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A Professional Program of the MWC Office of Continuing Professional Education
After completing this continuing education article, the pharmacist should be able to:
Respiratory tract infections (RTIs) are a major cause of morbidity and mortality worldwide, accounting for 2.7 million emergency room visits per year in the United States alone.1 According to a survey conducted by the World Health Organization, RTIs were responsible for 750,000 of 14 million deaths overall in 1990 and are the 3rd leading cause of mortality in children <14 years of age.2
Respiratory infections are classified, based on the area of involvement, into either upper or lower RTIs. Upper RTIs include acute otitis media (AOM) and acute bacterial rhinosinusitis (ABRS), and lower RTIs include acute exacerbation of chronic bronchitis (AECB) and community-acquired pneumonia (CAP). The major bacterial pathogens associated with these infections are categorized in Table 1.3-7
Epidemiology, Pathophysiology, and Clinical Presentation of RTIs
Acute Otitis Media
AOM is the most frequent infection in infants and children, and it is the most common reason for physician office visits among this patient population.8,9 Annually, ?30 million prescriptions are written for otitis media-related antibacterials.9 AOM usually follows a viral infection (Table 1) of the nasopharynx, which leads to a disruption of eustachian-tube function.3 Patients present to their physician with acute onset of fever, otalgia (tugging on the ear), and hearing loss. Atypical symptoms, generally seen in very young children, include lethargy, jitteriness, vomiting, and anorexia. The tympanic membrane may get perforated in severe cases, and children may present with purulent discharge, termed otorrhea.8
Acute Bacterial Rhinosinusitis
ABRS affects approximately 37 million patients yearly. It is estimated that $2 billion is spent on medications to treat sinus-related problems. Sinusitis most commonly affects adult patients. It is defined as inflammation of the mucosal lining of the paranasal sinuses.8 Patients usually present with mucopurulent nasal discharge, congestion, facial pain or pressure, fever, and maxillary toothache.10
Acute Exacerbation of Chronic Bronchitis
AECB is a frequent lower respiratory tract complication among smokers. In 1994, approximately 14 million people in the United States were affected, representing approximately 5.4% of the adult population.9 The chronic inhalation of irritating noxious substances results in diminished mucociliary function of the bronchial mucosal lining. In addition, this lining becomes thickened, and the number of mucoussecreting goblet cells increases. Due to these changes, patients with chronic bronchitis are predisposed to bacterial infections, which result in acute exacerbations of symptoms. Patients with AECB present with worsening cough accompanied by increased purulent sputum production, worsening in shortness of breath and overall lung function, and fever.8
CAP has established itself as the 6th leading cause and the most common infectious cause of death in the United States.1,9 At least 4 million cases of pneumonia are diagnosed annually, and the cost of care approaches $20 billion.1 Patients with pneumonia have an acute onset of symptoms that include fever, chills, dyspnea, productive cough, tachypnea, and tachycardia. Patients' lung examination is usually significant for inspiratory crackles and diminished breath sounds. The chest radiograph is the most useful diagnostic tool and usually reveals an infiltrate in the affected lobe(s) of the lung.1
Treatment Options for RTIs
Numerous antimicrobial options are available for the management of RTIs. An ideal oral agent for treating these infections should possess all of the following characteristics: efficacy against all possible pathogens, excellent concentration at the site of action, minimal potential for selection of resistant bacterial strains, good pharmacokinetic profile allowing for a convenient dosing regimen, and an excellent safety profile. Unfortunately, no single agent is on the market today that possesses all of these characteristics. Currently available oral antimicrobials indicated for the treatment of bacterial RTIs include beta-lactams (penicillins and cephalosporins), macrolides, ketolides, tetracyclines, and fluoroquinolones. The antimicrobial agents and dosing regimens used in the management of RTIs are summarized in Table 2.
Penicillins are active against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. They do not have any activity against atypical pathogens. Penicillin nonsusceptibility has reached approximately 35% of S pneumoniae isolates. In addition, 35% of H influenzae isolates and 90% of M catarrhalis isolates are resistant to penicillin antimicrobials.2,9 There are 2 major mechanisms of resistance to beta-lactams among respiratory tract pathogens: alterations in penicillin binding proteins (target site of antibiotic action) and production of beta-lactamases (enzyme responsible for the breakdown of the beta-lactam ring). When penicillin binding proteins are involved, as is the case with S pneumoniae, resistance can be overcome with the use of higher doses of the beta-lactam antimicrobial. In fact, amoxicillin doses up to 4 g per day have been used in the management of patients with resistant or intermediate-resistant S pneumoniae RTIs.11 On the other hand, when resistance is secondary to production of beta-lactamase, which is seen with H influenzae and M catarrhalis, the addition of a beta-lactamase inhibitor, such as clavulanate, is necessary.12
Oral cephalosporins are similar to penicillins in terms of spectrum of activity and resistance. The increased resistance to cephalosporins among pneumococcal isolates is worrisome. The emergence of beta-lactamase-producing strains of H influenzae and M catarrhalis has significantly reduced the efficacy of older cephalosporins (cephalexin, cefadroxil, cefaclor, and cefuroxime) in the management of RTIs. Newer third-generation agents, such as cefdinir and cefditoren, are more stable to hydrolysis by beta-lactamases, thus retaining efficacy against beta-lactamase-producing organisms.9
Macrolides have activity against most common respiratory tract pathogens, including atypical organisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Erythromycin was the first macrolide antibiotic to be developed, and it was launched in the 1950s for treatment of upper and lower RTIs. Erythromycin is no longer preferred in the treatment of RTIs due to its inferior activity against H influenzae, frequent dosing schedule, and an increased incidence of adverse effects, specifically, gastrointestional (GI) effects. Newer agents such as clarithromycin and azithromycin are better tolerated and possess better pharmacokinetic characteristics and enhanced spectrum of activity.
Like beta-lactam agents, macrolides have not been devoid of bacterial resistance issues. S pneumoniae resistance to macrolides approaches 52%.2 This is usually the result of inducible macrolide-lincosamide-streptograinB (MLSB) resistance type coded by the erm gene, which prevents the binding of the macrolide to its ribosomal binding site. Options to overcome this resistance mechanism are as yet unavailable. For this reason, empiric macrolide monotherapy is not recommended in the management of RTIs. Macrolide resistance among M catarrhalis and H influenzae is much less widespread, resulting in maintenance of activity against these organisms.2
The ketolide class of antibiotics has been synthetically derived from macrolides to enhance the activity of the latter. They have the same mode of action as macrolides, which involves binding to the 23S rRNA of the 50S ribosomal subunit of the bacteria, resulting in inhibition of protein synthesis. Whereas both macrolides and ketolides bind at domain V of the 23S rRNA, ketolides also bind at domain II, leading to sustained efficacy against macrolide-resistant strains of bacteria, including S pneumoniae. Ketolides are also characterized as having minimal potential to induce resistance.13 Telithromycin is the only ketolide currently available in the United States.
Tetracyclines were discovered in the 1940s, and the first agents were marketed in the 1950s. Generally, tetracyclines are broad-spectrum agents with activity against all respiratory tract pathogens, including atypical pathogens. Out of the available tetracycline derivatives, only doxycycline is in widespread use today due to its favorable pharmacokinetic and safety profiles, and low cost.14
High rates of tetracycline resistance have been documented among S pneumoniae and other pathogens since the 1970s. The most common mechanism of tetracycline resistance is through acquisition of the tet family of genes. These genes code for the efflux pump, which exports tetracycline out of the cell, preventing the drug from binding to the target site.14
Quinolone antibiotics were introduced in 1962 with the discovery of nalidixic acid. The first fluoroquinolone to be approved by the FDA was norfloxacin in 1984.15 This first-generation agent possessed good activity against urinary tract pathogens, such as Escherichia coli, but did not have any meaningful efficacy against respiratory tract organisms. Respiratory fluoroquinolones include levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin. These agents possess enhanced activity against S pneumoniae while maintaining excellent efficacy against H influenzae, M catarrhalis, and intracellular atypical pathogens. Respiratory fluoroquinolones are active against penicillin-and macrolide-resistant S pneumoniae, which allows them to be used as monotherapy for CAP.
Fluoroquinolone resistance among respiratory pathogens has not been of major concern until recently. Two mechanisms of bacterial resistance to fluoroquinolones are known: bacterial pathogens can evade fluoroquinolones through chromosomal mutation of the target enzymes, DNA gyrase and or topoisomerase IV, or the action of the efflux pump allows them to export the drug out of the cell. Both of these mechanisms have been identified among pneumococcal isolates.15,16
Safety Profile of Antimicrobials
Antibiotics are generally seen as safe drugs with few serious adverse effects, and the majority of the side effects that do occur are mild and transitory. In certain situations, however, such as high-dose therapy, advanced age, concomitant medical conditions, concomitant drug therapy, and extended duration of use, antibiotics can be associated with serious safety concerns. The pharmacist, through patient education and evaluation of therapy, can help prevent the potentially serious adverse reactions associated with antibiotic use.
Penicillins are generally considered safe compounds with extensive history of use and low incidence of reported serious adverse effects. The most common adverse reactions that occur during therapy are allergic or hypersensitivity reactions. An estimated 3% to 10% of patients are allergic to this class of antibiotics.17 Allergic reactions can manifest as anaphylaxis, cutaneous vasculitis, rashes including urticaria, and interstitial nephritis. Anaphylaxis is an infrequent, but life-threatening reaction, where patients may present with hives, angioedema, hypotension, and bronchospasms. These symptoms usually begin between 10 and 20 minutes after the administration of the penicillin. Once a patient has experienced an anaphylactic reaction, he or she should not be exposed to a betalactam agent again.17
Oral penicillins have been associated with frequent GI disturbances, which can manifest as nausea, vomiting, diarrhea, or abdominal pain. Ampicillin has a higher incidence of diarrhea than amoxicillin and therefore has fallen out of favor.17
Penicillin use has rarely been associated with a series of immune-mediated reactions including interstitial nephritis, serum sickness, and hemolytic anemia.18-21 Interstitial nephritis is more common with intravenous agents, but reports with oral agents have also been published.18,19 Patients generally present with fever, eosinophilia, and acute renal failure. Amoxicillin discontinuation and treatment with corticosteroids results in return of renal function to baseline.18,19
Serum sickness has been reported with amoxicillin and amoxicillin/ clavulanate in less than 1% of patients.20,21 The symptoms usually appear anywhere from 7 to 10 days after the discontinuation of the offending agent. Typically, manifestations of serum sickness include fever, arthralgias, lymphadenopathy, and painful cutaneous eruptions. Corticosteroid therapy has resulted in complete symptom resolution in all reported cases.20,21
Hemolytic anemia can occur when an antigenic penicillin-erythrocyte complex is formed, causing antibody formation and ultimately leading to red-blood-cell destruction or hemolysis. This reaction, affecting less than 1% of patients, has been reported to occur in patients after receiving oral doses of penicillin VK and amoxicillin.22-24 The reaction was reversible with discontinuation of the offending agent.
Amoxicillin/clavulanate therapy has been associated with hepatotoxicity, including hepatocellular and cholestatic injury. The incidence rate has been estimated to be 1:200,000. It is believed to be the clavulanic acid component, and not amoxicillin, that is responsible for this adverse effect. The incidence is believed to be higher in elderly patients and those who receive 2 or more courses of amoxicillin/clavulanate therapy. The onset of liver damage is delayed, with most cases presenting 1 to 4 weeks after discontinuation of therapy. Liver enzymes usually normalize within 3 to 4 months, but may take up to 1 year to return to baseline.25-27
Neurologic adverse effects, including irritability, delirium, hallucinations, and generalized seizures, have been reported with intravenously administered penicillin compounds, but not with standard doses of oral agents. In an overdose situation, these adverse effects should be taken into consideration as well.17
Similar to penicillins, cephalosporins as a group are considered to be well tolerated. The most common reactions to oral cephalosporins used in the treatment of RTIs are GI in nature. Nausea, vomiting, or diarrhea may ensue during therapy but rarely necessitate discontinuation of the drug. Allergic reactions are seen in 1% to 3% of patients receiving oral cephalosporins, and these patients may present with reactions similar to those described for penicillins.28 It should be noted that, in patients with a known allergy to penicillin, the rate of cross-reaction to cephalosporins has been estimated to be approximately 5.4% to 16.5%.28 In general, for patients with a known immunoglobulin E-mediated allergic reaction to penicillins (ie, anaphylaxis, hives, angioedema), it is, advised to avoid the cephalosporin family of antibiotics.
Immune-mediated reactions have been reported with oral cephalosporins in less than 1% of patients. Case reports associate the use of cefaclor and loracarbef, 2 structurally related second-generation agents, with immune-mediated thrombocytopenia.29,30 This acute reaction results in an abrupt decrease in platelet count, which may potentially lead to bleeding complications. In the reported cases, patients responded to withdrawal of the offending antibiotic and repeated courses of corticosteroids.29,30
Other immune-mediated reactions that have been described with oral cephalosporin use occur in less than 1% of patients and are similar to those seen with penicillins, including serum sickness, interstitial nephritis, and, rarely, hemolytic anemia.31-34 These reactions have been seen mostly with cefuroxime, cefaclor, and loracarbef, but other agents may be implicated as well.
Fluoroquinolones as a class are generally well tolerated. The most common side effects of these compounds seen in clinical trials were GI and included nausea, vomiting, abdominal pain, and diarrhea. Fluoroquinolones are known to have phototoxic potential, and all patients should be advised to use sunscreen SPF 15 or above when exposed to prolonged sunlight.
Tendinopathy is another classrelated toxicity of fluoroquinolones, with over 98 cases published since 1983.35 This rare adverse effect, affecting less than 3% of patients, most often involves the Achilles tendon, where inflammation occurs, and may lead to tendon rupture in up to 40% of cases.15 Tendinopathy tends to occur within 2 weeks of fluoroquinolone therapy, but tendon rupture may occur up to 6 months after discontinuation of the fluoroquinolone.36 Most of the time discontinuation of the offending agent and rest will reverse the tendinopathy, but surgical intervention may be required in up to 7% of patients. Time to recovery is 1 to 2 months.35 Risk factors associated with quinolone-induced tendinopathy include male sex, chronic corticosteroid use, chronic renal failure, and advanced age.15,36
Fluoroquinolone use has been associated with QTc interval prolongation. This adverse effect was observed in 1.1% of patients treated with sparfloxacin. However, the incidence of QTc prolongation with currently utilized respiratory fluoroquinolones has only been demonstrated in isolated case reports. The potential prolongation can range froma a mild, clinically insignificant increase in the QTc interval to potential progression to life threatening torsades de pointes, a polymorphic ventricular arrhythmia that can lead to sudden death. This seems to be a class effect of the fluoroquinolone family of antibiotics. Levofloxacin, gatifloxacin, and moxifloxacin have been implicated in causing torsades. Patients with cardiovascular risk factors, such as those with preexisting arrhythmias or those receiving concomitant QTc prolonging drugs or agents that inhibit the metabolism of fluoroquinolones, should avoid fluoroquinolones altogether. If started on a fluoroquinolone, these patients require close monitoring of the QTc interval. Agents that may potentiate quinolone QTc prolongation include class Ia and class III antiarrhythmics (eg, quinidine, amiodarone), quinine, and tricyclic antidepressants.15 Fluoroquinolones are less likely to lead to QTc prolongation than clarithromycin and erythromycin, but are more likely to cause this adverse effect as compared to azithromycin.37
Fluoroquinolones have also been associated with potentially fatal hepatotoxicity in less than 1% of patients. Liver toxicity may manifest as cholestasis, jaundice, pancreatitis, hepatocellular necrosis, or fulminant hepatic failure.38-43 The onset of liver failure has occurred as early as 2 days from first exposure to a fluoroquinolone, on reexposure, or after long-term use of these agents.38 No cases of liver failure have been reported to our knowledge with gemifloxacin, although mild liver enzyme elevations were noted in a pharmacokinetic study in 3 healthy volunteers. These enzyme elevations were self-limiting and reversible upon discontinuation of gemifloxacin.44 All respiratory quinolones display some degree of central nervous system (CNS) toxicity, including headache, dizziness, and rarely seizures. Case reports have been published in the literature that associate seizures with levofloxacin and gatifloxacin use.45-48 To date, moxifloxacin and gemifloxacin have not been reported to induce seizures. Risk factors that may predispose patients to this adverse effect include renal insufficiency, baseline electrolyte abnormalities, and concomitant administration of other agents that may reduce seizure threshold (eg, meperidine, theophylline, bupropion).47
Recently, fluoroquinolones have been implicated in negative changes in glucose homeostasis. A plethora of case reports established the hypoglycemic or hyperglycemic potential of gatifloxacin.49-51 Among the patients with hypoglycemia, most were on concomitant oral sulfonylureas, such as glyburide. Hypoglycemia has been persistent in some patients, necessitating high-concentration dextrose infusions. Risk factors for this reaction include pre-existing diabetes mellitus, advanced age, and concomitant oral hypoglycemic agents. In addition to gatifloxacin, this reaction has been reported with levofloxacin, but not moxifloxacin.52 To our knowledge hyperglycemia has been described only with gatifloxacin. Patients'blood sugar was within normal range at baseline but increased to 400 to 700 mg/dL after the initiation of gatifloxacin. All patients received insulin with return of glycemic control upon gatifloxacin discontinuation. The risk factors for gatifloxacin- induced hyperglycemia include advanced age and renal insufficiency. History of diabetes was absent in all the affected patients.51,53
The safety of clarithromycin and azithromycin has been well established via the extensive use of these products. The most commonly reported side effects include diarrhea, nausea, and abnormal taste (especially with clarithromycin) in adults and diarrhea, vomiting, headache, and abdominal pain in children.54 These events are secondary to the drugs'prokinetic effects and tend to occur less frequently with azithromycin. A decrease in adverse GI effects may be achieved by taking macrolides with food.55,56
Less than 1% of patients have developed cholestatic hepatitis and fulminant hepatic failure with clarithromycin and azithromycin.57-59 The onset of this side effect appears to range from 2 to 25 days and is reversible within 1 to 3 weeks of discontinuation of the offending agent.58 Macrolide therapy has also been associated with tinnitus and hearing loss. This adverse reaction is most commonly seen with the administration of erythromycin, although cases involving clarithromycin and azithromycin have been reported in the literature.
Macrolide-induced ototoxicity occurs in less than 1% of patients. It is a dosedependent, reversible adverse reaction that is associated with the presence of hepatic or renal dysfunction and longterm therapy (>4 weeks). Patients may present with decreased hearing, deafness, tinnitus, and dizziness. Hearing abnormalities generally resolve within 2 to 4 weeks of macrolide therapy discontinuation.60-62
Additional rare side effects, affecting less than 1% of patients on macrolide therapy, include aggravation of myasthenia gravis, QTc prolongation, torsades de pointes, and azithromycininduced interstitial nephritis.55,63,64 Risk factors associated with the development of torsades include preexisting cardiovascular conditions, concomitant drug administration (antiarrhythmics, azole antifungals, and pentamidine), age, and female sex.65 The risk of QTc interval prolongation is highest with clarithromycin and erythromycin and is negligible with azithromycin.37
The safety of telithromycin has been established with the widespread use of this product. The most frequent adverse effects associated with telithromycin therapy include diarrhea, nausea, vomiting, headache, and dizziness.66,67 Serious adverse effects are rare (0.2%-2%) and include gastroenteritis, hepatitis, vasculitis, and allergic reactions, and although they have been reported in clinical trials, no case reports have been published to date.67 In clinical trials, a small increase in QTc interval has been documented with the use of telithromycin 800 mg, although no cardiovascular morbidity or mortality was associated with the use of telithromycin (no head-to-head trials).67 Post marketing surveillance studies involving approximately 1 million patient exposures worldwide (as of October 1, 2002) revealed that the most common adverse events were GI in nature. Rarer adverse events associated with telithromycin therapy included 37 cardiac events, 42 hepatic adverse effects, and 168 adverse visual effects. The adverse cardiac events included tachycardia, palpitations, cardiovascular disorder, atrial fibrillation, supraventricular arrhythmia, and 1 case of torsades de pointes. Hepatocellular damage was seen in 2 patients, and 4 patients developed hepatitis. The hepatic side effects for the most part were reversible. Blurred vision, visual disturbances, and accommodation disorders were the most common visual disturbances reported.68 Visual effects are usually mild to moderate in severity and are more likely to occur after the first or second dose. Risk factors for ocular toxicity are female gender and age less than 40 years.69
The most common adverse reactions associated with tetracycline therapy are dose-related GI effects including nausea, vomiting, diarrhea, and abdominal pain. These side effects are more pronounced with tetracycline and minocycline and are less likely to occur with doxycycline therapy, possibly due to decreased effects of doxycycline on intestinal microflora.70 Numerous case reports of pill-induced esophageal ulcerations have been documented in the literature secondary to doxycycline use.71-73 The typical clinical presentation of pill esophagitis includes sudden- onset odynophagia and retrosternal pain. Esophageal injury usually resolves within 3 to 10 days following drug discontinuation. Acid reflux symptoms may be treated with antacids, proton-pump inhibitors, histamine2 blockers, or sucralfate. The risk of esophagitis can be minimized by taking doxycycline in an upright position well before lying down to sleep and drinking at least 100 mL of water after swallowing the medication.71,72
Doxycycline therapy is also associated with a <5% risk of phototoxic cutaneous reactions, including paresthesias, erythema, and photoonycholysis. Photoonycholysis refers to separation of the nail plate from the nail bed after exposure to ultraviolet light (Figure).74 Rarely, Stevens-Johnson syndrome and exanthematous pustulosis may be seen.70,75,76
Tetracycline antimicrobial agents have the ability to chelate calcium ions and can therefore be incorporated into teeth, cartilage, and bone. The effects of tetracyclines on tooth discoloration have been known since the 1950s. The discoloration is permanent and varies from yellow or gray to brown in color. These effects occur most frequently with tetracycline and minocycline and are minimal with doxycycline.70,77,78
Tetracyclines are capable of crossing the placenta and may interfere with the developing fetus. Possible toxicity to the fetus includes dental discoloration, enamel hypoplasia, and inhibition of bone growth. Therefore, tetracycline administration should be avoided during pregnancy and in children up to 8 years of age.70,77
Additional adverse effects of tetracycline therapy include possible worsening of renal function and hypersensitivity reactions.70
Role of the Pharmacist
Pharmacists are in a unique position to help patients avoid potential antibiotic- related problems. Before dispensing antibiotics, potentially serious drug interactions need to be ruled out, the patient's renal and hepatic function should be assessed if possible, and finally patient counseling must be provided. A description of clinically significant drug interactions and major counseling points is provided in Tables 3 and 4.
Among the public and health care providers, most antibiotics are seen as safe drugs with few serious adverse effects. This is generally true, but in certain situations, such as high-dose therapy, advanced age, concomitant medical conditions, concomitant drug therapy, and extended duration of use, antibiotics can be associated with serious safety concerns. Pharmacists are among the most accessible and trusted health care professionals. Therefore, the role of the pharmacist, through patient education and evaluation of therapy, is crucial in preventing potentially serious adverse reactions associated with antibiotic use.
Boris Nogid, PharmD: Clinical Pharmacy Coordinator, Infectious Diseases, Critical Care, The Brooklyn Hospital Center; Clinical Assistant Professor, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University. Anna Nogid, PharmD: Assistant Professor of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University; Critical Care Pharmacist, Bellevue Hospital Center
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CE REVIEW QUESTIONS
This educational lesson will be available to pharmacists on-line at www.pharmacytimes.com. (Based on the article starting on page 92.) Choose the 1 most correct answer.
1. The most common bacterial pathogen seen in community-acquired pneumonia is
2. Which of the following is the most common respiratory tract infection (RTI) in infants and children?
3. S pneumoniae resistance to penicillins may be overcome by:
4. Which of the following is true regarding the use of macrolides in RTIs?
5. Respiratory fluoroquinolones include all of the following agents EXCEPT:
6. Which of the following is an example of an immune-mediated reaction associated with penicillin administration?
7. In patients with a history of penicillin allergy, the rate of cross-reactivity to cephalosporins has been estimated to be approximately:
8. Which of the following is TRUE regarding fluoroquinolone-induced tendinopathy?
9. All of the following are risk factors for fluoroquinolone-induced hypoglycemia EXCEPT:
10. Which of the following is a possible side effect of macrolide therapy?
11. Which of the following agents is known to cause visual disturbances?
12. Which of the following is FALSE regarding doxycycline-induced pill esophagitis?
13. Possible side effects of doxycycline include all of the following EXCEPT:
14. Prolongation of QTc interval may be seen when clarithromycin is coadministered with
15. Which of the following combinations may result in a clinically significant drug interaction?
16. All of the following agents may lead to a clinically significant interaction when combined with telithromycin EXCEPT:
17. Which of the following agents may lead to decreased seizure threshold when coadministered with fluoroquinolones?
18. All of the following cephalosporins should be taken with food EXCEPT:
19. Which of the following antibiotics should be avoided in children?
20. All of the following are appropriate counseling points for a patient receiving moxifloxacin EXCEPT: