COMBATING INFECTIOUS DISEASE
| ANTIBIOTIC ISSUES —Michael D. Poole, MD, PhD, Georgia Ear Institute, Savannah, Georgia |
| Temporal guidelines: basis for decisions about antibiotic therapy; patients with bacterial sinus infection sick for 7 to 10 days; among patients with rhinovirus infection—fever and sore throat generally improve ≤1 wk after onset; rate of persistent drainage and cough ≤40% at 2 wk |
 | Problems associated with reliance on temporal guidelines: failure to focus on natural history of disease—most respiratory viral infections produce nagging cough; respiratory syncytial virus (RSV), influenza A and B, and parainfluenza infections cause greater degree of tissue damage and remain symptomatic for longer time; focus on short-term (ie, 5-day) antibiotic therapy—viral disease most likely cause of persistent drainage and coughing associated with sinusitis; after initial short course of antibiotics, patients with viral infections tend to seek additional antibiotics to control persistent symptoms |
| Aminopenicillins, ie, amoxicillin, combination of amoxicillin and potassium clavulanate (Augmentin): bacteria of concern—Streptococcus pneumoniae; Haemophilus influenzae (replacing pneumococcus as predominant cause of otitis media and sinusitis); Moraxella (more common in children; impact appears to be on regional basis) |
| S pneumoniae: progressively more resistant to penicillin, ampicillin, and amoxicillin; resistance—unrelated to β-lactamase production as in Haemophilus, Staphylococcus, or Moraxella; develops in response to alterations in penicillin-binding proteins, ie, more penicillin required to effectively occupy penicillin binding site; high-dose amoxicillin and Augmentin program—designed to counteract bacteria with minimal inhibitory concentrations (MICs) of ≈4 mg/L; relatively successful; doses range from 80 to 150 mg/kg in children to 3 to 4 g of amoxicillin component divided bid in adults; point—low doses of ampicillin or Augmentin no longer effective for treating S pneumoniae infections; for resistance to develop, antibiotic must be administered—to patients commonly carrying S pneumoniae, eg, children during winter; in doses incapable of eradicating resistant bacteria; factors contributing to development of drug-resistant strains—administering low-dose amoxicillin as prophylaxis for recurrent acute otitis media; introduction of oral cephalosporins that cannot eradicate carrier state of resistant bacterial strains, eg, loracarbef (Lorabid), cefpodoxime (Vantin), and cefprozil (Cefzil); bottom line—quantity of amoxicillin or Augmentin remaining in tissue of middle ear or sinus after low-dose therapy inadequate for eliminating pneumococci with MICs ≥4 mg/L |
| MIC distribution: Augmentin—has high-dose pharmacokinetic/pharmacodynamic (PK/PD) breakpoint at MIC of 4 mg/ L, ie, drug cannot handle bacterial strains with MIC >4 mg/L; remains effective against most β-lactamase–producing bacteria with MICs <4 mg/L; high-dose therapy may select for some strains of S pneumoniae with MICs >4 mg/L; H influenzae—generally has MIC <4 mg/L; infections can exist in respiratory tract without producing significant inflammation, ie, H influenzae cultured from ≤40% of patients with serous or mucoid otitis and minimal inflammation; low-dose amoxicillin or Augmentin therapy associated with 15% to 25% treatment failure rate for otitis, ie, problem related to intrinsic activity of amoxicillin against H influenzae; treatable with high-dose amoxicillin or Augmentin; pneumococcal failures—generally treatable with high-dose therapy; approach may increase MIC levels in future |
| Oral cephalosporins: no oral cephalosporin effective against penicillin-resistant S pneumoniae; cefprozil, cefaclor (Ceclor), and loracarbef—cannot treat sinus infections; activity close to placebo against H influenzae; drugs with similar efficacy against ≈50% of intermediate strains of S pneumotniae—cefpodoxime (Vantin) most potent; cefixime; cefdinir (Omnicef); cefuroxime (Ceftin); drugs with ≈75% rate of efficacy against H influenzae—cefixime; cefdinir; cefuroxime; Vantin—structural analogue of ceftriaxone; ≈100% effective against H influenzae; caveat— half-lives of cefdinir and Vantin inadequate for once-daily administration |
| Macrolides and ketolides: kill in concentration-dependent fashion; efficacy determined by MIC breakpoint of 0.5 mg/ L, ie, ketolides and macrolides effective against Moraxella and most S pneumoniae; S pneumoniae—strains resistant to macrolides led to development of ketolides; new ketolide telithromycin (Ketek) more effective than macrolides (eg, azithromycin and clarithromycin) against resistant strains; macrolides and ketolides—no more effective than placebo for treating H influenzae; less effective than amoxicillin for first-line therapy; markedly less effective than fluoroquinolones and high-dose Augmentin for managing patients who fail other treatment |
| Fluoroquinolones: most important drugs; have similar clinical efficacy; gemifloxacin (Factive)—new and available; not indicated for sinusitis; active against respiratory pathogens; when compared to ciprofloxacin, levofloxacin—has similar MIC for S pneumoniae and other gram-positive bacteria; achieves better tissue concentrations; less likely to produce treatment failures; concerns—side-effect and safety profiles problematic and require fluoroquinolones be reserved for second-line therapy; problems include changes in QT interval for all drugs, arthropathy with levofloxacin, and glucose hemostasis problems with gatifloxacin (Tequin); overusing drugs to treat Escherichia coli can increase risk for drug resistance and adversely affect E coli carriage in gut, ie, ciprofloxacin preferred for treating E coli infection causing traveler’s diarrhea |
| Antibiotic guidelines in sinusitis: traditional guidelines developed, in part, by using biased evidence-based medicine |
| Amoxicillin as first-line therapy for sinusitis: argument against amoxicillin—patients require drug with proven efficacy against β-lactamase producing strains of H influenzae and Moraxella; arguments in favor of amoxicillin—≥50% of patients undergoing antibiotic treatment have viral infection; many patients with nontypable H influenzae or Moraxella infections experience spontaneous resolution without suppurative complications; ≤6% difference in clinical efficacy between amoxicillin, Augmentin, and fluoroquinolones |
| Clinical efficacy and susceptibility based on effective drug concentrations relative to MICs: penicillin resistance exerts greater impact on cephalosporins than on amoxicillin and Augmentin; amoxicillin and Augmentin exert similar efficacy against S pneumoniae; older cephalosporins such as cefaclor, loracarbef, and cefprozil have low efficacy against H influenzae; high-dose Augmentin and respiratory fluoroquinolones proved most effective |
| Drug ranking by decreasing clinical efficacy: high-dose Augmentin; low-dose Augmentin; high-dose amoxicillin (superior to oral cephalosporins in efficacy against S pneumoniae); trimethoprim–sulfamethoxazole; clindamycin; older cephalosporins; macrolides; placebo |
| Lack of statistically useful comparative studies for evaluating efficacy of antibiotic therapy in sinusitis: traced to differing methods used to perform comparative trials, including—assessment of diagnostic and outcomes data that includes patients with viral infections, ie, at best, bacterial yield ≤60%; use of unpleasant single and double sinus-tap techniques; bottom line—based on current study designs, data may provide information on safety and tolerability, but cannot identify significant differences in clinical efficacy |
| Community-acquired methicillin-resistant Staphylococcus aureus (MRSA): has reached epidemic levels in Houston and Chicago, ie, ≈60% incidence; produces tissue-destructive toxins with increased virulence and transmissibility, ie, more invasive, more contagious, and individual does not have to be immunocompromised to develop infection; can be resistant to macrolides, clindamycin, fluoroquinolones, and sulfonamides; susceptible to vancomycin and rifampin |
| Clindamycin and erythromycin: resistance to both drugs comes from same gene; erythromycin more potent inducer of expression of resistance, with resistance rate 60% to 70%; D-test—useful tool for determining whether erythromycin-resistant bacteria susceptible to clindamycin; in Chicago, 90% of erythromycin-resistant, potentially clindamycin-susceptible strains actually clindamycin resistant; most strains remain susceptible to trimethoprim– sulfamethoxazole and rifampin; management—patients with MRSA and drainage require treatment with 2-drug combination of rifampin and clindamycin, or rifampin and trimethoprim–sulfamethoxazole; problem—many neonates developing deep neck abscesses caused by MRSA acquired from parents; when patient hospitalized for infectious complications of ear, nose, and throat (ENT) problem—primary care physician must obtain culture and discuss situation with otolaryngologist before initiating drug therapy, eg, vancomycin, ceftriaxone (Rocephin) |
| Resistance scenario with otic infections, eg, MRSA: point—laboratory definitions of resistance apply to systemic therapy, not topical therapy; resistance to aminoglycosides and fluoroquinolones—not all-or-none phenomenon; problem can be overcome by administering higher concentrations; points—essentially no bacterial resistance to concentrations of fluoroquinolones used to treat otic infections; aminoglycosides contraindicated because these drugs ototoxic in small percentage of cases; dexamethasone— major impact on efficacy of drug therapy; data show combination of dexamethasone and ciprofloxacin proved ≈15% more effective than ofloxacin alone (level of efficacy greater in presence of granulation tissue); yeast infection—noted with topical therapy, ie, high-dose amoxicillin selects for yeast in ear; can develop when patient receives neutral pH ear drop without antifungal |
| Prolonged QT interval and sudden cardiac death: prolongation of QT interval—class effect of macrolides, ketolides, and fluoroquinolones; problematic drugs include erythromycin, clarithromycin, and telithromycin; points— anything prolonging QT interval in patient already at risk for fatal arrhythmia should be viewed with concern; risk for fatal arrhythmia increases with degree of prolongation of QT interval; clinical data suggest thousands of cases of antibiotic-related sudden death may occur in United States each year |
| CHRONIC SINUSITIS: BACTERIA AND THE SUPERANTIGEN —Bradley F. Marple, MD, Associate Professor and Vice Chairman, Department of Otolaryngology—Head and Neck Surgery, University of Texas Medical Center at Dallas; Parkland Memorial Hospital and Zale Lipshy University Hospital, Dallas |
| Chronic rhinosinusitis (CRS): inflammatory process that may be infectious in some cases, noninfectious in others; can be viewed as syndrome with variety of factors contributing to clinical picture; microbiology—variety of bacteria associated with disease process; regardless of study evaluated, Staphylococcus aureus tends to be cultured regularly |
| Concepts linking bacterial infection to CRS: osteitis; anatomic abnormalities producing ventilation or outflow problems; external factors—can cause barrier disruption at level of mucosal surfaces; concept consistent with idea that eosinophil degranulation could affect integrity of mucosal barrier and allow colonizing bacteria to invade tissue deep to mucosal surface; biofilm—exopolysaccharide matrix secreted by some bacteria; provides protective environment around bacteria; identified in individuals with CRS; may make it more difficult to eradicate bacteria |
| Noninfectious ways in which bacteria can stimulate inflammatory process: allergic response to bacteria colonizing paranasal sinuses, ie, patients with CRS more likely to have systemic allergy to bacteria in sinuses; superantigen activity |
| Superantigen: concept—developed from assessing patients with toxic shock syndrome; suggests that bacterial secretion can elicit inflammatory response in absence of frank infection; S aureus—commonly cultured from patients with inflammatory rhinosinusitis; can elicit exotoxins; normal T-cell stimulation—antigen-presenting cells link up with CD4 cells via major histocompatability complex at site of T-cell receptor (process antigen specific); antigen fits between 2 receptors and regulates stimulation of CD4 cell; at most, <0.1% of total body T-cell pool stimulated when patient with significant allergic history subjected to high antigenic load; superantigens—bind to variable β region located outside of antigen-specific binding site; bypass antigen-specific linkage of major histocompatability complex at T-cell receptor; stimulate ≤30% of total body T-cell pool |
| Findings derived from study data: among 20 patients with CRS and nasal polyposis—statistically significant increase in local IgE production to staphylococcal exotoxin A (SEA) and staphylococcal exotoxin B (SEB) occurred; discordance with systemic allergy noted in all 20 patients; superantigen appeared to work as traditional antigen at local level; finding provides evidence that superantigens present in patients with chronic inflammatory rhinosinusitis and nasal polyposis; superantigen production—elicited by bacterial colonization; can lead to T-cell stimulation and eosinophilic inflammation; other associated inflammatory processes can occur—systemic IgE production or typical allergy or local allergy can feed back to create inflammation cycle; data analysis—can produce model of inflammatory rhinosinusitis and establish objective targets for pharmacotherapy |
| Antibiotic therapy: appropriate for treating bacterial infection in CRS or in adjacent site, eg, osteitis; may help alter bacterial colonization of nose if superantigen proves to be significant entity; may play supportive role for other types of anti-inflammatory therapy; caveats—biofilm may block treatment; questions exist concerning selection, delivery, and duration of therapy; proper site for obtaining culture must be determined |
Educational Objectives
| The goal of this program is to educate the listener about current concepts in managing infectious disease. After hearing and assimilating this program, the clinician will be better able to: |
| 1. Review the clinical efficacy of various classes of antibiotics used by otolaryngologists. |
| 2. Address concerns involving the development of community- acquired methicillin-resistant Staphylococcus aureus (MRSA). |
| 3. Investigate the correlation between antibiotic use and sudden cardiac death. |
| 4. Describe the potential role of superantigen activity in the development of inflammatory chronic rhinosinusitis (CRS). |
| 5. Determine the role of antibiotics in the management of CRS. |
Discussed on This Program
Amoxicillin (Amoxil, others) Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR] Ampicillin [Principen] Azithromycin [Zithromax] Cefaclor [Ceclor, Ceclor CD, Ceclor Pulvules] Cefdinir [Omnicef] Cefixime [Suprax] (discontinued) Cefpodoxime proxetil [Vantin] Cefprozil [Cefzil] Ceftriaxone sodium [Rocephin] Cefuroxime [Ceftin, Kefurox, Zinacef] Ciprofloxacin [Ciloxan, Cipro, Cipro I.V., Cipro XR] Ciprofloxacin and dexamethasone [Ciprodex Otic] Clarithromycin [Biaxin, Biaxin XL] Clindamycin (several trade names and preparations) Dexamethasone (several trade names and preparations) Erythromycin (Several trade names and preparations) Gatifloxacin [Tequin, Zymar] Gemifloxacin mesylate [Factive] Levofloxacin [Levaquin, Quixin] Loracarbef [Lorabid] Methicillin sodium [Celbenin, Staphcillin] Ofloxacin [Floxin, Floxin Otic, Ocuflox Ophthalmic Solution] Penicillin (several trade names and preparations) Rifampin (rifampicin) [Rifadin, Rimactane] Telithromycin [Ketek] Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, others] Vancomycin [Vancocin, Vancoled]
Suggested Reading
Bernstein JM, Kansal R: Superantigen hypothesis for the early development of chronic hyperplastic sinusitis with massive nasal polyposis. Curr Opin Otolaryngol Head and Neck Surg 13:39, 2005; File TM Jr et al: Evolution of amoxicillin/clavulanate in the treatment of adults with acute bacterial rhinosinusitis and community-acquired pneumonia in response to antimicrobial-resistance patterns. Clin Lab Med 24:531, 2004; File TM Jr, Hadley JA: Rational use of antibiotics to treat respiratory tract infections. Am J Manag Care 8:713, 2002; Marple BF et al: Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngology Head and Neck Surgery 129:S1, 2003; Poole MD: Acute bacterial rhinosinusitis: clinical impact of resistance and susceptibility. Am J Med 117 Suppl:29S, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed: Dr. Poole is affiliated with GlaxoSmithKline, Abbott Laboratories, Pfizer Inc., Alcon Inc., Bristol-Myers Squibb Company, Bayer Pharmaceuticals Corporation, and Aventis Pharmaceuticals Inc.
Dr. Marple gave his scientific presentation at the annual Combined Otolaryngological Spring Meetings (COSM) conference of the American Rhinologic Society (ARS) held April 30 to May 1, 2004, in Phoenix; Dr. Poole gave his scientific presentation at the Chicago Laryngological and Otological Society Program held February 7, 2005, in Chicago. The Audio-Digest Foundation thanks the speakers, the American Rhinologic Society, and the Chicago Laryngological and Otological Society for their cooperation in the production of this program.
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