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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 163: Pharmacology of Antimicrobials Ralph H. Raasch

ANTIBACTERIAL DRUGS

E�ective antibacterial drugs can either inhibit the growth of (bacteriostatic) or kill (bactericidal) bacteria. Antibacterial e�ects result from theinhibition of cell wall synthesis, inhibition of intrabacterial protein synthesis, alteration in nucleic acid metabolism, or intrabacterial enzymeinhibition (Table 163-1). The drug mechanism of action does not necessarily correlate with bacteriostatic or bactericidal e�ects, because the latter area�ected also by the concentration of antibiotic to which bacteria are exposed. Drugs of choice for most infections are not based on a bacteriostatic orbactericidal e�ect of an agent, but rather are chosen based on whether the drug reaches the site of infection in adequate quantities, the spectrum ofthe agent, its safety, and cost.

TABLE 163-1

Mechanisms of Action of Antibacterial Drugs

Cell wall active agents Nucleic acid inhibitors

Penicillins Fluoroquinolones

Vancomycin Rifampin

Cephalosporins Nitrofurantoin

Teicoplanin Enzyme inhibitors

Telavancin Fosfomycin

Daptomycin Sulfonamides

Colistin Trimethoprim

Polymyxin B

Protein synthesis inhibitors

Aminoglycosides

Macrolides

Linezolid

Tetracyclines (including tigecycline)

Clindamycin

Quinupristin/dalfopristin

MECHANISMS OF ACTION

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CELL WALL ACTIVE AGENTS

β-Lactam (penicillins, cephalosporins) and glycopeptide antibiotics (vancomycin, telavancin, teicoplanin) bind to receptors in the bacterial cell wall.The target receptors for penicillins and cephalosporins are called penicillin-binding proteins. Autolytic enzymes within the cell wall bind to penicillin-binding proteins; once activated, the enzymes damage the peptidoglycan component of the cell wall, creating weakening and eventual cell lysis.Glycopeptide antibiotics bind to a terminal dipeptide (alanine-alanine) in the cell wall peptidoglycan and prevent the necessary cross-linking for acompetent cell wall structure. At usual doses, β-lactam and glycopeptide antibiotics are bactericidal. Resistance arises due to mutations in thepenicillin-binding proteins, leading to reduced β-lactam binding (e.g., by oxacillin-resistant Staphylococcus aureus or penicillin-resistantStreptococcus pneumoniae) or changes to the terminal dipeptide (e.g., by vancomycin-resistant Enterococcus faecium) that reduce the level ofbinding. Daptomycin inserts a lipophilic part of the molecule into the cell wall of gram-positive bacteria, depolarizing the cell wall, which causes theleakage of intracellular content and a bactericidal e�ect.

The emergence of multidrug-resistant organisms (most commonly in species of Pseudomonas, Acinetobacter, and Klebsiella) has led to the reneweduse of older, but more toxic drugs such as colistin and polymyxin B. These agents interact with the lipids within the cell wall, increasing cell wallpermeability, which leads to a bactericidal e�ect because of the leakage of intracellular contents.

PROTEIN SYNTHESIS INHIBITORS

Several classes of antibacterial drugs bind to ribosomes within bacteria, blocking necessary protein synthesis. Aminoglycosides and tetracyclines(including tigecycline) bind to the 30S ribosomal subunit, whereas macrolide antibiotics and clindamycin bind to the 50S subunit. Ribosomal bindinginhibits transfer RNA function, decreasing the amount of protein synthesis. Ribosomal-binding drugs enter through the cell wall and bind in adequateconcentrations to reversibly inhibit protein synthesis. Resistance mechanisms arise with reduced cell wall permeability, an active e�lux pump thatremoves the antibiotic from the cell, or ribosomal-binding site mutations that decrease antibiotic a�inity.

NUCLEIC ACID INHIBITORS

Fluoroquinolone antibiotics inhibit DNA gyrase, the enzyme responsible for DNA unwinding for transcription and recoiling during bacterialreplication. Fluoroquinolones must reach the nucleus of the bacterial cell to provoke these e�ects; resistance can arise when cell wall permeability isreduced, active e�lux occurs, or a DNA gyrase mutation has arisen that reduces fluoroquinolone binding. Rifampin is a broad-spectrum antimicrobialagent active against many gram-positive and gram-negative bacteria and mycobacteria. Rifampin (or rifampicin) inhibits RNA synthesis by binding toDNA-dependent RNA polymerase, thereby blocking the initiation of RNA chain formation. Nitrofurantoin is modified by bacterial metabolism to acompound that damages DNA. Susceptible bacteria rarely become resistant to nitrofurantoin.

ENZYME INHIBITORS

Sulfonamides and trimethoprim block sequential steps in the formation of folic acid. Sulfonamides inhibit dihydropteroate synthase, the enzyme thatconverts p-aminobenzoic acid to dihydrofolic acid; trimethoprim inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic totetrahydrofolic acid. Together, this paired action is an e�ective bactericidal process and not far removed from the intracellular actions ofmethotrexate. Fosfomycin inactivates enolpyruvate transferase, inhibiting cell wall synthesis; it is gaining resurgent popularity for single-dosetreatment (3 grams orally) of uncomplicated urinary tract infections given the activity against the common pathogens involved. Resistance to these

drugs arises by enzyme mutations that reduce the a�inity of sulfonamide, trimethoprim, or fosfomycin to their respective enzyme targets.1 Theseantibacterial drug mechanisms of action are summarized in Figure 163-1. Table 163-2 summarizes the classification, names, and routes of the most

common antibiotics within each antibiotic class.1

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TABLE 163-2

Classification of Antibacterial Drugs with Common Trade Names

Penicillins

Natural

PenicillinsAminopenicillins

Penicillinase-

Resistant

Penicillins

Antipseudomonal

Penicillins

β-Lactam/β-Lactamase

Inhibitor Combination

Monobactams

and

Carbapenems

Aminoglycosides Fluoroquinolones

Penicillin G

IV, PO

Ampicillin IV, PO Oxacillin

(Bactocill®)

IV, PO

Piperacillin IV Amoxicillin-clavulanic

acid (Augmentin®) PO

Aztreonam

(Azactam®) IV

Amikacin IV Moxifloxacin

(Avelox®) IV, PO

Penicillin V

PO

Amoxicillin

(Amoxcil®) PO

Dicloxacillin

PO

Ticarcillin-clavulanic

acid (Timentin®) IV

Ertapenem

(Invanz®) IV

Gentamicin IV Ciprofloxacin

(Cipro®) IV, PO

Nafcillin

(Nallpen®) IV,

PO

Ampicillin-sulbactam

(Unasyn®) IV

Meropenem

(Merrem®) IV

Neomycin (Neo-

Fradin®) PO

Levofloxacin

(Levaquin®) IV,

PO

Piperacillin-tazobactam

(Zosyn®) IV

Imipenem

(Primaxin®) IV

Streptomycin IM,

IV

Gemifloxacin

(Factive®) PO

Doripenem

(Doribax®) IV

Tobramycin IV

Cephalosporins

First

Generation

Second

Generation

Third

Generation

Fourth/Fi�h

Generation

Macrolides/Tetracyclines Enzyme

Inhibitors

Miscellaneous

Cefazolin

(Ancef ®) IV

Cefaclor PO

Cefotetan IV

Ce�ibuten

(Cedax®) PO

Cefepime

(Maxipime®) IV

Erythromycin

(Erythrocin®) IV, PO

Trimethoprim-

sulfamethoxazole

(Bactrim®,

Septra®) IV, PO

Clindamycin (Cleocin®) IV, PO

Cefadroxil

PO

Cefuroxime

axetil (Ce�in®)

PO

Cefotaxime

(Claforan®) IV

Ce�aroline

(Teflaro®) IV

Azithromycin

(Zithromax®) IV, PO

Trimethoprim PO Metronidazole (Flagyl®) IV, PO

Cephalexin

(Keflex®)

PO

Cefprozil PO

Cefoxitin

(Mefoxin®) IV

Ce�azidime

(Fortaz®,

Ceptaz®,

Tazicef ®) IV

Clarithromycin (Biaxin®)

PO

Fosfomycin

(Monurol®) PO

Nitrofurantoin (Macrodantin®,

Macrobid®) PO

Cefuroxime

(Zinacef ®) IV

Ce�riaxone

(Rocephin®)

IV

Tetracycline PO Quinupristin/dalfopristin (Synercid®)

IV

Cefpodoxime

PO

Minocycline (Minocin®)

PO

Vancomycin (Vancocin®) IV, PO

Cefdinir PO Doxycycline

(Vibramycin®) IV, PO

Linezolid (Zyvox®) IV, PO

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Penicillins

Natural

PenicillinsAminopenicillins

Penicillinase-

Resistant

Penicillins

Antipseudomonal

Penicillins

β-Lactam/β-Lactamase

Inhibitor Combination

Monobactams

and

Carbapenems

Aminoglycosides Fluoroquinolones

Cefixime

(Suprax®) PO

Tigecycline (Tygacil®) IV Daptomycin (Cubicin®) IV

FIGURE 163-1.

Mechanisms of action of antibacterial drugs. The peptidoglycan layer in the bacterial cell wall is a crystal lattice structure formed from linear chains oftwo alternating amino sugars, namely N-acetylglucosamine (GlcNAc or NAG) and N-acetylmuramic acid (MurNAc or NAM). Penicillins, cephalosporins,and vancomycin are cell wall active agents, preventing the necessary cross-linking within the peptidoglycan layer, rendering it incompetent. Otherlisted antibiotics exert their actions on cellular mechanisms within the bacteria as shown. AA = amino acids; DHO = dihydropteroate; FH2 =

dihydrofolate, FH4 = tetrahydrofolate; (G2) = glucose; K+ = potassium; PA = peptide donor-acceptor site; PABA = p-aminobenzoic acid; + = enhance; – =

inhibit.

INDICATIONS IN THE ED AND DRUGS OF CHOICE

Drugs of choice for specific infections are based on clinical e�ectiveness and adverse events. Successful e�ectiveness is based on the knowledge ofthe likely bacterial pathogen responsible for a specific infection type and the usual antimicrobial spectrum of antibiotics. Alternate drugs of choiceare selected in cases of resistance to an initial drug, a history of intolerance or allergy to the drug of choice, or because of a higher risk of adverse

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events. Taking into account those infections most likely to be present in ED patients and the most likely pathogens involved in these infections, Table

163-3 summarizes drugs of choice for common infections.2

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TABLE 163-3

Antibiotics of Choice for Treatment of Common Adult Infections in the ED

Site/Type of Infection Suspected Organisms Drug of Choice Alternative

Respiratory

Pharyngitis Group A streptococci Penicillin V Macrolide

Bronchitis,* otitis,*

acute sinusitis*

Streptococcus pneumoniae

Haemophilus influenzae

Amoxicillin, amox/clav,

or cefuroxime

Macrolide or doxycycline

Epiglottitis H. influenzae, Group A streptococci Ce�riaxone Cefuroxime

Community-acquired

pneumonia

Normal host S. pneumoniae, viral, Mycoplasma Azithromycin or

doxycycline

Levofloxacin

Aspiration Aerobes and anaerobes Clindamycin Pip/TZ, ce�riaxone plus metronidazole

Alcoholic S. pneumoniae, Klebsiella Ce�riaxone Levofloxacin

Urinary tract infection Escherichia coli and other enteric

gram-negative rodsTMP/SMX† Ciprofloxacin, cephalexin, nitrofurantoin, or fosfomycin

(latter single dose 3 grams PO)

Sexually transmitted

infections

Urethritis Neisseria gonorrhea, Chlamydia Ce�riaxone,

azithromycin

Cefixime, doxycycline

Genital ulcers Treponema pallidum, herpes

simplex virus

Penicillin G

Acyclovir

Doxycycline

Valacyclovir

Skin/so� tissue

Cellulitis Group A streptococci,

Staphylococcus aureusCephalexin† Dicloxacillin, clindamycin, TMP/SMX, or vancomycin

Necrotizing fasciitis Polymicrobial Imipenem or

meropenem

Plus vancomycin

—

Fresh/brackish water

infections

Mixed flora, Aeromonas TMP/SMX Fluoroquinolone

Cat bite Pasteurella, mixed flora Amox/clav Clindamycin and ciprofloxacin

Meningitis

Normal host S. pneumoniae, Neisseria

meningitidis, S. aureus

Ce�riaxone and

vancomycin

—

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Abbreviations: amox/clav = amoxicillin/clavulanate; Pip/TZ = piperacillin/tazobactam; TMP-SMX = trimethoprim-sulfamethoxazole.

*Note: Many authorities question the need for antibiotics for uncomplicated presentations of these diseases; see appropriate chapters in this text to determine

indications for treatment.

†Resistance to the listed antibiotic is a significant clinical issue; see chapter 152, "So� Tissue Infections" for a discussion of alternatives for treatment in the event of

known resistance in your community.

Site/Type of Infection Suspected Organisms Drug of Choice Alternative

Immunocompromised

or >50 y old

Listeria, H. influenzae Add ampicillin —

Acute abdomen

(perforation)

Gram-negative rods, anaerobes,

enterococci

Ampicillin/sulbactam or

Pip/TZ

Cefoxitin or cefotetan or imipenem

ANTIBIOTIC DOSAGE AND DOSAGE ADJUSTMENTS

Adequate drug dosage takes into account achievable serum and tissue levels plus the concentrations necessary (determined in the laboratory) toinhibit the growth of susceptible bacteria. Standard dosing guidelines usually result in successful treatment when a susceptible organism is presentand barriers to drug penetration (i.e., abscess) are absent. If antibiotic penetration issues exist, such as in suspected meningitis, endocarditis, orosteomyelitis, give the highest doses recommended to improve e�ect.

Dosage adjustments of many antibiotics are necessary for patients with renal disease to prevent adverse events from drug accumulation, mostnotably when using IV administration. Oral doses are typically lower, so toxic drug accumulation is less likely in those with renal dysfunction. Dosagemodifications in liver disease are less clear because of limited ways to accurately assess decreases in drug elimination characteristics or rate.Fosfomycin in single-dose use for urinary tract infection requires no adjustment. Guidelines for dosing adjustment, primarily with IV therapy, are

summarized in Table 163-4.3

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TABLE 163-4

IV Dosage Guidelines for Selected Antibacterial Drugs in Adults

DrugMajor Route of

Elimination

Maximum Daily IV

Dose (grams)Dose Adjustment for Creatinine Clearance (mL/min)

>50 10–50 <10

Ampicillin Renal 12 1–2 grams every 4–8 h 1 gram every 6 h 1 gram every 12 h

Ampicillin/sulbactam Renal 12 1.5–3 grams every 6 h 1.5–3 grams every

12 h

1.5–3 grams

every 24 h

Aztreonam Renal 8 1–2 grams every 6–8 h 1–2 grams every

12 h

1 gram every 12 h

Cefazolin Renal 8 1–2 grams every 8 h 1 gram every 12 h 1 gram every 24 h

Cefotaxime Renal 12 1–2 grams every 4–8 h 1–2 grams every

12 h

1 gram every 12 h

Ce�azidime Renal 6 1–2 grams every 8 h 1–2 grams every

24 h

0.5 gram every 24

h

Ce�riaxone Biliary 4 1–2 grams every 12–24 h No adjustments No adjustments

Cefepime Renal 4 1–2 grams every 12 h 1–2 grams every

24 h

0.5–1 gram every

24 h

Ciprofloxacin Renal 1.2 0.4 gram every 8–12 h 0.4 gram every 12

h

0.4 gram every 24

h

Levofloxacin Renal 0.75 0.25–0.75 gram every 24 h 0.25–0.75 gram

every 48 h

0.25–0.5 gram

every 48 h

Clindamycin Biliary 4.8 0.6–0.9 gram every 6–8 h

In hepatic failure, limit dose to 0.6

gram every 8 h

No adjustments No adjustments

Imipenem Renal 2 0.5 gram every 6–8 h 0.5 gram every 12

h

0.5 gram every 24

h

Meropenem Renal 3 0.5–1 gram every 8 h 0.5 gram every 12

h

0.5 gram every 24

h

Metronidazole Biliary 2 0.5 gram every 6–8 h

In hepatic failure, limit dose to 0.5

gram every 12 h

No adjustments No adjustments

Nafcillin, oxacillin Biliary 12 1–2 grams every 4–6 h No adjustments No adjustments

Penicillin G Renal 24 MU 3–4 MU every 4 h 2 MU every 6 h 1 MU every 6 h

Piperacillin/tazobactam Renal 18 3.375 grams every 6 h 2.25 grams every

6 h

2.25 grams every

8 h

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Abbreviation: MU = million units.

DrugMajor Route of

Elimination

Maximum Daily IV

Dose (grams)Dose Adjustment for Creatinine Clearance (mL/min)

>50 10–50 <10

Tobramycin,

gentamicin

Renal 7 milligrams/kg per

dose

Every 24 h Every 36–48 h Do not use

Vancomycin Renal 15 milligrams/kg per

dose

Every 12–24 h Every 24–48 h Use levels

ADVERSE EFFECTS AND CONTRAINDICATIONS OF ANTIBACTERIAL DRUGS

Allergic reactions and direct pharmacologic-based toxicity are the two general categories of adverse drug reactions to antibiotics.

Allergic reactions are not dose related, are unpredictable, and cannot be studied e�ectively in animal models. Allergic reactions vary from mild skinrashes to life-threatening events, such as toxic epidermal necrolysis or anaphylactic reactions. Drug fever, hepatitis, and interstitial nephritis are alsoexamples of allergic drug reactions.

Direct dose-related toxicity is the result of the pharmacologic properties of the drug. These reactions are possible in any recipient if the dose oraccumulated drug in the body is high. Dose-related adverse events typically are reversible once the antibiotic is discontinued. There is somepredictability to these reactions, such as renal dysfunction caused by an aminoglycoside; these drugs are ideal candidates for appropriate doseadjustments of antibiotics (Table 163-4).

Certain adverse e�ects of antibiotics, such as pseudomembranous colitis, do not fall into either category; all antibiotics can cause this side e�ect. The

common allergic and dose-related adverse e�ects of antibacterial drugs are summarized in Table 163-5.3

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*U.S. Food and Drug Administration Safety-in-Pregnancy Code: A: controlled human studies show no risk. B: no evidence of risk in humans; the chance of fetal harm is

remote but remains a possibility. C: risk cannot be ruled out; well-controlled human studies are lacking, and animal studies have shown risk or are lacking; there is a

chance of fetal harm if administered during pregnancy. D: positive evidence of risk; studies in humans have demonstrated fetal risk. X: contraindicated in pregnancy;

the risk of fetal abnormalities outweighs the potential benefit of the drug.

†LactMed is an NLM database providing information on drugs and lactation http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT

TABLE 163-5

Antibacterial Adverse E�ects

Antibiotic ClassPregnancy

Category*,†Allergic Reactions Dose-Related E�ects

β-Lactams

(penicillins,

cephalosporins,

monobactams,

carbapenems)

B Anaphylaxis, urticaria, rash, fever, serum

sickness; hepatitis, nephritis, anemia,

thrombocytopenia

Cross-reactivity between penicillins and

cephalosporins is <5%; little cross-

reactivity between cephalosporin and

aztreonam or imipenem

Diarrhea (amoxicillin/clavulanate), biliary sludging (ce�riaxone);

phlebitis; seizures (imipenem, penicillin G); antiplatelet e�ects and

hemolytic anemia; decreased vitamin K synthesis and disulfiram

reaction (cefotetan); nausea, hypotension (rapid infusion of imipenem)

Aminoglycosides C Rare Nephrotoxicity: incidence 10%–15%, usually reversible

Ototoxicity: incidence 1%–5%, causes deafness and/or dizziness; toxicity

is both dose and duration-related

Macrolides B/C Cholestatic jaundice: associated with IV

erythromycin

GI toxicity: nausea, vomiting, diarrhea, cramping—mostly with

erythromycin

Clindamycin B Rash Diarrhea—most common adverse e�ect; pseudomembranous colitis

Tetracyclines,

including

tigecycline

D Rash (including photosensitivity),

anaphylaxis, urticaria, fever, hepatitis

Nausea, vomiting, diarrhea; increase in blood urea nitrogen; deposits in

and discolors teeth and bone (avoid in pediatrics); dizziness and vertigo

(minocycline)

Vancomycin C Rash (rare) Infusion-related reactions: phlebitis, "red-person syndrome" from rapid

infusions—give 1 gram over 60 min; oto- and nephrotoxicity with high

doses, or in combination with other oto or nephrotoxins

Fluoroquinolones C Rare Nausea, vomiting, diarrhea; confusion, headache, seizures; tendonitis

and tendon rupture; prolonged QT interval

Sulfonamides X Rash, Stevens-Johnson syndrome,

exfoliative dermatitis (more common in

acquired immunodeficiency syndrome);

cholestatic hepatitis; bone marrow

suppression

Nausea, vomiting, diarrhea; crystalluria (doses taken with insu�icient

fluids); hyperkalemia (with trimethoprim); kernicterus (in neonates)

CONTRAINDICATIONS AND DRUG INTERACTIONS

DRUG ALLERGY

In general, previous allergy is a contraindication for use. This circumstance is most pertinent for patients with a penicillin or cephalosporin allergy;between 1% and 10% of patients report a penicillin allergy. Some agents exhibit cross-reactivity; those with penicillin or amoxicillin allergy have ahigher risk of the same with oral first-generation cephalosporins, likely due to similarities in antibiotic side chain structure, with about a 10% cross-

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Abbreviation: CNS = central nervous system.

reactivity occurrence. However, true allergies, as documented by antibiotic skin tests, are less common than o�en stated, so obtaining a cleardescription is important before choosing alternate therapy. For example, a patient with a history of respiratory distress, wheezing, angioedema, orhives (an immediate-type hypersensitivity) during a previous course of β-lactam treatment may be at higher risk for a life-threatening reaction uponre-exposure to another β-lactam, particularly if the patient reacts to skin tests with the other β-lactam. Unfortunately, with the exception of penicillin,these antibiotic skin tests are not commercially available and not used in clinical practice. So in this case, it would be wise to avoid a penicillin or first-generation cephalosporin, although a carbapenem or third-generation cephalosporin would have little cross-reactivity. On the other hand, if thepatient history is a mild maculopapular rash while taking amoxicillin or other penicillin (a delayed-type hypersensitivity reaction), treatment laterwith a cephalosporin would not likely provoke an allergic event. Similarly, a fainting spell with injection may not represent a drug allergy at all,although it clearly was an adverse event for that treatment interval. Note that sulfa moieties are contained in many other drugs, such as furosemide,thiazides, sulfonylureas (glyburide), and celecoxib. Despite package labeling that suggests cross-sensitivity in a patient who is allergic tosulfonamides is a risk, the frequency of any allergic reaction upon exposure to one of the nonantibiotic sulfas is not common. A patient allergic to

sulfonamides is at a higher risk to develop another allergic reaction to another drug, including penicillins.4 Several of the human immunodeficiencyvirus protease inhibitor agents also contain a sulfa moiety (amprenavir, fosamprenavir, tipranavir, darunavir), but the risk of cross-reactivity in a

sulfonamide-allergic patient is not well known.4

DRUG INTERACTIONS

Drug interactions with antibacterial drugs derive from two mechanisms. The first mechanism is an inhibition of absorption of oral antibiotics. Thebest example of this interaction occurs when any of the tetracycline or fluoroquinolone antibiotics are given at the same time as divalent cations

(Ca2+, Mg2+, Fe2+). This reduces absorption, so these agents must not be given orally with calcium or iron preparations or with antacids.

Second, certain antibiotics can slow the metabolism of other drugs by inhibiting several of the hepatic cytochrome P450 enzymes in the liver. Inparticular, ciprofloxacin, clarithromycin, and trimethoprim-sulfamethoxazole are drugs that are able to provoke this enzyme inhibition. Summaries of

these antibiotic contraindications and drug interactions are included in Tables 163-6 and 163-7.3

TABLE 163-6

Antibiotic Contraindications

Antibiotic Class Contraindications

Aminoglycosides Prior allergic or toxic reactions to aminoglycosides

Cephalosporins Sensitivity to cephalosporins, imipenem (carbapenems), penicillins

Clindamycin Sensitivity to clindamycin; meningitis (inadequate CNS penetration)

Fluoroquinolones Sensitivity to fluoroquinolones; tendonitis or tendon rupture; use of QT interval–prolonging drugs (amiodarone, procainamide);

myasthenia gravis

Macrolides Sensitivity to macrolides; meningitis (inadequate CNS penetration)

Metronidazole Sensitivity to metronidazole; first trimester of pregnancy

Penicillins Sensitivity to penicillins, cephalosporins, imipenem (carbapenems)

Sulfonamides Sensitivity to sulfonamides, pregnancy at term, lactation

Tetracyclines Sensitivity to tetracyclines

Vancomycin Sensitivity to vancomycin

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TABLE 163-7

Antibacterial Drug Interactions

Antibiotic Class Drug Interactions

Aminoglycosides Neuromuscular blockers—may prolong respiratory depression; loop diuretics—may increase auditory toxicity

Cephalosporins Antacids—may reduce the oral absorption of cefaclor, cefdinir, and cefpodoxime

Warfarin—cefotetan enhances the anticoagulant e�ect of warfarin

Fluoroquinolones Antacids, iron salts, sucralfate—absorption of the fluoroquinolone is reduced by chelation

Theophylline—metabolism is slowed by ciprofloxacin, may cause theophylline toxicity; warfarin elimination is slowed by

fluoroquinolones—follow clotting times carefully

Macrolides Clarithromycin can increase levels of warfarin, cyclosporine, lovastatin, theophylline—monitor additive e�ects carefully

Penicillins Allopurinol—increased rash with ampicillin

Aminoglycosides—when administered IV simultaneously, inactivation occurs

Probenecid—reduced renal elimination of penicillin

Tetracyclines Antacids, iron salts—bind to tetracycline and reduce oral absorption (occurs least with doxycycline)

Oral contraceptives—failure

Trimethoprim-

sulfamethoxazole

Warfarin—can prolong clotting times; phenytoin—increase in serum levels and possible toxicity

Vancomycin Aminoglycosides—may increase risk of nephrotoxicity

ANTIFUNGAL DRUGS

The mechanism of action of antifungal agents is primarily based on actions that decrease cell wall integrity. Amphotericin B and its lipid-basedderivatives bind to cell wall ergosterol, increasing cell wall permeability that eventually results in cell lysis. Triazole antifungals (e.g., fluconazole,itraconazole) block ergosterol synthesis by inhibition of a fungal cytochrome P450–dependent enzyme. Echinocandin antifungals (caspofungin,micafungin, and anidulafungin) are other enzyme inhibitors; in this case, the inhibition is of β-glucan synthetase. β-Glucan, like ergosterol, is anothernecessary component of the cell wall of several fungal species. Flucytosine is an antimetabolite that disrupts DNA function a�er conversionintracellularly to 5-fluorouracil. These mechanisms of action of antifungal agents are illustrated in Figure 163-2. These agents for systemic fungalinfections are summarized in Table 163-8. Multiple topical antifungal preparations are available, as summarized in Table 163-9, and are indicated for

Candida or tinea infections.1,3

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TABLE 163-8

Antifungal Agents for Systemic Infections

Drug Spectrum Usual Doses

Amphotericin B, IV

Conventional

(Fungizone®)

Lipid complex

(Abelcet®)

Liposomal

(AmBisome®)

Colloidal

dispersion

(Amphotec®)

Aspergillus, Candida, Cryptococcus, histoplasmosis,

mucormycosis

0.5–1.0 milligram/kg/d

5.0 milligrams/kg/d

5.0 milligrams/kg/d

5.0 milligrams/kg/d

Triazoles

Fluconazole

(Diflucan®) IV, PO

Itraconazole

(Sporanox®) IV, PO

Posaconazole

(Noxafil®) PO

Voriconazole

(Vfend®) IV, PO

Candida, Cryptococcus, Aspergillus (not fluconazole),

histoplasmosis, mucormycosis (posaconazole)

400–800 milligrams per day

200 milligrams twice daily

200 milligrams three times daily with food

6 milligrams/kg IV every 12 h for 2 doses, then 4 milligrams/kg IV

every 12 h; 200 milligrams PO every 12 h

Echinocandins

Anidulafungin

(Eraxis®) IV

Caspofungin

(Cancidas®) IV

Micafungin

(Mycamine®) IV

Aspergillus, Candida (not Cryptococcus) 200 milligrams × 1, then 100 milligrams every day

70 milligrams × 1, then 50 milligrams every day

100 milligrams every day

Antimetabolite

Flucytosine

(Ancobon®), PO

Candida, Cryptococcus (should not be used as monotherapy) 25.0–37.5 milligrams/kg every 6 h

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TABLE 163-9

Selected Topical Antifungal Agents

Class and Products Dosage Forms Comments

Allylamines/benzylamines

Butenafine (Mentax®, Lotrimin®

ultraTM)

Na�ifine (Na�in®)

Terbinafine (Lamisil AT®)

1% cream, gel, solution, spray Treatment for 1–4 wk for tinea

Imidazoles

Clotrimazole (Lotrimin AF®,

Mycelex 7®)

1% cream, lotion, 100- and 200-milligram vaginal

suppositories

Topical (Candida, tinea) apply twice daily

Vaginal suppository, 100 milligrams × 7 d or 500 milligrams at

bedtime × 1

Miconazole (Micatin®, Monistat®) 2% cream, ointment, vaginal suppository As above, except 200-milligram vaginal suppository × 3 d, or 500

milligrams once

Tioconazole (Vagistat-1®) 6.5% vaginal ointment Application at bedtime × 1

Miscellaneous (for tinea only)

Tolna�ate (Tinactin®, Ting®) 1% cream, solution, gel, powder, spray Apply twice daily for 2–6 wk

Less e�ective than imidazoles

FIGURE 163-2.

Mechanisms of action of antifungal agents.

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Abbreviations: HSV = herpes simplex virus; VZV = varicella-zoster virus.

Of the various lipid-based amphotericin B preparations, liposomal amphotericin B (AmBisome®) is preferred because of a lower rate of infusion-related reactions and a lower frequency of renal dysfunction compared with the other lipid products. Because amphotericin B has the broadestantifungal spectrum of all these systemic agents, it is the preferred drug for empiric therapy until further diagnostics determine the pathogeninvolved. All amphotericin B infusions, whether conventional (infused over 4 hours) or lipid-based (infused over 2 hours), can be preceded by

acetaminophen (650 milligrams PO) and diphenhydramine (Benadryl®, 25 to 50 milligrams PO or IV) given 30 minutes prior to attenuate developmentof fever and rash.

In addition to infusion-related reactions, amphotericin B also causes renal dysfunction. The lipid-based products reduce but do not eliminate the riskof renal toxicity. The kidney dysfunction created includes renal tubular acidosis and renal wasting of bicarbonate, potassium, and magnesium. Whenusing this antifungal, monitor electrolyte levels and supplement as needed. Amphotericin B may elevate blood urea nitrogen and serum creatinine,although slightly less when using lipid-based products. If this occurs, reduce the daily dose or extend the infusion intervals to every other day if thecreatinine level rises to >2.5 to 3.0 milligrams/dL.

Fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and micafungin do not provoke the renal dysfunction associated withamphotericin B. Occasionally, liver function test elevations and hepatitis result from triazole therapy, so patients on prolonged courses of these drugsshould have liver function tests assessed monthly.

Triazoles (particularly itraconazole) can interact with other drugs metabolized by the cytochrome P450 system. In particular, warfarin, phenytoin,cyclosporine, and tacrolimus levels routinely increase in patients on itraconazole. Fluconazole is a less potent inhibitor of cytochrome P450, sointeractions are less frequent. Flucytosine can cause reversible bone marrow suppression, with leukopenia and thrombocytopenia. Dose-modification issues are relevant for fluconazole and flucytosine. For creatinine clearance <50 mL/min, reduce fluconazole to 200 milligrams daily andflucytosine to 25 to 37.5 milligrams/kg every 12 hours; for creatinine clearance <10 mL/min, reduce flucytosine to 25 to 37.5 milligrams/kg every 24

hours.3

The pregnancy category for the amphotericin products is category B; for the triazoles, caspofungin, and flucytosine, the category is C.

ANTIVIRAL AGENTS

Advances in antiviral agents can treat infections caused by herpes simplex virus I and II, varicella-zoster virus, cytomegalovirus, influenza A and B,human immunodeficiency virus, and hepatitis B and C. Table 163-10 summarizes the mechanism of action of the agents and spectrum of use for

these drugs outside of human immunodeficiency virus and hepatitis.1 Human immunodeficiency virus care is discussed elsewhere in the text,including postexposure prophylaxis. Uses for the non–human immunodeficiency virus antiviral agents for patients in the ED are summarized in Table163-11. Table 163-12 summarizes the drugs available and common side e�ects of drugs for hepatitis B and hepatitis C; dosing is usually outside ED

care and not reviewed.1,3,5,6

TABLE 163-10

Antiviral Agents for Cytomegalovirus, Systemic Herpes, Varicella, and Influenza

HSV I and II, VZV HSV I and II, VZV, Cytomegalovirus Influenza A Influenza A and B

Acyclovir (Zovirax®), valacyclovir

(Valtrex®), famciclovir (Famvir®)

Valganciclovir (Valcyte®)

Mechanism: nucleoside analogue

(guanine); when phosphorylated,

inhibits viral DNA polymerase

Amantadine (Symmetrel®),

rimantadine (Flumadine®)

Oseltamivir (Tamiflu®), zanamivir

(Relenza®)

Mechanism: purine nucleoside analogues;

triphosphate form inhibits HSV DNA

polymerase and viral DNA replication

Foscarnet (Foscavir®)

Mechanism: inorganic

pyrophosphate analogue that

inhibits DNA polymerase

Cidofovir (Vistide®)

Mechanism: nucleotide analogue

that inhibits viral DNA polymerase

Mechanism: inhibits

uncoating of virus and

uptake of nucleic acid by

host cells

Mechanism: inhibitor of influenza virus

neuraminidase with possible alteration

in viral aggregation and release

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TABLE 163-11

Antiviral Therapy (Non–Human Immunodeficiency Virus) in the ED

Diagnosis Drug Dosage Route

Herpes encephalitis Acyclovir 10 milligrams/kg every 8 h × 10 d (adult)

500 milligrams/m2 every 8 h (6 mo–12 y old)

IV

Mucocutaneous herpes

(immunocompromised)

Acyclovir 5 milligrams/kg every 8 h × 7 d (adult)

250 milligrams/m2 every 8 h (<12 y old)

IV

Varicella-zoster

(immunocompromised)

Same as above for herpes encephalitis IV

Herpes zoster (normal host) Acyclovir, or famciclovir, or

valacyclovir

800 milligrams five times/day × 7–10 d

500 milligrams three times daily × 7 d

1 gram three times daily × 7 d

PO

PO

PO

Varicella (chickenpox) Acyclovir 20 milligrams/kg (≤800 milligrams) four times a day (adults and

children >2 y old) × 5 d

PO

Influenza A Amantadine 100 milligrams twice daily × 10 d (adults and children >9 y old)

4.4–8.8 milligrams/kg/d, but <150 milligrams/d (children 1–9 y old)

PO

Rimantadine 100 milligrams twice daily × 7 d (adults and children >10 y old)

5 milligrams/kg/d, but <150 milligrams/d (children 1–10 y old)

PO

Oseltamivir 75 milligrams twice daily (adults and children >12 y old) × 5 d

Pediatrics (age 2 wk thru 12 y): based on weight

Also active against influenza B

PO

Zanamivir 10 milligrams (two inhalations) twice daily × 5 d (adults and

children >6 y old)

Also active against influenza B

Inhalation

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1. 

TABLE 163-12

Antiviral Agents for Hepatitis B and Hepatitis C

Hepatitis B Hepatitis C

Interferons: interferon

alfa-2b (Intron A®);

peginterferon alfa-2a

(Pegasys®)

Nucleotide or nucleoside analogues:

Preferred agents:

Entecavir (Baraclude®) 0.5–1 milligram PO

daily

Tenofovir (Viread®) 300 milligrams PO daily

Alternate agents:

Adefovir (Hepsera®) 10 milligrams PO daily

Lamivudine (Epivir-HBV®) 100 milligrams

PO daily

Telbivudine (Tyzeka®) 600 milligrams PO

daily

Interferons:

Products for

hepatitis B:

Interferon

alfa-2a

(Roferon®)

Peginterferon

alfa-2b

(Pegintron®)

Interferon

alfacon-1

(Infergen®)

Ribavirin

(CoPegus®, Rebetol®)

800–1400 milligrams PO every

day depending upon hepatitis C

virus genotype and body weight

Enzyme inhibitors:

Boceprevir (Victrelis®) 800

milligrams PO three times

daily with food

Simeprevir (Olysio®) 150

milligrams PO once daily

with food

Sofosbuvir (Sovaldi®) 400

milligrams PO once daily

with or without food

Sofosbuvir 400mg +

ledipasvir 90mg

(Harvoni®) one tablet PO

once daily with or without

food

Mechanism:

immunostimulant;

activates cytolytic T cells

against infected

hepatocytes

Adverse e�ects: flu-like

syndrome, nausea,

diarrhea, fatigue,

depression,

myelosuppression

Mechanism: inhibitor of viral DNA

polymerase

Adverse e�ects: headache, fatigue, nausea,

asthenia, abdominal pain and distention,

insomnia, lactic acidosis, hepatomegaly,

increased creatinine

Mechanism

and adverse

e�ects: See

Hepatitis B

Mechanism:

nucleoside analogue, inhibits

hepatitis C virus polymerase

Adverse e�ects: hemolytic

anemia and pancytopenia,

allergic reactions, dyspnea,

pneumonitis, bacterial

infections

Mechanism:

boceprevir and

simeprevir inhibit NS3/4A

protease;

sofosbuvir inhibits RNA

polymerase

Adverse e�ects: anemia,

nausea, fatigue,

headache, rash, pruritus

ledipasvir inhibits NS5A

protein

Acyclovir, valacyclovir, famciclovir, and valganciclovir are oral drugs for the treatment of herpes simplex virus and cytomegalovirus infections. Of all,the absorption of acyclovir is less than others, requiring higher doses to achieve adequate blood and tissue levels to inhibit viral replication.

The development of new agents for hepatitis B and C infections has been similar to that of several of the antiretroviral drug classes. E�ective drugsare analogues of nucleotides or nucleosides that result in nucleic acid polymerase inhibition (for example, entecavir for hepatitis B or simeprevir forhepatitis C) or directly inhibit RNA polymerase (sofosbuvir for hepatitis C). These agents are used in combination (for example, sofosbuvir withribavirin and peginterferon).

HYPERSENSITIVITY SYNDROME

Used in human immunodeficiency virus care, abacavir (Ziagen®, also contained in Trizivir® and Epzicom®) causes a hypersensitivity syndrome. This is

more common in individuals who are positive for the major histocompatibility complex class I allele HLA-B*5701, and this allele is now screened

before a patient is placed on abacavir.5 The syndrome is characterized by rash and other systemic complaints. The reaction is reversible withdiscontinuation of abacavir. However, if the patient then takes abacavir again, life-threatening cardiovascular and respiratory insu�iciency candevelop.

Many other infrequent adverse reactions are possible but beyond the scope of one chapter. Multiple online sources can aid if needed.3,5

REFERENCES

Katzung  BG, Masters  SB, Trevor  AJ (eds): Basic and Clinical Pharmacology , 12th ed. New York: The McGraw-Hill Companies, 2012.

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2. 

3. 

4. 

5. 

6. 

Cline  DM, Ma  OJ, Cydulka  RK, Meckler  GD, Handel  DA, Thomas  SH (eds): Tintinalli’s Emergency Medicine Manual , 7th ed. New York: The McGraw-Hill Companies, 2012.

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (U.S. Food and Drug Administration. Drugs@FDA.) Accessed April 1, 2014.

Strom  BL, Schinnar  R, Apter  AJ  et al.: Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med349: 1628, 2003.

[PubMed: 14573734]  

http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for theuse of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.) Accessed on April 1, 2014.

http://www.hcvguidelines.org/sites/default/files/full_report.pdf (American Association for the Study of Liver Diseases, Infectious Diseases Societyof America: Recommendations for the testing, managing, and treating hepatitic C.) Accessed on April 1, 2014.

USEFUL WEB RESOURCES

AccessMedicine drug monograph information—http://www.accessmedicine.com/drugs.aspx

Drug interactions checker—http://www.drugs.com/drug_interactions.php

Web site with common prescribing information—http://www.rxmed.com

Web site for HIV treatment information—http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

Web site for HIV treatment information in children—http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf.

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