance
Resistance to an antibiotic may be inherent in a particular
bacterial species or may be acquired through mutations or acquisition of
genes for antibiotic resistance that are obtained from another
organism. Different mechanisms for resistance are encoded by these genes
(see table Common Mechanisms of Antibiotic Resistance). Resistance genes can be transmitted between 2 bacterial cells by the following mechanisms:
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Transformation (uptake of naked DNA from another organism)
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Transduction (infection by a bacteriophage)
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Conjugation (exchange of genetic material in the form of either plasmids, which are pieces of independently replicating extrachromosomal DNA, or transposons, which are movable pieces of chromosomal DNA)
Plasmids and transposons can rapidly disseminate resistance genes.
Antibiotic use preferentially eliminates nonresistant bacteria,
increasing the proportion of resistant bacteria that remain. Antibiotic
use has this effect not only on pathogenic bacteria but also on normal
flora; resistant normal flora can become a reservoir for resistance
genes that can spread to pathogens.
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