TREATING RESPIRATORY TRACT INFECTIONS IN THE ERA OF ANTIBIOTIC RESISTANCE An interview with Richard H. Drew, PharmD, MS, BCPS Dr Richard H. Drew is Infectious Diseases Clinical Pharmacist at Duke University Medical Center in Durham, Professor of Pharmacy at Campbell University in Buies Creek, NC, and Assistant Research Professor in the School of Medicine at Duke University. Dr Drew received his bachelor s degree in pharmacy at the University of Rhode Island (Kingston) and both a Master of Science and Doctor of Pharmacy degree from the University of North Carolina (Chapel Hill). He completed a residency in hospital pharmacy practice at Duke University Medical Center. Dr Drew is board-certified as a pharmacotherapy specialist with added qualifications in infectious diseases pharmacotherapy. Dr Drew maintains an active clinical practice in the areas of adult internal medicine and infectious diseases. He currently serves as codirector to postgraduate education programs for pharmacists in the area of infectious diseases at Duke University Medical Center. He has held leadership roles in professional organizations such as the Infectious Diseases Practice Research Network of the American College of Clinical Pharmacists (chairman), the Triangle College of Clinical Pharmacy (president), and North Carolina Association of Pharmacists (Pharmacotherapy Special Interest Group chairman). Dr Drew also holds active memberships in the American Society of Microbiology and the Society of Infectious Diseases Pharmacists. He currently serves on numerous professional and academic committees. Dr Drew has authored and/or coauthored numerous publications (including research papers and book chapters) and presented at several national and international meetings on the topic of infectious diseases pharmacotherapy. His practice and research interests include antimicrobial utilization, information technology, respiratory tract infections, gram-positive infections, and invasive fungal infections in the compromised host. He currently serves as a scientific reviewer for Pharmacotherapy, the Annals of Pharmacotherapy, Clinical Infectious Diseases, Antimicrobial Agents and Chemotherapy, the American Journal of Transplantation, Urology, and UpToDate. A senior clinical editor for Advanced Studies in Pharmacy (ASiP) interviewed Dr Drew to discuss the treatment of respiratory tract infections (RTIs) in the era of antibiotic resistance. ASiP: As a clinician, what is your impression of the impact of antimicrobial resistance demonstrated in bacteria most commonly isolated in patients with community-acquired RTIs? Dr Drew: In situations where a causative organism can be identified, Streptococcus pneumoniae continues to be the bacteria most frequently isolated in patients with many types of community-acquired RTIs. 1,2 Infections caused by this organism can result in significant morbidity. In the case of very young and elderly patients with severe infections and/or significant comorbidities, such infections can be fatal. Haemophilus influenzae and Moraxella catarrhalis, while less frequently isolated in patients with community-acquired pneumonia (CAP), are common causative pathogens in patients with acute bacterial exacerbations of chronic bronchitis, acute sinusitis, and acute otitis media. 1,2 Group A streptococci is the most frequent causative bacterial pathogen in acute Advanced Studies in Pharmacy 231
pharyngitis. 3 Finally, atypical pathogens, namely Legionella spp, Mycoplasma pneumoniae, and Chlamydophila pneumoniae, may result in monomicrobial or mixed infections in patients with CAP. 4 Empiric treatment of many community-acquired RTIs used to be relatively straightforward, and included the use of various beta-lactams (eg, penicillin, amoxicillin, and cephalosporins) or macrolides. However, increasing rates of in vitro resistance to both penicillin and macrolides have been observed in S pneumoniae over the past 2 decades. 1 Depending upon the geographic location, population studied, and breakpoints utilized, approximately 25% of US isolates are fully resistant to penicillin and 30% to macrolides. 2 Beta-lactamase production (a common mechanism of drug resistance to beta-lactams) can be observed in up to 30% of H influenzae and in more than 90% of M catarrhalis. 1,2 Such high rates of resistance result in diminished activity of penicillin, amoxicillin, and many cephalosporins. While overall rates of in vitro macrolide resistance in group A streptococci are low in the United States, 2 concerns have been raised regarding increased levels of resistance in some areas of the country. 5,6 Debates regarding the clinical relevance of the in vitro resistance of S pneumoniae to penicillins and macrolides in patients with RTIs have focused on a relative lack of studies to document the impact of such laboratory findings on treatment outcomes. 7-11 This prompted a re-evaluation (and subsequent redefinition) of the interpretive criteria used for the determination of in vitro resistance to penicillin for S pneumoniae isolated from patients with RTIs. Despite the controversy regarding the clinical relevance of in vitro resistance of common RTI pathogens, numerous observations have emerged. First, the clinical relevance of penicillin resistance in S pneumoniae has been established in closed space infections, most notably in central nervous system infections and (likely) middle ear infections. Second, despite revised interpretive criteria for in vitro testing in patients with RTIs, high-level resistance to penicillin (minimum inhibitory concentrations >2 mcg/l) still exceeds 20% in many geographic regions. 1 Such organisms more frequently exhibit in vitro resistance to other common classes of antibiotics, including macrolides, tetracyclines, and sulfonamides. 1 Persistence of resistant pathogens as respiratory tract colonizers may be associated with transmission of resistant pathogens and to either relapse or reinfection. 12 The rising use of fluoroquinolones (a class of antibiotics that has maintained potency in vitro against common bacterial etiologies of RTIs) has raised concern about increasing rates of resistance in other pathogens (such as Staphylococcus aureus and many gram-negative pathogens). 13,14 Finally, new strategies to combat the potential impact of antimicrobial resistance must be formulated. ASiP: Can you list treatment strategies for community-acquired RTIs that attempt to address the issue of drug resistance? Dr Drew: Many of these strategies are discussed in detail elsewhere in this monograph. To briefly summarize, restricting antimicrobial prescribing to patients with bacterial etiologies of infection who are most likely to benefit is the first step. 15 Many community-acquired RTIs are due to viral pathogens, and will not respond to antibacterial therapy. An example is acute, uncomplicated bronchitis in otherwise healthy individuals, where (with the exception of patients with pertussis) antibacterials are not indicated for treatment. 16 Once the decision is made to prescribe antibiotics, patient-, pathogen-, and disease-specific factors must be considered in selecting the optimal agent. Patientspecific considerations may include (but are not limited to) comorbidities, risks for drug-resistant pathogens (such as prior antimicrobial therapy), allergies, organ function, and ability to comply with the prescribed treatment course. Knowledge regarding common bacterial etiologies and their local in vitro susceptibilities are important pathogen-specific considerations. Disease severity may impact both the site of treatment and the need for parenteral therapy. Drug-specific factors for selection should include (but are not limited to) spectrum of activity, established efficacy and safety, pharmacokinetic profile, stability against resistance, convenience, and cost. Evolving data regarding the pharmacodynamic activity of antibiotics has led to improvements in the ability to compare the potency of antibiotics against common RTI pathogens. 17 This has also prompted new dosing strategies for established antibiotics. For example, recently published treatment guidelines have recommended increasing doses of amoxicillin in select patients with acute otitis media 18 and sinusitis 19 to address the need to maintain optimal antibiotic exposure in the setting of increasing drug resistance. 232 Vol. 2, No. 6 October 2005
Strategies of dose intensification may be combined with shorter treatment durations, such as the use of higherdose, short-course levofloxacin therapy for the treatment of mild to moderate CAP. 20 Shorter courses of therapy, also approved for select macrolides and ketolides, 21 may improve patient compliance with prescribed therapy. Other strategies to address the issue of drug resistance for community-acquired RTIs include combination therapy and use of new antimicrobials. Combination anti-biotic therapy has been recommended in certain settings, such as treatment-refractory sinusitis 19 and as an option to monotherapy in select patients with CAP. 22 While antibiotic drug development has slowed considerably in the past several years, newer treatment options (such as the fluoroquinolone gemifloxacin and the ketolide telithromycin) have been introduced that demonstrate both favorable in vitro activity and treatment outcomes for patients with select community-acquired RTIs. 23 ASiP: What are some patient-oriented strategies the pharmacist can employ to optimize antibiotic use and protect from future resistance? Dr Drew: I believe the first step in reducing the impact of drug resistance is disease prevention. Routine vaccination in patients at highest risk of infections is a cost-effective strategy to prevent infections. Pneumococcal vaccine (7-valent) is now routinely recommended in children, while the 23-valent vaccine should be administered to adults at highest risk of infection. Although the role of vaccination in the prevention of invasive pneumococcal infection has been clearly established, 24 the impact on the prevention of RTIs due to drug-resistant pathogens is less well known. 25,26 Influenza virus vaccine should also be administered to at risk patients and has a role in the prevention of secondary bacterial infections. Comprehensive information regarding the use of these vaccines is available from the Centers for Type of Information Pneumococcal vaccine Disease Control and Prevention (Table 1). Pharmacists should familiarize themselves with vaccination Influenza virus vaccine Patient educational materials guidelines, since pharmacists are assuming an increasing role in programs aimed at identifying and vaccinating eligible patients. 27,28 Another major role pharmacists can play in optimizing antibiotic use is to educate patients regarding the consequences of inappropriate antibiotic prescribing. 29 Many authorities believe that clinicians prescribe antibiotics in the setting of acute viral illnesses to meet expectations of patients or parents of patients for antibiotic treatment. Numerous patient-oriented educational materials are available to help pharmacists advise patients regarding the implications of inappropriate use (Table 1). Once the decision is made to prescribe antibacterials, patient education regarding appropriate use is essential. Common elements of patient counseling (eg, frequency of administration, treatment duration, administration relative to food, anticipated side effects, and common drug interactions) also apply to antibiotic therapy. In addition, it is not uncommon for patients to discontinue treatment courses prematurely if symptoms resolve. This may leave supplies of incomplete or inappropriate antibiotic treatments in the household for this patient or other family members. Common counseling for antibiotics should include instructions to complete the entire treatment course. Detection of potential patient noncompliance or treatment failures through sequential courses of therapy for the same infection should prompt discussions with both the patient and prescriber. ASiP: Can you describe how pharmacists can collaborate with physicians in the selection of the most appropriate antimicrobial for communityacquired RTIs? Dr Drew: Perhaps the greatest impact would be in the promotion of appropriate antibiotic use. This requires knowledge and promotion of published Table 1. Useful Websites for Pharmacists Treating Patients with RTIs Website http://www.cdc.gov/nip/vaccine/pneumo/default.htm http://www.cdc.gov/nip/default.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/rr54e713a1.htm Centers for Disease Control and Prevention: http://www.cdc.gov/drugresistance/community/tools.htm Alliance for Prudent Use of Antibiotics: http://www.tufts.edu/med/apua/index.html Advanced Studies in Pharmacy 233
guidelines that identify patients for whom antibacterials would most likely benefit. 30 Consensus treatment guidelines for many community-acquired RTIs are listed in Table 2. 3,18,19,22,31,32 Increasing support for the no antibiotic alternative or delayed antibiotic prescribing is appearing in the literature. For example, recently published guidelines for the treatment of acute otitis media identify an observation option in patients 2 years of age and older with nonsevere illness as long as appropriate follow-up can be assured. 18 Delayed antibiotic prescribing involves the prescribing of antibiotics to patients with nonsevere RTIs of uncertain etiology conditional on the persistence or worsening of symptoms without the requirement of a return visit. 33 Although the initial antibiotic treatment choice for bacterial community-acquired RTIs is empiric, antimicrobial treatment should provide coverage for the most likely causative bacterial pathogens (S pneumoniae, H influenzae, and M catarrhalis). Coverage for atypical pathogens (Legionella spp, M pneumoniae, and C pneumoniae) 34-36 should be considered for patients with pneumonia. Whenever possible, selection should include consideration of local antibiotic susceptibility information. Antibiotic therapy can be adjusted following identification of the offending pathogen, and use of agents with excessively broad spectrums of activity avoided whenever possible. As previously discussed here (and in detail elsewhere in this monograph), antibiotic selection should incorporate knowledge of the antibiotic s pharmacodynamic profile. The pharmacist s unique knowledge regarding the patient s medication history may help identify patients at greatest risk of resistance due to prior drug exposure. Treatment options can then be selected from agents from a different class of antibiotics that do not share common mechanisms of resistance with prior therapies. For example, patients with a bacterial RTI prescribed azithromycin 500 mg on Day 1 followed by 250 mg/day on Days 3 to 5 returning to the pharmacy for retreatment with the same agent likely indicate that the patient is not receiving appropriate coverage of the causative agent. In these instances, the pharmacist should contact the prescriber and discuss other treatment options. ASiP: In addition to avoiding inappropriate antibiotic use, what can the pharmacist do to promote safe antibiotic use? Table 2. Consensus Treatment Guidelines for RTIs RTI Reference for Guideline Pharyngitis Bisno et al 3 Acute otitis media Subcommittee on Management of Acute Otitis Media 18 Acute sinusitis Sinus and Allergy Health Partnership 19 CAP Mandell et al 22 Acute bronchitis Snow et al 31 AECB Balter et al 32 AECB = acute exacerbations of chronic bronchitis; CAP = communityacquired pneumonia; RTI = respiratory tract infection. Dr Drew: Careful attention should be paid to the patient s medical history in order to screen for issues pertaining to safe use of antibiotic therapy. This includes (but is not limited to) allergy history, comorbidities that predispose patients to toxicities, and clinically significant drug interactions. In addition, patients should be queried as to their use of herbal and vitamin products. While it is obvious that medications should be avoided in situations where prior allergies have been documented, such documentation is generally sparse or erroneous. Such histories may be inaccurate due to a reflection of drug-related side effects (such as gastrointestinal intolerance) rather than true allergic reactions. This seems especially true in patients with a history of allergic reactions to penicillin. A detailed discussion of this issue as it relates to histories of penicillin allergy has been published elsewhere. 37 Concerns exist regarding cross-allergenicity between members of the same family of compounds. Because of structural similarities, allergic reactions across antimicrobial drug classes are a concern for the macrolides, azalides, and ketolides. The incidence of cross-allergenicity between penicillins and cephalosporins has been reported to range between 5% and 15%. However, cephalosporins have been safely administered to patients with a history of penicillin allergy in the absence of a history of an immediate (life-threatening) hypersensitivity reaction. 38 Comorbidities that may predispose patients to drug-related toxicities vary by antibiotic class. 234 Vol. 2, No. 6 October 2005
However, as is common with other classes of therapy, elderly patients may be at increased risk of antibiotic-related side effects. Most beta-lactam and fluoroquinolones require dosing adjustment in patients with renal impairment. Safe use of antibiotics also requires consideration and appropriate action in situations of clinically significant drug interactions. Examples of common or serious drug-drug interactions and side effects of antibiotics commonly used for RTIs are provided in Table 3. The pharmacist should counsel patients on the potential side effects and drug interactions associated with their antimicrobial thera- Table 3. Common or Serious Drug-Drug Interactions and Side Effects of Antibiotics Commonly Used for RTIs* RTI Therapy Drug-Drug Interaction Side Effect Beta-lactams All --Efficacy of oral contraceptives may be reduced, but definitive --Gastrointestinal studies are lacking intolerance --Probenecid administration decreases renal clearance of many beta-lactam antibiotics --Allergic reactions --May increase INR in patients on previously stable doses of warfarin Cefuroxime, axetil, cefdinir, --Reduced plasma concentrations with concomitant administration and cefpodoxime of antacids, H2 antagonists, and (for cefdinir) iron supplements Macrolides Clarithromycin and --Increased serum levels of lipophilic statin (atorvastatin, lovastatin, and simvastatin) --Gastrointestinal --Inhibition of drugs metabolized by CYP4503A, including (but not limited to) intolerance erythromycin theophylline, cyclosporine, benzodiazepines (various), cisapride, tacrolimus, --QT prolongation statins (various), sildenafil, diltiazem, verapamil, ergot alkaloids, and itraconazole --Concomitant administration with class IA and class III antiarrhythmics, astemizole, terfenadine, and other drugs that increase QT prolongation should be avoided --Increased effects of warfarin --Increased plasma concentration with agents that inhibit CYP3A (erythromycin only) Azalides Azithromycin --Concomitant administration of antacids may reduce absorption of azithromycin Fluoroquinolones Ciprofloxacin, --Decreased absorption and bioavailability of fluoroquinolone with divalent --QT prolongation levofloxacin, and trivalent cations (calcium, aluminum, magnesium, and iron) such as --Tendon rupture gatifloxacin, those found in nutritional supplements and antacids --CNS side effects such as gemifloxacin, and --Increased prothrombin time when used with warfarin dizziness and headaches moxifloxacin --Gastrointestinal intolerance --Some fluoroquinolones (most notably gatifloxacin) have been associated with hypo- and hyperglycemia Ketolides Telithromycin --Increased serum levels of lipophilic statins (atorvastatin, lovastatin, and simvastatin) --Gastrointestinal --Inhibition of drugs metabolized by CYP4503A, including (but not limited to) intolerance theophylline, cyclosporine, benzodiazepines (various), cisapride, tacrolimus, --Visual symptoms statins (various), sildenafil, diltiazem, verapamil, ergot alkaloids, and itraconazole --Concomitant administration with class IA and class III antiarrhythmics, astemizole, terfenadine, and other drugs that increase QT prolongation should be avoided --Inducers of CYP4503A isoenzymes (such as rifampin, carbamazepine, and phenytoin) may result in decreased concentrations of telithromycin --Concomitant administration may increase serum concentrations of digoxin; however, no signs of digoxin toxicity have been observed. Note: This list is not intended to be comprehensive. Consult product information for individual drugs for more information. CNS = central nervous system; CYP = cytochrome P; INR = international normalized ratio; RTI = respiratory tract infection. Advanced Studies in Pharmacy 235
py. A thorough discussion of each of these potential interactions is beyond the scope of this interview. Many common or potentially serious drug-drug interactions with antibiotics used to treat RTIs are outlined in Table 3. For example, patients who take products containing calcium, iron, zinc, magnesium/aluminum, or sucralfate should be counseled to take their fluoroquinolone antibiotic 2 hours before or 6 hours after taking these products. 39 In addition, fluoroquinolone antibiotics should not be taken with dairy products (such as milk or yogurt) or calcium-fortified juices alone because the absorption of the antibiotic may be significantly reduced. However, the patient may take the fluoroquinolone antibiotic with a meal that contains these products. 39 Subjects should be counseled to not take aluminum- and magnesiumcontaining antacids at the same time as azithromycin due to a risk of decreased absorption of azithromycin with concurrent administration. 40 Another drug-drug interaction, which may potentially result in serious consequences, involves an interaction between telithromycin and lipophilic statin therapy, such as atorvastatin, lovastatin, or simvastatin, which results in increased plasma levels of the statin. 41 As discussed in the case study presented by Glen E. Farr, PharmD, in this monograph, patients who are prescribed telithromycin and are also taking a lipophilic statin should hold their statin therapy until they complete their course of telithromycin. Pharmacists should also provide patients with some helpful hints as to how they may manage or even possibly avoid side effects with antibiotic therapy used to treat RTIs. Many common or serious such side effects are listed in Table 3. Again, a complete review of all side effects for these antibiotics is beyond the scope of this interview. However, a few comments regarding patient counseling for some of these side effects is warranted. In some cases, antibiotics such as macrolides and fluoroquinolones causing dyspepsia may be taken with meals. Visual symptoms (blurred vision, diplopia, or difficulty focusing) associated with telithromycin appear to be experienced at a higher incidence in patients under 40 years old and in females. 41 Patients prescribed telithromycin should be counseled regarding the risk of visual symptoms. Visual adverse events have been reported as having occurred after any dose of telithromycin during treatment, but most of these events occurred after the first or second dose. 41 As mentioned previously, the incidence of treatmentemergent visual adverse events in controlled phase 3 studies of telithromycin was 1.1%. 41 REFERENCES 1. Karchmer AW. Increased antibiotic resistance in respiratory tract pathogens: PROTEKT US-an update. Clin Infect Dis. 2004;39(suppl 3):S142-S150. 2. Doern GV, Brown SD. Antimicrobial susceptibility among community-acquired respiratory tract pathogens in the USA: data from the PROTEKT US 2000-01. J Infect. 2004;48:56-65. 3. Bisno AL, Gerber MA, Gwaltney JM Jr, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125. 4. Blasi F. Atypical pathogens and respiratory tract infections. Eur Respir J. 2004;24:171-181. 5. 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