6/11/2019 1/18 Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8eChapter 163: Pharmacology of Antimicrobials Ralph H. Raasch ANTIBACTERIAL DRUGS Eective antibacterial drugs can either inhibit the growth of (bacteriostatic) or kill (bactericidal) bacteria. Antibacterial eects result from the inhibition of cell wall synthesis, inhibition of intrabacterial protein synthesis, alteration in nucleic acid metabolism, or intrabacterial enzyme inhibition ( Table 163-1). The drug mechanism of action does not necessarily correlate with bacteriostatic or bactericidal eects, because the latter are aected also by the concentration of antibiotic to which bacteria are exposed. Drugs of choice for most infections are not based on a bacteriostatic or bactericidal eect of an agent, but rather are chosen based on whether the drug reaches the site of infection in adequate quantities, the spectrum of the 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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MECHANISMS OF ACTION · inhibition of cell wall synthesis, inhibition of intrabacterial protein synthesis, alteration in nucleic acid metabolism, or intrabacterial enzyme inhibition
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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.
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
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 =
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
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
*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
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
*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
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-
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
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
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, 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.
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.