Bugs and Drugs

From Masters of Pediatric Leadership Conferences, sponsored by the University of Miami Miller School of Medicine, Department of Pediatrics and Department of Dermatology and Cutaneous Surgery

Educational Objectives

The goals of this program are to improve the diagnosis of childhood tuberculosis (TB) and to encourage the judicious use of antibiotics in clinical practice. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the pathogenesis of TB infection and disease.

2.   Discuss techniques of diagnostic microbiology and their usefulness in diagnosing childhood TB.

3.   Explain the basic premise of the in vitro interferon-g release assay (IGRA) and summarize recent studies on its role in the immunodiagnosis of TB.

4.   Cite national data on the overprescribing of antibiotics in pediatric patients.

5.   Describe and follow American Academy of Pediatrics guidelines for management of acute otitis media, group A streptococcal pharyngitis, bacterial sinusitis, upper respiratory infections, and cough illness or bronchitis.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning com­mittee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mitchell is on the Speakers’ Bureau of MedImmune. Dr. Pichichero has received research grants, has been a consultant for, and/or has received honoraria from Electro­sonics Medical, GlaxoSmithKline, HemoCue, Innovia Medical, Merck, Novartis, sanofi-aventis, sanofi pasteur, and Wyeth. The planning committee reported nothing to disclose. In his lecture, Dr. Pichichero discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Mitchell and Dr. Pichichero spoke at Masters of Pediatric Leadership Conferences, held January 28 to February 2, 2009, in Miami Beach, FL, and sponsored by the University of Miami Miller School of Medicine, Department of Pediatrics and Department of Dermatology and Cutaneous Surgery. The Audio-Digest Foundation thanks the speakers and the University of Miami Miller School of Medicine for their cooperation in the production of this program.

Diagnostic Update: Tuberculosis

Charles D. Mitchell, MD, Professor of Clinical Pediatrics, University of Miami Miller School of Medicine, Miami, FL

Pathogenesis of tuberculosis (TB): infection spread by droplet nuclei that can remain suspended in air for several hours (expelled when person with infectious TB coughs, sneezes, or speaks); nuclei containing tubercle bacilli in­haled, reach alveoli, and multiply in alveolar macrophages (dividing every 25-32 hr for next 2-12 wk); bacilli spread via lymphatic channels to regional lymph nodes and via blood to distant tissues and organs; in persons with intact cell-mediated immunity, collections of activated T cells and macrophages form granulomas that limit multi­plication and spread of organism; antibodies against Mycobacterium tuberculosis (MTB) form but do not appear to be protective; in many cases, only evidence of infection positive tuberculin skin test (TST)

Diagnosis of TB: Centers for Disease Control and Prevention (CDC) case definition of TB based on laboratory isola­tion of MTB from clinical specimens, or on clinical signs and symptoms with supporting radiographic studies; cri­teria for clinical case definition include positive result on TST; clinical signs and symptoms consistent with MTB (somewhat different in children); abnormal, unstable findings on chest x-ray (CXR) compatible with TB

TB microbiology: MTB nonmotile, aerobic, nonspore-forming bacillus; cell wall has high content of high-molecu­lar-weight lipids and contains both peptidoglycans and complex glycolipids; region of difference 1 (RD1) antigens  —may account for immunologic differences developed by MBT to resist intracellular killing; secreted by MTB, but not by other members of Mycobacterium complex; include early secretory antigenic target 6 (ESAT6) and culture filtrate protein 10 (CFP10); CFP10 and ESAT6 major targets of interferon-g (IFN-g)-secreting T cells

TB immunology: innate immunity  —  postingestion, MTB parasitizes alveolar macrophages but arrests maturation of phagosomes (at early endosome stage), thus avoiding fusion with hydrolytically active lysosomes; adoptive immunity  —immune system both protects against and exacerbates illness (ie, much of morbidity and lung damage induced by clinical TB due to inflammatory response); activation of lymphocytes results in balance of T-helper 1 (T_h1; proinflammatory) and T_h2 (anti-inflammatory) responses; T_h1 facilitates protective cell-mediated responses

Diagnostic microbiology: appropriate specimen type for bacteriologic examination depends on location of disease; gastric aspirates most commonly processed samples for children, but positive in only 20% to 30% of cases; cultur­ing specimens  —positive culture gold standard for diagnosis; however, MTB grows slowly and typically requires 3 to 6 wk to generate visible colonies; automated radiometric culture methods useful (growth generally detected within 9-16 days); mycobacterial growth indicator tubes provide quantitative index of MTB growth; nucleic acid hybridization assay  —  targets ribosomal RNA and identifies organism once growth detected; sensitivity 38% to 72% in extrapulmonary specimens and 50% to 80% in acid-fast bacillus (AFB) smear-negative sputum specimens; has little utility in gastric aspirates; positive specimens still require culture for susceptibility testing

In vitro IFN-g release assay (IGRA): biologic basis similar to that of TST; entails mixing blood samples with anti­gens from MTB and from other organisms (eg, Mycobacterium avium), and controls, and incubating for varying times; lymphocytes that recognize antigen secrete IFN-g; amount of IFN-g released in response to stimulating anti­gen compared to amount released in response to other antigens and controls; 2 commercially available tests  —  QuantiFERON-TB Gold (whole-blood enzyme immunoassay [WB EIA]); T-Spot.TB assay (enzyme-linked immu­nosorbent spot [ELISPOT] assay)

Data from Pai et al (2004) systematic review of IGRAs: authors looked at sensitivity in patients with active TB (ATB), specificity in low-risk patients without ATB, sensitivity of IGRA in patients with suspected latent TB, TST and IGRA concordance, correlation of IGRA vs TST with MTB, and effect of previous Bacillus Calmette-Guérin (BCG) vaccination; summary  —  IGRAs employing MTB-specific RD1 antigens (ESAT6 and CFP10) may have ad­vantages over TST (higher specificity, better correlation with MTB exposure, and less cross-reactivity due to BCG); IGRAs employing cocktails of these antigens appear to have highest accuracy and demonstrated best combi­nation of sensitivity and specificity; utility among compromised hosts needs to be addressed

Comments: current CDC guidelines advocate use of IGRA, but do not recommend it be used as gold standard for di­agnosing TB (CDC states that IGRA should be used in conjunction with clinical determinants, epidemiologic his­tory, and TST); growing body of data since 2004 on utility of IGRA (mostly comparison studies of results of TST vs QuantiFERON-TB Gold vs ELISPOT assay); still much discordance between IGRAs and TST

Microscopic observation drug susceptibility (MODS) test: uses inverted light microscope and liquid culture tech­nique to detect mycobacterial growth; can expedite diagnosis of TB (median time to culture positivity »7 days vs 13 days with standard Lowenstein-Jensen [LJ] culture); can fairly rapidly detect isolates resistant to isoniazid (INH) and rifampin by incorporating variety of anti-TB drugs into MTB broth culture

Lessons from diagnosing TB in Africa: for past several years, speaker has been head of International Maternal Pe­diatric Adolescent AIDS Clinical Trial (IMPAACT) P1041 (double-blind placebo-controlled trial of primary INH prophylaxis for prevention of TB and latent TB infection among infants with perinatal exposure to HIV); speaker’s experience has highlighted difficulty physicians have diagnosing childhood TB; factors complicating diagnosis in­clude natural history of disease and global HIV pandemic; in Africa, World Health Organization history and clini­cal algorithm adopted to address these difficulties

Judicious Antibiotic Use in Clinical Practice

Michael E. Pichichero, MD, Professor of Microbiology and Immunology, Pediatrics, and Medicine, University of Rochester Medical Center, Rochester, NY

National data on antibiotic prescribing: among children presenting with chief complaint of earache, 30% to 60% actually have bacterial disease (acute otitis media [AOM]), yet 85% to 99% given antibiotics; overprescribing sim­ilarly reported for children who present with chief complaint of sore throat, green or yellow nasal discharge, symp­toms of upper respiratory infection (URI), and “cough illness” (bronchitis)

Factors that influence clinical outcome: proper diagnosis most important; other factors include spontaneous cure rate and choice of antibiotic treatment (only »50% of patients receive antibiotic likely to be effective, based on data about known pathogens and their current susceptibility patterns; »50% of practitioners prescribe wrong medica­tion)

Relationship between pharmacokinetics, pharmacodynamics and clinical outcome: today, choice of drug based on pharmacokinetics (PK; serum concentration of drug, which predicts penetration to site of infection) and pharma­codynamics (PD; potency of drug, measured in minimum inhibitory concentrations [MICs]; mechanism of killing); incorporating models of PK and PD into guidelines allows prediction (with 80%-85% accuracy) of drug efficacy

American Academy of Pediatrics (AAP) guidelines for otitis media: AOM vs otitis media with effusion (OME)  —  many children with URIs develop OME without later developing bacterial AOM; in child who presents with ear­ache, probability of finding AOM equal to probability of finding OME (50% for each); antibiotics indicated for treatment of AOM; however, diagnosis must be documented by physical examination (PE); AOM requires visual diagnosis (wax must be removed to visualize eardrum); speaker uses soft plastic curette, or if necessary, water pick; can also use adjunctive tool (tympanometry or acoustic reflectometry [equally reimbursable]); duration of treat­ment of uncomplicated AOM  —  5 to 7 days, with exception of child who has had episode of AOM in past 30 days (give 10-day course); antibiotics not indicated for OME; antibiotic prophylaxis for OME and recurrent AOM inef­fective and leads to development of resistant bacteria

AAP guidelines for treatment of AOM: azithromycin (Zithromax) not recommended for treatment of AOM and si­nusitis; currently, Haemophilus influenzae dominant bacterium causing ear and sinus infections in children; azithromycin excellent for lower respiratory infections but poor drug for ear and sinus infections; choice for initial treatment of AOM high-dose amoxicillin, 90 mg/kg per day (maximum dose 3 g/day); cefdinir (Omnicef), cefpo­doxime (Vantin), cefuroxime (Ceftin), and amoxicillin/clavulanate (Augmentin) recommended as second-line op­tions or for use when amoxicillin fails; cephalosporins may be prescribed, even for patients allergic to penicillin; taste of drug, ease of dosing, and duration of therapy should be considered when prescribing antibiotics to pediatric patients

AAP guidelines for pharyngitis: diagnosis of group A streptococcal (strep) pharyngitis should be made on basis of appropriate laboratory test (rapid strep test or throat culture) in conjunction with clinical and epidemiologic find­ings; antibiotics should not be given in absence of confirmed diagnosis of group A streptococcal or other bacterial infection; penicillin treatment of choice; only »50% of children who present with sore throat tested (many pediatri­cians treat any case of sore throat as strep throat and give antibiotic)

Comparison of clinical course of acute bacterial sinusitis and URI: in cases of uncomplicated URI, fever (when present) occurs early and usually peaks by day 2 or 3; nasal discharge peaks by day 5 and resolves by day 10; child with purulent nasal discharge and fever for >3 days can be considered to have acute bacterial sinusitis and should receive antibiotic; even in absence of fever, purulent nasal discharge for >7 to 10 days may warrant antibiotic

AAP guidelines for sinusitis: most uncomplicated URIs improve after 10 days; presence of signs and symptoms without improvement for ³10 days or worsening of symptoms after clinical improvement indicate bacterial infec­tion requiring antibiotic treatment; no radiologic studies of proven value in identifying bacterial sinusitis (diagnosis based on history and PE); antibiotic treatment recommended to achieve more rapid clinical cure, and to prevent complications and transmission

Speaker’s technique for evaluating patient with possible bacterial sinusitis: makes diagnosis on basis of patient history and PE; performs brief sinus transillumination test; satisfies parent, and in many cases, allows speaker to avoid unnecessary use of antibiotics

Clinical practice guidelines for treatment of acute bacterial sinusitis: if patient with diagnosis of acute bacterial sinusitis does not respond to treatment within 48 to 72 hr, antibiotic needs to be changed or diagnosis incorrect; rec­ommendations for alternative antimicrobials include amoxicillin–clavulanate (Augmentin), cefdinir (Omnicef), ce­fpodoxime (Vantin), cefuroxime (Ceftin), and single-dose ceftriaxone by injection

AAP guidelines for URI (common cold): antibiotics not indicated; if physician can determine, based on history and PE, that antibiotic not necessary, family generally satisfied; studies do not support preempting secondary bacterial infection with antibiotics; causes selection for drug-resistant strains, and may result in more difficult-to-treat sec­ondary infection

AAP cough/bronchitis guidelines: nonspecific cough illness or bronchitis in children rarely warrants antibiotics; however, cough lasting ³10 days may require antibiotic treatment; for cough associated with Mycoplasma or Chla­mydia (2 most common bacterial causes of cough illness in children), speaker recommends starting antibiotic within 7 days of onset of illness (if started after 10 days, as recommended by guidelines, antibiotic will not be of much benefit in reducing symptoms); macrolide agents recommended

Interventions to improve judicious antibiotic prescribing: community-wide campaign in Tennessee achieved 11% decline in antibiotic prescriptions; group practice intervention study in Cincinnati produced no difference; prospec­tive randomized community trial in Utah achieved 56% decrease in diagnosis of bronchitis, 13% decrease in mac­rolide use, and 15% overall reduction in antibiotic use

Telephone prescribing: risk to prescriber; when prescribing by telephone, must document time of call and person who called, clinical status of patient, advice given, and reasoning for decision

Safety net antibiotic prescription (SNAP): when giving SNAP, must always put expiration date on prescription and document it; studies show that >50% of patients given SNAPs do not fill them

White blood cell count (WBCC) as aid in judicious antibiotic prescribing: in speaker’s practice, routinely do WBCC in most febrile children without definitive diagnosis; 2003 study  —  involved »1956 children with URIs or nonspecific febrile illness; 62% had diagnosis established by history and PE; of those without established diagno­sis, »351 got WBCC testing (because patient appeared ill or had temperature >101°F, or due to concerns of physi­cian or parents); 96% had WBCC <15,000/mL and did not get antibiotic; 4% had WBCC >15,000/mL (suggesting possible bacterial infection) and received antibiotic; antibiotic prescription avoided in >90% of patients; compari­son of 2 WBCC devices  —  study compared automated Cell-Dyn counter (requires »100 mL of blood) and HemoCue device (requires only »10 mL [one drop]); correlation between devices high; HemoCue device currently under re­view by Food and Drug Administration for Clinical Laboratory Improvement Amendments waiver; in speaker’s ex­perience, WBCC can be useful for reassuring child’s parents and avoiding unnecessary use of antibiotics

Conclusions: guidelines for judicious antibiotic prescribing available; all emphasize accurate diagnosis and careful selection of medications; SNAP is option; if it becomes available, in-office WBCC might become significant aid in judicious use of antibiotics

Suggested Reading

Ak O et al: The evaluation of the Quantiferon-TB Gold test in pulmonary and extrapulmonary tuberculosis. Jpn J Infect Dis 62(2):149, 2009; Brook I: Current issues in the management of acute bacterial sinusitis in children. Int J Pediatr Otorhinolaryn­gol 71(11):1653, 2007; Casey JR et al: White blood cell count can aid judicious antibiotic prescribing in acute upper respiratory infections in children. Clin Pediatr (Phila) 42(2):113, 2003; Casey JR, Pichichero ME: A comparison of 2 white blood cell count devices to aid judicious antibiotic prescribing. Clin Pediatr (Phila) 48(3):291, 2009; Dheda K et al: T-cell interferon-gamma release assays for the rapid immunodiagnosis of tuberculosis: clinical utility in high-burden vs. low-burden settings. Curr Opin Pulm Med 15(3):188, 2009; Low DE et al: Optimizing antibacterial therapy for community-acquired respiratory tract infec­tions in children in an era ofbacterial resistance. Clin Pediatr (Phila) 43(2):135, 2004; Marais BJ, Pai M: Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 92(5):446, 2007; Moore DA et al: Microscopic-observation drug-susceptibil­ity assay for the diagnosis of TB. N Engl J Med 355(15):1539, 2006; Pai M et al: Interferon-gamma assays in the immunodiagno­sis of tuberculosis: a systematic review. Lancet Infect Dis 4(12):761, 2004; Pichichero ME, Brixner DI: A review of recommended antibiotic therapies with impact on outcomes in acute otitis media and acute bacterial sinusitis. Am J Manag Care 12(10 Suppl):S292, 2006; Pichichero ME, Casey JR: Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis. Otolaryngol Head Neck Surg 136(3):340, 2007; Pichichero ME, Reed MD: Variations in amoxicillin pharmacoki­netic/pharmacodynamic parameters may explain treatment failures in acute otitis media. Paediatr Drugs 11(4):243, 2009; Wang JY et al: Diagnosis of tuberculosis by an enzyme-linked immunospot assay for interferon-gamma. Emerg Infect Dis 13(4):553, 2007.