THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

30. Anti-infective Agents - Ronald L. Braden, PharmD, W. Andrew Bell, PharmD

30-1. Aminoglycosides

Introduction

Aminoglycosides are antibiotics active against most aerobic Gram-negative bacteria and select aerobic Gram-positive bacteria, but they are not effective against most anaerobic bacteria. Aminoglycosides are primarily used in serious infections because of their significant toxicity. The most commonly used aminoglycosides include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, and tobramycin.

Mechanism of Action

Aminoglycosides inhibit bacterial protein synthesis through binding to the 30S ribosomal subunit, thereby irreversibly inhibiting bacterial RNA (ribonucleic acid) synthesis. Aminoglycosides are bactericidal.

Spectrum of Activity

Amikacin is a semisynthetic parenteral aminoglycoside with the broadest antimicrobial activity of the class, and it frequently possesses activity against bacteria resistant to other aminoglycosides.

Gentamicin is a parenteral aminoglycoside that is more active against Acinetobacter, Serratia, and enterococci than is tobramycin.

Kanamycin and neomycin are minimally absorbed oral aminoglycosides used to decrease bacterial content of the bowel. They have been used for preoperative bowel preparation and as an adjunct in hepatic encephalopathy.

Netilmicin is a parenteral aminoglycoside that may be the least ototoxic aminoglycoside.

Streptomycin is a parenteral aminoglycoside active against enterococci, streptococci, mycobacteria, and some Gram-negative anaerobes. It is used as an adjunct agent only because many bacterial isolates are resistant to streptomycin monotherapy. Streptomycin should be administered only by intramuscular (IM) injection.

Tobramycin is a parenteral aminoglycoside that is more active against Pseudomonas than is gentamicin.

Adverse Drug Events

Nephrotoxicity is demonstrated by an increase in blood urea nitrogen (BUN) and serum creatinine. It usually manifests as nonoliguric renal failure and may cause potassium, calcium, and magnesium wasting. Nephrotoxicity may occur in 10-25% of patients receiving aminoglycosides and is usually reversible on discontinuation of the agent. Risk factors include the following:

• Preexisting renal dysfunction

• Prolonged duration of therapy

• Concomitant use of other nephrotoxic agents

• Possibly elevated trough concentrations:

• Gentamicin and tobramycin > 2 mcg/mL

• Amikacin > 8 mcg/mL

Neuromuscular blockade is an uncommon but potentially serious toxicity. Risk factors include the following:

• Concomitant use of neuromuscular blocking agents

• Myasthenia gravis

• Hypocalcemia

• Elevated peak serum concentrations

Ototoxicity is due to eighth cranial nerve damage demonstrated by auditory and vestibular symptoms. Auditory symptoms include tinnitus and loss of high-frequency hearing. Vestibular toxicity is demonstrated by dizziness, nystagmus, vertigo, and ataxia. The incidence of ototoxicity is not clearly known because profound high-frequency hearing loss can occur prior to detection.

Pharmacokinetics

Aminoglycosides are renally eliminated:

• t1/2 = 2.5-2.7 hours (normal renal function)

• t1/2 = ~69 hours (anephric clearance)

• Vd = 0.27-0.3 L/kg (ideal body weight, or IBW)

Target serum concentrations

Traditional dosing is described in

Table 30-1.

• Amikacin peak = 15-30 mcg/mL

• Amikacin trough ≤ 5 mcg/mL

• Gentamicin and tobramycin peak = 4-10 mcg/mL

• Gentamicin and tobramycin trough ≤ 2 mcg/mL

Extended interval dosing

• Amikacin trough ≤ 3 mcg/mL (< 5 mcg/mL for VAP [ventilator-associated pneumonia] or HCAP [health care-associated pneumonia])

• Gentamicin and tobramycin ≤ 1 mcg/mL

30-2. Penicillins

Mechanism of Action

Penicillin-binding proteins make up the cell wall. When penicillin binds to these proteins, it is able to inhibit cell wall synthesis in the bacteria, causing cell wall lysis and ultimately cell death.

Penicillins are bactericidal; they inhibit bacterial cell wall synthesis. They are known as β-lactam antibiotics because their chemical structure consists of a β-lactam ring adjoined to a thiazolidine ring.

Penicillinase-resistant penicillins have substitutions to the β-lactam ring that sterically inhibit penicillinase.

Spectrum of Activity and Dosing

See

Tables 30-2 and

30-3 for information about the spectrum of activity and dosing of penicillins.

Adverse Drug Events

Allergic or hypersensitivity reaction occurs in 3-10% of patients. Rash (4-8% of patients) or anaphylaxis (0.01-0.05% of patients) can occur within 10-20 minutes and is more common in intravenous (IV) than in oral administration.

Neurologic reactions (seizures) are seen with high doses of penicillin given to patients with renal insufficiency.

Gastrointestinal (GI) effects, including nausea and vomiting, may occur with oral use.

Hypokalemia and hypernatremia may occur with carboxypenicillins.

Increased transaminases occur with oxacillin and nafcillin.

Cholestatic jaundice may occur with ureidopenicillins.

Hematologic reactions (hemolytic anemia) are possible.

Interstitial nephritis is possible.

Drug-Drug Interactions

Probenecid competitively inhibits tubular secretion of penicillins, thus increasing plasma levels. This interaction is employed in serious central nervous system (CNS) infections to increase drug concentrations.

Aminoglycosides are either incompatible or synergistic.

[Table 30-1. Aminoglycosides]

[Table 30-2. Spectrum of Activity of the Penicillins]

Concomitant use with an oral contraceptive may decrease the effectiveness of the oral contraceptive and increase incidence of breakthrough bleeding.

Other Characteristics

Nafcillin and oxacillin are eliminated primarily by biliary excretion; therefore, there is no need to adjust dosage for patients with renal dysfunction.

Penicillin G benzathine is a repository drug formulation. When it is given IM, insoluble salt allows slow drug absorption from the injection site, and therefore, penicillin G has a longer duration of action (12-24 hours).

30-3. Cephalosporins

Introduction

Cephalosporins are β-lactam antibiotics that are structurally and pharmacologically similar to penicillins.

Mechanism of Action

Cephalosporins are bactericidal agents. Antimicrobial activity is achieved through inhibition of mucopeptide

[Table 30-3. Dosing of Penicillins]

synthesis in the bacterial cell wall, which results in the formation of defective cell walls and subsequent cell lysis and cell death.

Spectrum of Activity

Cephalosporins are broad-spectrum antimicrobial agents; however, the spectrum of activity varies greatly among the individual agents. Thus, cephalosporins are grouped into four broad classes, or generations, according to their antimicrobial coverage (

Table 30-4).

First-generation agents (cefadroxil, cefazolin, cephalexin)

Gram-positive activity is extensive, including many strains of Staphylococcus aureus and Staphylococcus epidermidis in addition to Streptococcus pyogenes (group A betahemolytic streptococci), Streptococcus agalactiae (group B streptococci), and Streptococcus pneumoniae. First-generation agents are inactive against enterococci, methicillin-resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), and Listeria monocytogenes.

[Table 30-4. Cephalosporins]

Gram-negative activity is limited, although some strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Shigella may display susceptibility. First-generation agents are inactive against Haemophilus influenzae, Pseudomonas, Enterobacter, Citrobacter, Serratia, other Proteus spp., and anaerobes such as Bacteroides fragilis.

Second-generation agents (cefaclor, cefotetan, cefoxitin, cefprozil, cefuroxime)

Gram-positive activity is similar to that of first-generation agents.

Gram-negative activity of second-generation agents is generally more extensive than that of first-generation agents, including some strains of Acinetobacter, Citrobacter, Enterobacter, Neisseria, Proteus, and Serratia, in addition to Escherichia coli and Klebsiella. Second-generation agents are active against Haemophilus influenzae, and some (cefotetan and cefoxitin) also have anaerobic activity. Second-generation agents are inactive against Pseudomonas.

Third-generation agents (cefdinir, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone)

Gram-positive activity is decreased versus first- and second-generation agents.

Gram-negative activity is extensive, including Enterobacter, Citrobacter, Serratia, Neisseria, and Haemophilus. Some third-generation agents are active against Pseudomonas (ceftazidime). Anaerobic coverage varies among individual agents.

Fourth-generation agent (cefepime)

Gram-positive activity is increased versus third-generation agents. Cefepime is inactive against MRSA, enterococci, and Listeria.

Gram-negative activity is extensive, including enhanced activity against Pseudomonas and Enterobacteriaceae that produce inducible β-lactamases.

The extended spectrum of activity of cefepime is attributed to a more rapid penetration of the outer membrane of Gram-negative bacteria. Cefepime is also more resistant to inactivation by β-lactamases.

Adverse Drug Events

• Hypersensitivity, including fever, rash, pruritus, urticaria, anaphylaxis, and hemolytic anemia

• GI effects, such as nausea, vomiting, and diarrhea

• Nephrotoxicity (rare)

• Seizures (potential risk with high doses in patients with renal impairment)

• Clostridium difficile colitis

• Bleeding or hypoprothrombinemia (cefotetan), which is attributable to the presence of an N-methylthiotetrazole (NMTT) side chain in the structure of these agents (possible prevention or reversal with administration of vitamin K)

• Blood dyscrasias (rare)

Drug-Drug Interactions

Disulfiram-like reactions have been reported with ingestion of alcohol during treatment with cephalosporin antibiotics.

Probenecid competitively inhibits tubular secretion of cephalosporins, resulting in higher serum concentrations.

Drug-Disease Interactions

All cephalosporins (except ceftriaxone) require dosage adjustments in patients with renal insufficiency.

Monitoring Parameters

Serum concentration monitoring is not necessary. Patients should be monitored for clinical response and resolution of infection.

Patient Instructions and Counseling

Verify that the patient is not allergic to penicillins. Cross-sensitivity with penicillins has been reported in up to 10% of patients receiving cephalosporins. Obtain a thorough history of any patient with a previous hypersensitivity reaction to any β-lactam antibiotic. In general, cephalosporins should be avoided in these patients.

Other

Bacterial resistance to cephalosporins may result through production of β-lactamases.

30-4. Carbapenems

Introduction

Carbapenems are β-lactam-like antibiotics that are structurally and pharmacologically similar to penicillins.

Mechanism of Action

Carbapenems bind to penicillin-binding proteins in a manner similar to that of β-lactams, thereby inhibiting peptidoglycan synthesis. Carbapenems are bactericidal in susceptible isolates.

Spectrum of Activity

Carbapenems are very broad-spectrum antibiotics with activity against most Gram-positive and Gram-negative aerobes and anaerobes, as well as activity against some Mycobacterium and Chlamydia spp. Carbapenems other than ertapenem cover Pseudomonas and Acinetobacter and are the drug of choice for ESBL (extended spectrum β-lactamases)-producing Entreobactereacea species.

Adverse Drug Events

GI adverse effects are the most common events reported with imipenem. The effects include nausea, vomiting, diarrhea (including Clostridium difficile enterocolitis), gastroenteritis, abdominal pain, glossitis, papillary hypertrophy, staining of the teeth, heartburn, pharyngeal pain, and taste abnormalities.

Eosinophilia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, and thrombocytopenia have been reported.

Seizures have been reported in approximately 0.4% of patients receiving imipenem. Risk factors include the following:

• History of seizures or head trauma

• High doses

• Renal dysfunction

Imipenem-Cilastatin

Imipenem is a semisynthetic carbapenem β-lactam antibiotic. Cilastatin prevents renal metabolism of imipenem by dehydropeptidases.

Cilastatin competitively inhibits dehydropeptidase—an enzyme present on the brush border of the proximal renal tubule—which hydrolyzes imipenem. Cilastatin has no antibacterial activity.

Meropenem and Doripenem

These agents are similar to imipenem with the following differences:

• Decreased CNS toxicity

• No hydrolysis by dehydropeptidases

Ertapenem

Ertapenem is dosed once daily and does not cover Pseudomonas.

30-5. Monobactam

Introduction

Monobactam antibiotics are cell wall-active antibiotics like the β-lactams, but they do not have a β-lactam ring, thereby decreasing cross-reactivity with penicillins and cephalosporins.

Aztreonam

Aztreonam is the only monobactam antibiotic currently available.

Mechanism of action

Aztreonam inhibits synthesis of bacterial cell walls through binding to penicillin-binding protein 3 of susceptible Gram-negative bacteria, thereby inhibiting peptidoglycan synthesis. This action results in cell wall lyses and cell death.

Spectrum of activity

Aztreonam is active against many aerobic Gram-negative bacteria, but is not active against Gram-positive or anaerobic bacteria. Though some strains of Pseudomonas are susceptible, resistance is increasing.

Adverse drug events

• Hypersensitivity: Rash, injection site reactions, and eosinophilia

• GI effects: Nausea, vomiting, and diarrhea

• Rare effects: Hepatotoxicity, neutropenia, and pancytopenia

30-6. Gram-Positive Antibiotics

Linezolid

Linezolid is a synthetic oxazolidine antibiotic (

Table 30-5).

Mechanism of action

Linezolid binds to the 23S ribosomal subunit of the 50S RNA subunit that inhibits bacterial translation.

Spectrum of activity

Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against streptococci. Linezolid is active against Enterococcus faecium isolates, including vancomycin-resistant Enterococci (VRE), while most Enterococcus faecalis isolates are resistant.

[Table 30-5. Gram-Positive Antibiotics]

Adverse drug events

Hematologic effects, including myelosuppression (anemia, leukopenia, pancytopenia, and thrombocytopenia), have been reported. Hematologic effects appear to be reversible on discontinuation of the agent.

Monoamine oxidase (MAO) inhibition may occur. Linezolid is a weak MAO inhibitor and caution should be exercised in patients receiving vasopressors or serotonergic agents (SSRI [selective serotonin reuptake inhibitor], TCA [tricyclic antidepressant], meperidine, and triptans).

Quinupristin-Dalfopristin

Quinupristin-dalfopristin is a semisynthetic streptogramin antibiotic. The combination acts synergistically against Gram-positive bacteria.

Mechanism of action

Quinupristin inhibits late-phase protein synthesis, while dalfopristin inhibits early-phase protein synthesis through binding to the 50S subunit of bacterial RNA.

Spectrum of activity

Quinupristin-dalfopristin is bactericidal against staphylococci and streptococci and bacteriostatic against Enterococcus faecium, including VRE. Quinupristin-dalfopristin is not active against Enterococcus faecalis.

Adverse drug events

Thrombophlebitis and severe injection site reactions are common, and some sources recommend administration through a central venous catheter only.

Hyperbilirubinemia has been reported in up to 25% of patients receiving the agent.

Arthralgias and myalgias are common, some requiring discontinuation of the agent.

Daptomycin

Daptomycin is a cyclic lipopeptide antibiotic.

Mechanism of action

Daptomycin binds to bacterial cell membranes, causing rapid depolarization, which results in loss of membrane potential. The loss of membrane potential inhibits protein, DNA (deoxyribonucleic acid), and RNA synthesis, resulting in cell death.

Spectrum of activity

Daptomycin is bactericidal against Gram-positive bacteria including staphylococci, streptococci, enterococcus, and Corynebacterium. Daptomycin is active against MRSA, as well as enterococci that are resistant to vancomycin, linezolid, or quinupristin-dalfopristin.

Adverse drug events

Dermatologic reactions include injection site reaction, rash, and pruritis. Musculoskeletal effects include increased CPK (creatine phosphokinase), which can progress to rhabdomyolysis (weekly monitoring recommended). Nephrotoxicity and hepatotoxicity have been reported.

Other

Daptomycin is inactivated by the surfactant in the lung and cannot be used to treat pneumonia.

Daptomycin interacts with some PT (prothrombin time) and INR (international normalized ratio) assays, resulting in a false elevation.

Vancomycin

Vancomycin is a glycopeptide antibiotic.

Mechanism of action

Vancomycin binds to the bacterial cell wall, inhibiting peptidoglycan synthesis. This binding occurs at a site different from that of the penicillins. Vancomycin may also inhibit RNA synthesis.

Spectrum of activity

Vancomycin is active against most Gram-positive bacteria, such as staphylococci (including MRSA), streptococci, enterococci, Corynebacterium, and Clostridium (including Clostridium difficile). It is bactericidal against all susceptible isolates except enterococci (bacteriostatic). Vancomycin acts synergistically with aminoglycosides against enterococci.

Adverse drug events

Nephrotoxicity is manifested by an increase in serum creatinine and BUN. The incidence of nephrotoxicity is not well described, but it appears to be low in the absence of concomitant nephrotoxic agents. Renal dysfunction is normally reversible on discontinuation of the agent but may be irreversible.

Ototoxicity is induced by eighth cranial nerve damage and has been reported to cause permanent hearing loss. Vancomycin rarely causes vestibular toxicity. The incidence of ototoxicity appears to be low in the absence of concomitant ototoxic agents.

Thrombophlebitis is common and requires frequent IV site rotation.

Histamine release, or "red-man syndrome," is a reaction most commonly associated with rapid IV infusion. Histamine reactions can be minimized by slow IV infusion, not to exceed 500 mg/30 min.

Monitoring parameters

Vancomycin trough concentrations should be monitored in patients with preexisting renal dysfunction or patients with increased serum creatinine or BUN during therapy. Monitoring of vancomycin peak concentrations is not routinely required, except in patients with serious infections, those with CNS infections, or those not responding to therapy.

Pharmacokinetics

Vancomycin is renally eliminated:

• t1/2 = 6 hours (normal renal function)

• t1/2 = 7-10 days (anephric patients)

• Vd = 0.7 L/kg (total body weight [TBW])

• Dose = 15-20 mg/kg (TBW)

• Interval = q12h to pulse dosing (based on renal function and pharmacokinetic monitoring)

• Peak concentration = 20-40 mcg/mL

• Trough concentration = 10-20 mcg/mL

30-7. Fluoroquinolones

Introduction

Quinolones are broad-spectrum antibacterial agents (

Table 30-6).

Mechanism of Action

Fluoroquinolones are bactericidal agents. The mechanism of action of these agents is not understood entirely, but antimicrobial activity is known to involve

[Table 30-6. Fluoroquinolones and Nonfluorinated Quinolones]

inhibition of bacterial DNA topoisomerase and subsequent disruption of bacterial DNA replication.

Spectrum of Activity

Gram-positive activity includes many strains of staphylococci. Streptococcal activity is variable, and streptococcal resistance to quinolones is increasingly common. Newer fluoroquinolones (moxifloxacin and gemifloxacin) generally demonstrate superior Gram-positive coverage versus older agents (ciprofloxacin, ofloxacin, and levofloxacin). Fluoroquinolones have limited enterococcal activity and are inactive against MRSA.

Gram-negative activity is extensive, including Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Proteus, Salmonella, and Shigella, in addition to Moraxella catarrhalis and Haemophilus influenzae. Activity against Pseudomonas aeruginosa and Stenotrophomonas maltophilia varies among individual agents.

Anaerobic coverage is poor.

Atypical coverage varies among individual agents. All fluoroquinolones are highly active against Legionella. Newer agents have more reliable coverage of Mycoplasma pneumoniae and Chlamydia pneumoniae.

Adverse Drug Events

• GI effects: Nausea and dyspepsia

• CNS effects: Headache, dizziness, and insomnia

• Cardiovascular effects: QT prolongation (avoid use in patients with preexisting QT prolongation)

• Endocrine effects: Hypoglycemia or hyperglycemia (reason for withdrawal of gatifloxacin from market)

• Genitourinary effects: Crystalluria (at high doses with alkaline pH)

• Other effects: Tendinitis and photosensitivity

• Rare effects: Rash, urticaria, leukopenia, and hepatotoxicity (reason for withdrawal of trovafloxacin)

Drug-Drug Interactions

Ciprofloxacin increases theophylline levels. Concomitant use should be avoided, or theophylline levels should be monitored during treatment. The risk of theophylline toxicity is lower with other fluoroquinolones.

Antacids, sucralfate, and divalent or trivalent cations (calcium, magnesium, and iron) significantly decrease the absorption of fluoroquinolones. These agents should not be administered for at least 2 hours after each dose of a fluoroquinolone.

Fluoroquinolones may enhance the effects of oral anticoagulants. Monitor PT and INR if concomitant therapy cannot be avoided.

Agents that increase the QT interval (cisapride and class IA or III antiarrhythmics) increase the risk of torsades de pointes. Concomitant use of fluoroquinolones with these agents should be avoided.

Drug-Disease Interactions

Dosage adjustments should be made for renally cleared fluoroquinolones when CrCl (creatinine clearance) is < 40 mL/min.

Monitoring Parameters

Serum concentrations are not monitored. The patient should be monitored for clinical response and resolution of infection.

Kinetics

Quinolones display concentration-dependent activity and have a postantibiotic effect against most susceptible organisms.

Fluoroquinolones have a large volume of distribution and achieve high tissue concentrations in the lung, gallbladder, kidney, prostate, and genitourinary tract.

Patient Instructions and Counseling

• Fluoroquinolones should be avoided in children or pregnant or nursing females because of the risk of cartilage erosion in tendons and growing bone tissue.

• Do not take antacids; multivitamins; or other calcium, magnesium, or iron supplements for at least 2 hours after each dose.

30-8. Macrolides and Ketolides

Mechanism of Action

Macrolides are bacteriostatic against susceptible organisms (

Table 30-7). The agents bind to the 50S RNA subunit, thereby inhibiting RNA synthesis.

Ketolides are similar to the macrolides. Telithromycin is a derivative of 14-membered ring macrolides and is the first ketolide antibiotic.

[Table 30-7. Macrolides and Ketolide]

Spectrum of Activity

Macrolides, or erythromycins, are active principally against Gram-positive organisms, including penicillin-resistant streptococci. The macrolides are also effective against Chlamydia, Mycoplasma, Ureaplasma, spirochetes, and mycobacteria.

Macrolides are the drugs of choice in atypical pneumonia and Chlamydia sexually transmitted diseases.

Telithromycin possesses greater in vitro activity against multidrug-resistant Gram-positive organisms and Haemophilus influenzae than do the erythromycins.

Adverse Drug Events

• GI effects: Erythromycins stimulate GI motility, leading to abdominal pain and cramping, nausea, vomiting, and diarrhea. Clarithromycin appears to be the least stimulating to the GI tract.

• Local effects: Erythromycin lactobionate is reported to cause venous irritation and thrombophlebitis. The agent should be diluted in at least 250 mL and infused over 30-60 minutes to decrease the venous irritation.

• Cardiac effects: QT interval prolongation and torsades de pointes have been rarely reported with erythromycins. Adequate dilution and slow IV infusion appear to decrease this reaction.

• Ototoxicity: Erythromycin has been rarely reported to be ototoxic in doses of 4 g/d or more.

• Hepatotoxicity: Telithromycin appears comparable to the macrolides but carries a black box warning for hepatotoxicity.

30-9. Tetracyclines and Glycylcyclines

Mechanism of Action

Tetracyclines and glycylcyclines are bacteriostatic. They inhibit bacterial protein synthesis by reversible binding on the 30S ribosomal subunit and by blocking of the attachment of transfer RNA to an acceptor site on the messenger RNA ribosomal complex (

Table 30-8).

Glycylcyclines (tigecycline) share the same mechanism of action as tetracyclines but have a structural modification that increases affinity and binding to the bacterial ribosome and decreases efflux from the cell. These properties give tigecycline in vitro advantages when compared to tetracycline.

Spectrum of Activity

Tetracyclines are used to treat the following infections:

• Respiratory infections: Atypical pneumonia (Mycoplasma pneumoniae, Chlamydia pneumoniae)

• Genital infections: Chlamydia trachomatis, granuloma inguinale

• Systemic infections: Relapsing fever (Borrelia recurrentis) and Vibrio (V. cholerae, V. vulnificus, and V. parahaemolyticus)

• Other infections: MRSA and MRSE (minocycline) when vancomycin or other agents are not considered appropriate; Pasteurella multocida,

[Table 30-8. Tetracyclines and Glycylcyclines]

   Mycobacterium marinum, Yersinia pestis, and Helicobacter pylori (in combination with bismuth subsalicylate and metronidazole or clarithromycin)

• Prophylaxis: Mefloquine-resistant Plasmodium falciparum malaria

Doxycycline is used to treat infections caused by the following organisms:

• Mycobacterium fortuitum and Mycobacterium chelonae

• Streptococcus pneumoniae

Pseudomonas and Proteus organisms are now resistant to tetracyclines.

Tetracyclines are used in the treatment of Propionibacterium acnes.

Patient Instructions and Counseling

Administering the drug with food can minimize GI distress.

Adverse Drug Events

Photosensitivity reactions can occur, but may be less frequent with doxycycline and minocycline.

Tetracyclines and glycylcyclines are generally contraindicated during pregnancy and breast-feeding and in children younger than age 8 because of their association with tooth discoloration and interference with bone growth.

Hepatotoxicity—specifically acute fatty necrosis—may occur in pregnant women and in patients with renal impairment.

Minocycline use can cause the following:

• Vestibular side effects (dizziness, ataxia, nausea, and vertigo)

• Skin and mucous membrane pigmentation

• Lupus-like symptoms

GI intolerance includes diarrhea, nausea, vomiting, and anorexia.

Cross-sensitivity within the tetracycline group is common.

IV tetracyclines may cause phlebitis.

Drug-Drug and Drug-Disease Interactions

Milk, antacids, iron supplements, and probably other substances with calcium, magnesium, aluminum, and iron decrease tetracycline GI absorption considerably and should be ingested at least several hours before or after administration of tetracycline.

Although doxycycline and minocycline absorption may be less affected by these divalent and trivalent cations, avoiding administration within 1 to 2 hours after ingestion of interfering foods is recommended.

Anticonvulsants (e.g., barbiturates, carbamazepine, and phenytoin) induce hepatic microsomal metabolism of tetracyclines and therefore decrease tetracycline serum concentrations.

If tetracycline is given with cholestyramine or colestipol, these drugs may bind tetracycline and reduce GI absorption.

Oral contraceptive efficacy may be decreased with concurrent use of tetracyclines.

Tetracyclines and glycylcyclines may potentiate warfarin-induced anticoagulation; therefore, monitor PT and INR.

[

Table 30-9. Sulfonamides]

Demeclocycline antagonizes the action of antidiuretic hormones.

30-10. Sulfonamides

Introduction

Sulfonamides are synthetic derivatives of sulfanilamide (Table 30-9). Their usefulness has decreased over time because of the development of resistance.

Mechanism of Action

Sulfonamides interfere with bacterial folic acid synthesis by competitively inhibiting para aminobenzoic acid (PABA) utilization. Sulfonamides are bacteriostatic.

Spectrum of Activity

• Gram-positive bacteria: Staphylococci (methicillin-sensitive Staphylococcus aureus [MSSA] and MRSA), streptococci (not enterococci), Bacillus anthracis, Clostridium perfringens, and Nocardia

• Gram-negative bacteria: Enterobacter, Escherichia coli, Klebsiella, Proteus, Salmonella, and Shigella

• Other organisms: Chlamydia trachomatis, Toxoplasma gondii, and Plasmodium

Adverse Drug Events

Hypersensitivity reactions appear to be cross-reactive with other sulfonamides, diuretics (including acetazolamide and thiazides), and sulfonylurea antidiabetic agents.

Dermatologic reactions include rash, urticaria, and Stevens-Johnson syndrome.

30-11. Miscellaneous Antibiotics

Clindamycin

Clindamycin is a semisynthetic antibiotic derived from lincomycin (

Table 30-10).

Mechanism of action

Clindamycin inhibits the 50S subunit, thereby inhibiting RNA synthesis. Clindamycin is either bacteriostatic or bactericidal, depending on the serum concentration of the agent and the minimum inhibitory concentration (MIC) of the organism.

Spectrum of activity

Clindamycin is active against most aerobic Gram-positive and most anaerobic Gram-negative bacteria. It has no activity against aerobic Gram-negative bacteria.

Adverse drug events

Adverse GI effects occur frequently with all forms of clindamycin, and include nausea, vomiting, diarrhea, abdominal pain, and tenesmus. Clindamycin has induced Clostridium difficile enterocolitis.

IV administration can lead to thrombophlebitis, erythema, and pain and swelling at the IV site. IM administration can cause pain, induration, and sterile abscesses.

Clindamycin can cause transient leukopenia, neutropenia, eosinophilia, thrombocytopenia, and agranulocytosis. These effects are usually reversible on discontinuation of the drug.

Other Miscellaneous Antibiotics

See Table 30-10 for information about other miscellaneous antibiotics.

30-12. Antifungal Agents

Amphotericin B

Amphotericin B is a polyene antifungal agent used in the treatment of potentially life-threatening systemic fungal infections (

Table 30-11).

[Table 30-10. Miscellaneous Antibiotics]

[Table 30-11. Antifungal Agents]

Amphotericin B lipid formulations

Amphotericin B cholesterol sulfate complex (Amphotec), amphotericin B lipid complex (Abelcet), and amphotericin B liposomal (AmBisome) formulations are available for the treatment of severe fungal infections in patients who fail or are intolerant of conventional amphotericin B. The lipid formulations may decrease toxicity by 20-30%.

Mechanism of action

Amphotericin B binds to ergosterol in the fungal cell wall, leading to increased permeability and cell death. Amphotericin B is fungistatic.

Spectrum of activity

• Aspergillus, Coccidioides, Cryptococcus, Histoplasma, and Mucor

• Candida, including C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis (C lusitaniae exhibits variable sensitivity)

Adverse drug events

• Infusion reactions: Fever, chills, hypotension, rigors, pain, thrombophlebitis, and anaphylaxis can occur.

• Renal and electrolyte effects: Nephrotoxicity is the major dose-limiting toxicity, but Hypokalemia, hypocalcemia, and hypomagnesemia can occur. Effects are usually reversible on discontinuation of the agent. Renal tubular acidosis and nephrocalcinosis are possible.

• Hematologic effects: Normocytic and normochromic anemia secondary to decreased erythropoietin production may occur.

• Hepatic effects: Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin are possible.

Echinocandins

Echinocandins (caspofungin, micafungin, and anidulafungin) are a new class of IV antifungal agents.

Mechanism of action

Echinocandins inhibit β-(1,3) glucan synthase, thereby preventing fungi from forming an essential component of their cell wall. This loss of cell wall integrity results in cell lysis and death.

Spectrum of activity

Echinocandins are active against most Candida and Aspergillus species, but they lack activity against other invasive molds. Candida Parapsilosis, C. guilliermondii, and C. famata have increased MICs to echinocandins, which may result in an inadequate response to treatment.

Caspofungin

Caspofungin is approved for the treatment of aspergillosis in patients refractory to or intolerant of other therapies and in the treatment of invasive Candida infections. Caspofungin is dose adjusted in severe liver dysfunction.

Micafungin and Anidulafungin

Micafungin and anidulafungin are approved for the treatment of invasive Candida infections. Micafungin and anidulafungin do not require dose adjustment for renal or hepatic dysfunction.

Adverse drug events

• Hepatic effects: Increased AST and ALT

• Sensitivity reactions: Histamine-release reactions such as rash, pruritus, and anaphylaxis

• Infusion reactions: Fever, thrombophlebitis, nausea, vomiting, and myalgias

Azole Antifungals

Mechanism of action

The azole antifungals appear to inhibit fungal cytochrome P450 14-β-demethylase, thereby decreasing ergosterol concentrations in susceptible fungi.

Drug interactions

All azole antifungals are inhibitors of the cytochrome P450 system and have many critical drug interactions attributable to decreased metabolism and, thus, toxicity.

The azole antifungals have also been shown to prolong the QT interval; thus, coadministration with other drugs that prolong the QT interval is not advised.

Fluconazole

Fluconazole is a synthetic triazole antifungal and is fungistatic.

Spectrum of activity

Candida krusei, C. glabrata, and C. lusitaniae are commonly resistant.

Adverse drug events

• GI effects: Nausea, vomiting, abdominal pain, and diarrhea

• Hepatic effects: Cholestasis, increased AST, ALT, and GGTP (gamma-glutamyl transpeptidase); hepatic necrosis; and, rarely, severe hepatic dysfunction

• Hemolytic effects: Eosinophilia, anemia, leukopenia, neutropenia, and thrombocytopenia

• Nervous system effects: Rarely, dizziness, headache, somnolence, coma, and seizures

Itraconazole

Itraconazole is a synthetic triazole antifungal.

Spectrum of activity

Itraconazole is effective in aspergillosis, blastomycosis, histoplasmosis, oropharyngeal and esophageal candidiasis, sporotrichosis, onychomycosis, coccidioidomycosis, and cryptococcosis.

Adverse drug events

• GI effects: Nausea, vomiting, diarrhea, abdominal pain, dyspepsia, dysphagia, flatulence, gastritis, and ulcerative stomatitis

• Dermatologic and sensitivity reactions: Rash, pruritus, urticaria, angioedema, and Stevens-Johnson syndrome

• Nervous system effects: Headache, dizziness, tremor, and neuropathy

• Cardiovascular effects: Congestive heart failure, peripheral edema, pulmonary edema, prolonged QT interval, ventricular dysrhythmias, and death

• Hepatic effects: Increased AST and ALT

• Electrolyte and metabolic effects: Hypokalemia, adrenal insufficiency, and gynecomastia

Ketoconazole

Ketoconazole is a synthetic imidazole antifungal.

Spectrum of activity

The spectrum of activity includes blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and dermatophytosis.

Adverse drug events

• GI effects: Nausea, vomiting, abdominal pain, and GI bleeding

• Hepatic effects: Increased AST, ALT, and alkaline phosphatase

• Endocrine and metabolic effects: Gynecomastia and decreased cortisol production

• Dermatologic and sensitivity reactions: Pruritus, rash, dermatitis, and purpura

• Nervous system effects: Headache, dizziness, lethargy, photophobia, and abnormal dreams

Voriconazole

Voriconazole is a synthetic triazole antifungal.

Spectrum of activity

The spectrum of activity includes aspergillosis and Candida species (even fluconazole-resistant isolates).

Adverse drug events

• Hepatic effects such as hepatitis, cholestasis, and fulminant hepatic failure

• Visual disturbances and hallucinations

• Dermatologic and sensitivity reactions, including anaphylactoid reactions, pruritus, rash, Stevens-Johnson syndrome, and photosensitivity

Posaconazole

Posaconazole is a synthetic triazole antifungal.

Spectrum of activity

Posaconazole is approved for use in aspergillus and invasive Candida infections. It has a broad in vitro spectrum of activity and has been effective against fungi such as zygomycetes and aspergillus strains that are highly resistant to other azoles and amphotericin.

Adverse drug events

• GI effects: Nausea, vomiting, diarrhea, and abdominal pain

• Dermatologic and sensitivity reactions: Rash and pruritus

• Nervous system effects: Headache, dizziness, and confusion

• Cardiovascular effects: Hypertension, hypotension, edema, prolonged QT interval, and ventricular dysrhythmias

• Hepatic effects: Cholestasis and increased AST and ALT

Flucytosine

Mechanism of action

Flucytosine appears to enter fungal cells, where it is converted to 5-fluorouracil. Flucytosine is either fungistatic or fungicidal, depending on the concentration of the agent.

Spectrum of activity

Flucytosine is active against most strains of Candida and Cryptococcus.

Adverse drug events

• GI effects: GI hemorrhage, ulcerative colitis caused by the antiproliferative effects, anorexia, abdominal pain, nausea, vomiting, and diarrhea

• Hepatic effects: Increased AST, ALT, and bilirubin

• Renal effects: Increased serum creatinine, BUN, and crystalluria

• Nervous system effects: Confusion, hallucinations, psychosis, headache, parkinsonism, paresthesias, peripheral neuropathy, hearing loss, and vertigo

• Sensitivity reactions: Erythema, pruritus, urticaria, rash, and toxic epidermal necrolysis

Griseofulvin

Mechanism of action

Griseofulvin disrupts the fungal cell's mitotic spindle structure, thereby inhibiting the metaphase of cell division. Griseofulvin is fungistatic.

Spectrum of activity

The spectrum of activity includes Trichophyton, Microsporum, and Epidermophyton.

Adverse drug events

• Nervous system effects: Headache, fatigue, dizziness, and paresthesias of the hands and feet after prolonged therapy

• GI effects: Epigastric pain, nausea, vomiting, flatulence, and diarrhea

• Renal effects: Proteinuria and nephrosis

• Sensitivity reactions: Rash, urticaria, erythema multiforme, angioedema, serum sickness, photosensitivity, and lupus-like reactions

Nystatin

Mechanism of action

Nystatin binds to fungal sterols. It is fungistatic.

Spectrum of activity

The spectrum of activity includes cutaneous and mucocutaneous candidiasis.

Adverse drug events

Mild nausea and diarrhea may occur.

Terbinafine

Terbinafine is a synthetic allylamine antifungal.

Mechanism of action

Terbinafine interferes with sterol biosynthesis.

Spectrum of activity

The spectrum of activity includes Trichophyton, Microsporum, Epidermophyton, Aspergillus, blastomycosis, and yeasts.

Adverse drug events

• Hepatic effects: Hepatitis and hepatic failure

• Dermatologic and sensitivity reactions: Anaphylactoid reactions, Stevens-Johnson syndrome, and erythema multiforme

30-13. Antitubercular Agents

Aminosalicylic Acid

Mechanism of action

Aminosalicylic acid (para aminosalicylate, or PAS) inhibits folic acid synthesis in a manner similar to that of sulfonamides and is bacteriostatic (

Table 30-12).

Spectrum of activity

Aminosalicylic acid is active against Mycobacterium tuberculosis only.

[Table 30-12. Antitubercular Agents]

Adverse drug events

• GI effects: Nausea, vomiting, abdominal pain, diarrhea, and anorexia can occur.

• Vitamin and mineral absorption: Vitamin B12, folic acid, and iron malabsorption have been rarely reported.

• Hypersensitivity reactions: Fever, skin eruptions, joint pain, and leukopenia have been reported.

Capreomycin

Mechanism of action

The exact mechanism of action of capreomycin is unknown. The agent is bacteriostatic against susceptible isolates.

Spectrum of activity

Capreomycin is active against the following Mycobacterium species: M. tuberculosis, M. bovis, M. kansasii, and M. avium.

Adverse drug events

• Renal effects: Nephrotoxicity is exhibited in up to 30% of patients receiving the agent. It manifests as acute tubular necrosis, which is usually reversible on discontinuation of the agent.

• Ototoxicity: This problem is experienced by up to 30% of patients and is caused by eighth cranial nerve damage, which can produce irreversible hearing loss.

• Hepatic effects: Elevated liver function tests have been noted when capreomycin is used in conjunction with other hepatotoxins.

• Hypersensitivity reactions: Fever, urticaria, and skin eruptions have been noted.

Cycloserine

Mechanism of action

Cycloserine is structurally similar to D-alanine and inhibits cell wall synthesis by competing for incorporation into the bacterial cell wall.

Spectrum of activity

Cycloserine is active against the following Mycobacterium species: M. tuberculosis, M. bovis, M. avium, and some M. kansasii isolates.

Adverse drug events

CNS effects may occur, including headache, vertigo, confusion, psychosis, and seizures.

Ethambutol

Mechanism of action

Ethambutol appears to inhibit bacterial cellular metabolism and is bacteriostatic.

Spectrum of activity

Ethambutol is active against the following Mycobacterium species: M. tuberculosis, M. bovis, and some isolates of M. kansasii and M. avium.

Adverse drug events

Ocular effects may occur. Optic neuritis with decreased visual acuity, central and peripheral scotomas, and loss of red-green color discrimination have been noted. These effects are usually reversible on discontinuation of the agent.

Ethionamide

Mechanism of action

Ethionamide appears to inhibit cell wall synthesis by an unidentified mechanism. It is bactericidal or bacteriostatic, depending on tissue concentrations of the agent.

Spectrum of activity

Ethionamide is active against the following Mycobacterium species: M. tuberculosis, M. bovis, M. kansasii, and some M. avium isolates.

Adverse drug events

Hepatitis is a rare complication.

Isoniazid

Mechanism of action

Isoniazid (INH) appears to inhibit the bacterial cell wall of susceptible isolates and, therefore, is active against actively dividing cells only. It is bactericidal or bacteriostatic, depending on tissue concentrations of the agent.

Spectrum of activity

INH is active against the following Mycobacterium species: M. tuberculosis, M. bovis, and some strains of M. kansasii.

Adverse drug events

• CNS effects: Peripheral neuritis and rarely seizures, encephalopathy, and psychosis have been reported.

• Hepatic effects: Increases in bilirubin, AST, and ALT are noted in up to 20% of patients receiving this agent. INH has led to fulminant hepatitis and death.

• Hematologic effects: Agranulocytosis, eosinophilia, thrombocytopenia, and hemolytic anemia have been reported.

Pyrazinamide

Mechanism of action

Mycobacterium tuberculosis converts pyrazinamide (PZA) to pyrazinoic acid, which possesses antitubercular activity.

Spectrum of activity

PZA is active against Mycobacterium tuberculosis only.

Adverse drug events

• Hepatic effects: Increased liver enzymes are common, and fulminant hepatitis has been reported.

• Gout: PZA inhibits renal excretion of uric acid and may induce or worsen gout.

Rifampin

Mechanism of action

Rifampin inhibits RNA synthesis in susceptible isolates.

Spectrum of activity

Rifampin is active against the following Mycobacterium species: M. tuberculosis, M. bovis, M. kansasii, and some M. avium isolates. Rifampin also has activity against many Gram-positive and Gram-negative organisms.

Adverse drug events

• GI effects: Nausea, vomiting, diarrhea, and abdominal pain may require discontinuation of the agent. Clostridium difficile colitis has been reported with rifampin.

• CNS effects: Headache, dizziness, mental confusion, and psychosis have been reported.

• Hepatic effects: Increased bilirubin, AST, and ALT are common. Fulminant hepatitis has been reported.

• Hematologic effects: Thrombocytopenia, leukopenia, and hemolytic anemia have been reported rarely.

• Renal effects: Renal insufficiency and interstitial nephritis have been reported.

30-14. Key Points

Aminoglycosides

• Aminoglycoside antibiotics exhibit concentration-dependent bacterial killing.

• Aminoglycoside antibiotics are reserved for severe infections or for use against multidrug-resistant bacteria.

• Aminoglycoside antibiotic dosing should be pharmacokinetically tailored for each patient to optimize the therapeutic effect and minimize toxicity.

Antifungal Agents

• Amphotericin B, caspofungin, micafungin, anidulafungin, fluconazole, itraconazole, posaconazole, and voriconazole are effective against systemic fungal infections.

• Imidazole antifungal antibiotics are potent inhibitors of hepatic metabolism, thereby decreasing the elimination of numerous agents.

Gram-Positive Antibiotics

• Daptomycin, linezolid, and quinupristin-dalfopristin are clinically effective against MRSA, MRSE, and VRE.

• Daptomycin cannot be used to treat pneumonia.

• Vancomycin is a broad-spectrum Gram-positive antibiotic that should be pharmacokinetically tailored for each patient to maximize therapeutic benefit and minimize toxicity.

Miscellaneous Antibiotics

• Clindamycin is an effective anaerobic antibiotic and an effective Gram-positive aerobic antibiotic with activity against many MRSA isolates.

• The carbapenem antibiotics possess a very broad spectrum of activity and should be restricted to appropriate indications to minimize development of resistance.

Penicillins

• Penicillin antibiotics exhibit time-above-MIC-dependent bacterial killing.

• All penicillins, except nafcillin and oxacillin, are renally eliminated and require dosage adjustments in patients with renal dysfunction.

Cephalosporins

• Cephalosporin antibiotics exhibit time-above-MIC-dependent bacterial killing.

• In first-generation cephalosporins, Gram-positive activity is extensive, but Gram-negative activity is limited.

• In second-generation cephalosporins, Gram-positive activity is similar to that of first-generation agents, but Gram-negative activity is generally more extensive than that of first-generation agents.

• In third-generation cephalosporins, Gram-positive activity is decreased compared to that of first- and second-generation agents, but Gram-negative activity is extensive.

Fluoroquinolones

• Quinolone antibiotics exhibit concentration-dependent bacterial killing similar to that of the aminoglycosides.

• The later-generation quinolones possess improved Gram-positive activity, including resistant streptococci.

Sulfonamides

• Sulfonamides are primarily urinary anti-infectives whose usefulness has decreased because of the development of resistance.

Tetracyclines

• Tetracyclines are drugs of choice for Lyme disease and Rocky Mountain spotted fever.

Macrolides

• Macrolides are primarily active against Gram-positive bacteria, including penicillin-resistant streptococci.

• Macrolides are the drugs of choice in atypical pneumonia.

• Telithromycin possesses greater in vitro activity against multidrug-resistant Gram-positive organisms and Haemophilus influenzae than do the macrolides but has a black box warning for hepatotoxicity.

Antitubercular Agents

• Isoniazid, rifampin, and streptomycin exhibit the lowest incidence of resistance.

• Isoniazid, rifampin, and pyrazinamide are the agents of first choice.

30-15. Questions

1.

Which of the following are true regarding aminoglycoside antibiotics?

I. Aminoglycoside antibiotics are bactericidal against most susceptible isolates.

II. Aminoglycoside antibiotics exhibit concentration-dependent bacterial killing.

III. Aminoglycoside antibiotics should be reserved for serious infections.

A. I only

B. I and II

C. I and III

D. II and III

E. I, II, and III

 

2.

Which of the following most accurately characterize aminoglycoside toxicity?

I. Ototoxicity because of eighth cranial nerve damage

II. Nephrotoxicity exhibited as acute tubular necrosis

III. Bone marrow suppression

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

3.

Which of the following best characterize aminoglycoside antimicrobial activity?

I. Active against most aerobic Gram-negative bacteria

II. Active against most anaerobic Gram-negative bacteria

III. Active against most fungal isolates

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

4.

Which of the following antifungals are effective against systemic infections?

I. Amphotericin B

II. Fluconazole

III. Nystatin

A. I only

B. II only

C. III only

D. I and II

E. I and III

 

5.

Which of the following are true about amphotericin B-induced nephrotoxicity?

I. Nephrotoxicity is the major dose-limiting toxicity.

II. Nephrotoxicity is usually reversible on discontinuation of the drug.

III. Amphotericin B lipid formulations decrease nephrotoxicity by 20-30%.

A. I only

B. II only

C. I and II

D. II and III

E. I, II, and III

 

6.

Which of the following best describe the drug interactions noted with the imidazole antifungals?

I. Increased elimination of warfarin

II. Decreased elimination of warfarin

III. Increased metabolism of the oral contraceptives

A. I only

B. II only

C. III only

D. II and III

E. I, II, and II

 

7.

Linezolid is best described by which of the following?

I. Linezolid is bacteriostatic against staphylococci.

II. Linezolid is bactericidal against staphylococci.

III. Linezolid is a weak MAO inhibitor.

A. I only

B. II only

C. I and III

D. II and III

E. I, II, and III

 

8.

Linezolid possesses activity against which of the following bacteria?

I. MRSA

II. Enterococcus faecium

III. Enterococcus faecalis

A. I only

B. II only

C. III only

D. I and II

E. I and III

 

9.

Quinupristin-dalfopristin is best described by which of the following?

I. Quinupristin-dalfopristin exhibits activity against MSSA.

II. Quinupristin-dalfopristin exhibits activity against MRSA.

III. Quinupristin-dalfopristin exhibits activity against streptococci.

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

10.

Vancomycin is best described by which of the following?

I. Vancomycin exhibits activity against MRSA.

II. Vancomycin exhibits activity against Enterobacter.

III. Vancomycin exhibits activity against Clostridium difficile.

A. I only

B. II only

C. III only

D. I and II

E. I and III

 

11.

Vancomycin toxicity is best described by which of the following?

I. Nephrotoxicity exhibited as acute tubular necrosis that is seldom reversible

II. Ototoxicity that is commonly exhibited as vestibular toxicity

III. Histamine release, or "red-man syndrome," which is associated with rapid IV infusion

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

12.

Which of the following best describe appropriate vancomycin monitoring?

I. Trough serum concentrations should be routinely monitored in patients with preexisting renal dysfunction.

II. Peak serum concentrations should be routinely monitored in patients with preexisting renal dysfunction.

III. Serum concentration monitoring is of no benefit in vancomycin monitoring.

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

13.

Clindamycin exhibits antibacterial activity against which of the following microorganisms?

I. Aerobic Gram-positive bacteria

II. Anaerobic Gram-negative bacteria

III. Aerobic Gram-negative bacteria

A. I only

B. II only

C. III only

D. I and II

E. I and III

 

14.

Which of the following best describe the carbapenem antibiotics?

I. Carbapenem antibiotics exhibit activity against most Gram-positive and Gram-negative aerobes and anaerobes.

II. Meropenem induces seizures more commonly than imipenem.

III. Cilastatin exhibits activity against most Gram-positive aerobes.

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

15.

Which of the following best describe the penicillins?

I. Penicillins exhibit concentration-dependent bacterial killing.

II. Penicillins exhibit time-above-MIC-dependent bacterial killing.

III. Penicillins exhibit excellent MRSA activity.

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

16.

Which of the following penicillins require dosage adjustment in patients with renal dysfunction?

I. Ampicillin

II. Nafcillin

III. Oxacillin

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

17.

Which of the following best describe the cephalosporins?

I. Cephalosporins exhibit concentration-dependent bacterial killing.

II. Cephalosporins exhibit time-above-MIC-dependent bacterial killing.

III. Cephalosporins exhibit excellent MRSA activity.

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

18.

Which of the following best describe the antibacterial activity of the cephalosporins?

I. In first-generation cephalosporins, Gram-positive activity is extensive, but Gram-negative activity is limited.

II. In second-generation cephalosporins, Gram-positive activity is similar to that of first-generation agents, but Gram-negative activity is generally more extensive than that of first-generation agents.

III. In third-generation cephalosporins, Gram-positive activity is decreased compared with that of first- and second-generation agents, but Gram-negative activity is extensive.

A. I only

B. II only

C. III only

D. All of the above

E. None of the above

 

19.

Which of the following best describe the antibacterial activity of the quinolones?

I. Quinolones exhibit concentration-dependent bacterial killing.

II. Quinolones exhibit time-above-MIC-dependent bacterial killing.

III. Quinolones exhibit extensive anaerobic activity.

A. I only

B. II only

C. III only

D. I and III

E. II and III

 

20.

Which of the following best describe the important patient counseling points for the quinolones?

I. Avoid use in children and pregnant or nursing women because of the risk of cartilage erosion in growing bone tissue.

II. Do not take within 2 hours of taking antacids, multivitamins, calcium, magnesium, or iron supplements.

III. Take with a full glass of water and remain sitting or upright for 2 hours to avoid esophageal irritation.

A. I only

B. II only

C. III only

D. I and II

E. II and III

 

21.

Which of the following best describe the sulfonamides?

I. Drugs that interfere with vitamin B12 synthesis by competitively inhibiting PABA utilization

II. Drugs of choice for Clostridium difficile colitis

III. Primarily urinary anti-infectives whose usefulness has decreased because of the development of resistance

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

22.

Which of the following best describe the tetracyclines?

I. Tetracyclines exhibit bacteriostatic activity.

II. Tetracyclines are the drugs of choice for Lyme disease.

III. Tetracyclines are contraindicated in children under age 8.

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

23.

Which of the following best describe the macrolides?

I. Primarily effective against Gram-positive aerobic bacteria

II. Effective against penicillin-resistant streptococci

III. Ineffective against penicillin-resistant streptococci

A. I only

B. II only

C. III only

D. I and II

E. I and III

 

24.

Which antitubercular agents exhibit the lowest incidence of resistance?

I. Isoniazid

II. Rifampin

III. Streptomycin

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

25.

Which of the following drug combination regimens are considered the agents of first choice for empiric treatment of TB?

I. Isoniazid, rifampin, and streptomycin

II. Isoniazid, rifampin, and pyrazinamide

III. Isoniazid, ethambutol, and cycloserine

A. I only

B. II only

C. III only

D. All of the above

E. None of the above

 

30-16. Answers

1.

E. Aminoglycoside antibiotics are bactericidal against most susceptible isolates, exhibit concentration-dependent bacterial killing, and are usually reserved for serious infections due to toxicity.

 

2.

D. Ototoxicity is due to eighth cranial nerve damage and may be irreversible. Nephrotoxicity is exhibited as an acute tubular necrosis that is usually reversible and seldom requires dialysis. Neuromuscular blockade is the third most common toxicity noted with the aminoglycosides.

 

3.

A. Aminoglycosides are active against most aerobic Gram-negative and selected aerobic Gram-positive bacteria. They have no activity against anaerobic bacteria or fungi.

 

4.

D. Amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole are effective against systemic fungal infections.

 

5.

E. Acute renal dysfunction is the most common dose-limiting amphotericin B toxicity, the renal dysfunction is usually reversible and seldom requires dialysis, and lipid formulations decrease toxicity by 20-30%.

 

6.

B. The imidazole antifungals decrease hepatic clearance of numerous hepatically metabolized medications, thereby increasing their activity and risk for toxicity.

 

7.

C. Linezolid is bacteriostatic against staphylococci and enterococci. It is bactericidal against Streptococcus species only. The agent is a weak MAO inhibitor.

 

8.

D. Linezolid is active against MSSA, MRSA, and Enterococcus faecium (VRE). Enterococcus faecalis isolates are resistant.

 

9.

E. Quinupristin-dalfopristin is active against MSSA, MRSA, streptococci, and VRE. Enterococcus faecalis isolates are commonly resistant.

 

10.

E. Vancomycin is active against aerobic Gram-positive bacteria only; it has no clinically significant Gram-negative activity. Vancomycin is the second-line drug of choice for Clostridium difficile colitis.

 

11.

C. Vancomycin nephrotoxicity is uncommon and is exhibited as acute tubular necrosis, which is commonly reversible and seldom requires dialysis. Ototoxicity is due to eighth cranial nerve damage, which manifests as high-frequency hearing loss, seldom affecting the vestibular system. The histamine, or "red-man syndrome," reaction is most commonly related to the infusion rate.

 

12.

A. Vancomycin serum concentration monitoring is not required in patients responding well to therapy and with normal renal function. Vancomycin trough concentrations should be assessed in patients with preexisting or worsening renal function or those not responding to therapy.

 

13.

D. Clindamycin exhibits activity against aerobic Gram-positive bacteria and anaerobic Gram-positive and Gram-negative bacteria. It has no clinically significant aerobic Gram-negative activity.

 

14.

A. Carbapenems are active against most aerobic and anaerobic Gram-positive and Gram-negative bacteria. Imipenem is more likely to induce seizures, and cilastatin inhibits the metabolism of imipenem but has no antibacterial activity.

 

15.

B. Penicillins exhibit time-dependent bacterial killing and have no activity against MRSA.

 

16.

A. All penicillins—with the exception of nafcillin and oxacillin—require dosage adjustment in patients with renal dysfunction.

 

17.

B. Cephalosporins exhibit time-dependent bacterial killing and have no activity against MRSA.

 

18.

D. First-generation cephalosporins exhibit extensive Gram-positive activity but limited Gram-negative activity. Second-generation cephalosporins maintain Gram-positive activity similar to that of the first-generation agents, but their Gram-negative activity is generally improved. Third-generation cephalosporins exhibit decreased Gram-positive activity, but Gram-negative activity is significantly improved.

 

19.

A. Quinolones exhibit concentration-dependent bacterial killing similar to that of the aminoglycosides. They possess good aerobic Gram-positive and Gram-negative activity, but have limited anaerobic activity.

 

20.

D. Quinolones have been shown to decrease cartilage formation in beagle pups, but this effect in humans is somewhat controversial. Their use in children should be reserved for serious infections to avoid the risk. Quinolones are bound to divalent cations and should not be coadministered. They do not cause significant esophageal irritation.

 

21.

C. Sulfonamides interfere with folic acid metabolism by inhibiting PABA utilization. They have no activity against C. difficile colitis and are primarily relegated to urinary anti-infectives because of resistance.

 

22.

E. Tetracyclines are bacteriostatic. They are drugs of choice for Lyme disease, and they should not be administered to children under age 8 to avoid permanent tooth staining and potential deposition into bone.

 

23.

D. Erythromycins are primarily Gram-positive aerobic antibiotics with good activity against most penicillin-resistant Streptococcus isolates.

 

24.

E. Isoniazid, rifampin, and streptomycin exhibit the lowest incidence of Mycobacterium tuberculosis resistance.

 

25.

B. Isoniazid, rifampin, and pyrazinamide are considered agents of first choice for empiric treatment of tuberculosis (TB) because of a low incidence of resistance and acceptable tolerability profile. Ethambutol is commonly added to the regimen in areas of increased resistance.

 

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