Disclosures. Respiratory Infection and Antibiotics. What is the treatment of choice for ABRS? Acute Bacterial Rhinosinusitis

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1 Respiratory Infection and Antibiotics B. Joseph Guglielmo, Pharm.D. Professor and Dean School of Pharmacy University of California San Francisco Disclosures No disclosures regarding conflict of interest Acute Bacterial Rhinosinusitis What is the treatment of choice for ABRS? 1. Amoxicillin 2. Amoxicillinclavulanate 3. Azithromycin 4. No antibacterial therapy 25% 25% 25% 25%

2 Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a metaanalysis of individual patient data Searched the Cochrane Central Register of Controlled Trials, Medline, and Embase, and reference lists of reports Individual patients' data from 2547 adults in nine trials were checked and re-analyzed (Lancet 2008; 371: 908) Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a metaanalysis of individual patient data 15 patients with rhinosinusitis-like complaints would have to be given antibiotics before an additional patient was cured Patients who were older, reported symptoms for a longer period, or reported more severe symptoms took longer to cure but were no more likely to benefit from antibiotics than other patients (Lancet 2008; 371: 908) 2012 IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis Antibacterial choice Children: amoxicillin-clavulanate>amoxicillin (strong, moderate recommendation) Adults: amoxicillin-clavulanate>amoxicillin (weak, low recommendation) Other agents High dose amoxicillin-clavulanate: with severe infection, daycare, age<2 or >65, previous antibacterial use, immunocompromised No fluoroquinolones, macrolides, TMP-SMX, or 2 nd and 3 rd generation cephalosporins Doxycycline alternative to amoxicillin-clavulanate American College of Physicians (Jan 2016) Clinicians should reserve antibiotic treatment for acute rhinosinusitis for patients with persistent symptoms for more than 10 days, onset of severe symptoms or signs of high fever (>39 C) and purulent nasal discharge or facial pain lasting for at least 3 consecutive days, or onset of worsening symptoms following a typical viral illness that lasted 5 days that was initially improving (double sickening)

3 Acute Otitis Media What is the drug of choice for acute bacterial otitis media? 1. Azithromycin 2. Amoxicillinclavulanate 3. Amoxicillin 4. Cefdinir 5. Cefuroxime 20% 20% 20% 20% 20% S. pneumoniae % Resistance Streptococcus pneumoniae Isolates From Middle Ear and Mastoid Cultures INT RES Penicillin Amoxicillin Cefuroxime Cefpodoxime Cefdinir Percentage of Isolates Erythromycin S I R Clindamycin S I R (Clin Infect Dis Advance Access published February 26, 2015)

4 Meta-analysis: Macrolide Treatment of AOM 10 trials with 2766 children 15 months to 15 years old included Macrolides associated with increased risk of clinical failure (RR 1.31; 95%CI ; p=0.008) Rate of adverse event, particularly diarrhea, significantly less in macrolide group (Ann Pharmacother 2010; 44: ) 2013 AAP Treatment Guidelines Antibiotics indicated: Children ( 6 mos) with severe AOM (mod to severe otalgia or otalgia for 48 hrs or T 39Cº) Children (6-23 mos) with nonsevere bilateral AOM Antibiotics or observation with close follow-up Children (6-23 mos) with nonsevere unilateral AOM Older children with nonsevere AOM (Pediatrics 2013; 131: e964 -e999 ) 2013 AAP Treatment Guidelines Drug of choice: high dose amoxicillin If receipt of amoxicillin in the past 30 days or purulent conjunctivitis or history of recurrent AOM unresponsive to amoxicillin: an antibiotic with additional β-lactamase coverage should be prescribed (i.e. amoxicillin-clavulanate), cefdinir, cefuroxime, cefpodoxime) (Pediatrics 2013; 131: e964 -e999 ) Duration of TX: Acute Otitis Media in Children Children aged 6-23 months randomized to receive amoxicillin-clavulanate 90 mg/kg/day for standard duration of 10 days or shortened duration of 5 days (N Engl J Med 2016; 375: 2446)

5 Duration of TX: Acute Otitis Media in Children 5 days 10 days P value Clinical failure 77/229 (34%) 39/238 (16%) Mean symptom score Mean symptom score at D12-14 Score by >50% 181/227 (80%) 211/233 (91%) Isolation of PCN 78/177 (44%) 85/181 (47%) 0.58 non-s pathogen Diarrhea 75/258 (29%) 78/257 (30%) Topical antifungal 87/258 (34%) 85/257 (33%) Streptococcal Pharyngitis (N Engl J Med 2016; 375: 2446) True or False? Penicillin is the drug of choice in the treatment of bacterial pharyngitis? 1. True 2. False 50% 50% Streptococcus pyogenes (% Resistance) Penicillin 0% Cefdinir 0% Macrolides % Clindamycin 0.5% Levofloxacin 0.05%

6 How Common is Penicillin Allergy? 500 patients with medical record history of penicillin allergy skin tested with penicilloyl-polylysine (Pre-Pen ) and fresh penicillin G Negative tests followed by oral amoxicillin challenge Four patients reacted with any positive skin tests and another 4 had significant reactions to the amoxicillin (J All Clin Immunol 2013 Feb Abstract 829) IDSA 2012 Guidelines Group A Streptococcal Pharyngitis Rapid Antigen Detection Test and/or culture should be performed because clinical features alone do not reliably discriminate between GAS and virus Penicillin or amoxicillin for 10 days Alternatives: 1 st generation cephalosporin (if not anaphylactically sensitive, clindamycin, clarithromycin, azithromycin (Clin Infect Dis 2012; 55: 1279) American College of Physicians (Jan 2016) Clinicians should test patients with symptoms suggestive of group A streptococcal pharyngitis (for example, persistent fevers, anterior cervical adenitis, and tonsillopharyngeal exudates or other appropriate combination of symptoms) by rapid antigen detection test and/or culture for group A Streptococcus. Clinicians should treat patients with antibiotics only if they have confirmed streptococcal pharyngitis. Acute Bronchitis For >40 years, studies have demonstrated that antibiotics are not effective for acute bronchitis (Smith et al. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2014; 3 (4) CD000245) : rate of antibiotic prescribing in U.S. was 60-80% (Steinman et al. Ann Intern Med 2003; 138: 525)

7 Acute Bronchitis From: Antibiotic Prescribing for Adults With Acute Bronchitis in the United States, JAMA. 2014;311(19): doi: /jama Centers for Diseases Control (CDC) efforts have been ongoing to decrease antibiotic prescribing for acute bronchitis Since 2005, a Healthcare Effectiveness Data and Information Set (HEDIS) measure is that antibiotic prescribing rate for acute bronchitis should be zero Date of download: 6/5/2014 Copyright 2014 American Medical Association. All rights reserved. A case of prescription fatigue? Linder et al. JAMA Intern Med 2014; 174(12):

8 American College of Physicians (Jan 2016) Clinicians should not perform testing or initiate antibiotic therapy in patients with bronchitis unless pneumonia is suspected Antibacterial Options for Outpatient Treatment of Community Acquired Pneumonia Etiology Outpatient-Treated CAP (in order of association) S. pneumoniae (most common organism in older patients and those with significant underlying disease) M. pneumoniae (most common in patients <50 yo and no co-morbidities) C. pneumoniae Viruses 2007* IDSA/ATS Recommendations: Outpatient Treatment of CAP Healthy, no use of antimicrobials within the past 3 months: A macrolide (level I evidence) Doxycycline (level III evidence) *Update due Summer 2017

9 2007 IDSA/ATS Recommendations: Outpatient Treatment of CAP Presence of co-morbidities or receipt of antimicrobials within the past 3 months in which case an alternative from another class should be used: A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, 750 mg levofloxacin): strong recommendation and level I evidence Beta-lactam plus macrolide: level I evidence 2007 IDSA/ATS Recommendations: Outpatient Treatment of CAP In regions with a high rate (>25%) of infection with high level ( 16 mcg/ml) macrolide-resistant S. pneumoniae, consider the use of alternative agents. IDSA/ATS Recommended Antibiotics for CAP* (*Projected Publication, Summer 2017) Non-ICU 1. An IV or PO respiratory fluoroquinolone (levofloxacin (750mg), moxifloxacin, gemifloxacin) OR 2. An IV beta-lactam (ceftriaxone, cefotaxime, ampicillin) plus macrolide or doxycycline ICU 1. An IV beta-lactam (ceftriaxone, cefotaxime, ampicillin-sulbactam) plus an IV fluoroquinolone (levofloxacin, moxifloxacin) or IV azithromycin Seven days into an empirical course of ceftriaxone and azithromycin for CAP, a patient experiences respiratory decompensation associated with increased oxygen requirements and a new infiltrate (i.e. HAP). Multiple blood cultures are positive for an aerobic gramnegative rod.

10 Which of the following agents would be the best choice in a HAP patient (receiving ceftriaxone) with gram negative bacteremia? 1. Tigecycline 2. Cefepime 3. Piperacillintazobactam 4. Imipenem 5. Imipenem + tobramycin 20% 20% 20% 20% 20% Third-generation Agents (Ceftriaxone): Holes in Gramnegative Spectrum Citrobacter Acinetobacter Pseudomonas (however, ceftazidime strong) ESBLs AND Enterobacter Stenotrophomonas (and/or Serratia) Extended Spectrum Beta- Lactamase (ESBL): Key Points ß-lactamases hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid Often plasmid encoded and frequently carry genes encoding resistance to other drug classes (e.g. aminoglycosides, fluoroquinolones) (Ann Pharmacother 2007; 41: 1427) Extended Spectrum Beta- Lactamase (ESBL): Key Points Imipenem and meropenem are the most reliable agents in the treatment of ESBL While active in vitro, ertapenem, tigecycline, colistin, cefepime, piperacillintazobactam have limited clinical experience but are potential options (Ann Pharmacother 2007; 41: 1427)

11 Gram-negative Activity: Cefepime (expanded coverage over ceftriaxone) Enterobacter Pseudomonas E. coli (but MIC should be 2 mcg/ml for ESBLproducing isolates) Citrobacter* Klebsiella (but but MIC should be 2 mcg/ml for ESBL-producing isolates) First generation beta-lactamase inhibitor combinations Ampicillin-sulbactam (Unasyn ) Piperacillin-tazobactam (Zosyn ) Ticarcillin-clavulanate (Timentin ) (J Antimicrob Chemother 2014; 69: 871) Beta-lactamase inhibitor combinations: spectrum Addition of BLI results in reliable agents vs S. aureus (like nafcillin or cefazolin), H. influenzae (like ceftriaxone), B. fragilis (like metronidazole) Zosyn and Unasyn are active vs E. faecalis, but not E. faecium; Timentin has no enterococcal coverage Beta-lactamase inhibitor combinations: gram-negative spectrum Piperacillin-tazobactam approximates ceftazidime in gram-negative activity (including Pseudomonas) Piperacillin-tazobactam has similar weaknesses as ceftazidime vs Citrobacter, Acinetobacter, Enterobacter As with cefepime, BLI combinations are not as consistently effective as carbapenems in the treatment of ESBL BLI combinations should not be used as monotherapy in suspected severe ceftriaxone-resistant gram-negative infections They may have a role in combination therapy

12 Fluoroquinolones Five years ago fluoroquinolones were among those agents (cefepime, penems, aminoglycosides) that could logically be used in the treatment of resistant gram negative infection The decline in activity vs Pseudomonas, Enterobacter, and E.coli, including ESBLproducers have greatly diminished the role of these agents in the monotherapy treatment of third generation cephalosporin-resistant gram negative pathogens Carbapenems: gram negative spectrum Imipenem, meropenem are active vs most gramnegative pathogens (including third-generation cephalosporin-resistant and ESBL producers Cannot rely upon ertapenem for ceftriaxone-resistant gram negative infection: little to no Pseudomonas or Acinetobacter coverage and moderate coverage vs ESBL-producers (compared with other carbapenems) Weaknesses: Stenotrophomonas, Pseudomonas aeruginosa (rapid emergence of resistance over time). Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly more common Carbapenems: Adverse effects Hypersensitivity in penicillin-allergic patients: Immediate hypersensitivity to carbapenems occurs very infrequently Patients with a negative skin test to imipenem 0.5 mg/ml (or meropenem 1 mg/ml) can safely receive imipenem/meropenem. (NEJM 2006; 354: 2835; Ann Intern Med 2007; 146: 266) Seizures: Imipenem (but not meropenem or doripenem) is associated with seizures at >50 mg/kg/d or with unadjusted doses in renal failure Carbapenems decrease serum levels of valproic acid Aminoglycosides Spectrum: multidrug-resistant gramnegative bacilli (Citrobacter, Enterobacter, Pseudomonas) but rarely used as monotherapy in the treatment of these infections More commonly used as a synergistic addition in endocarditis due to viridans streptococci, enterococcus, S. aureus

13 Aminoglycoside Toxicity Dose, time related: toxicity with less than 5 days of therapy is unlikely Nephrotoxicity is generally reversible Ototoxicity (both cochlear and vestibular) is more often irreversible; elderly are particularly predisposed. Baseline audiometry is mandatory for long-term therapy, especially in elderly Drug levels do not reliably predict risk for ototoxicity Blood cultures return positive for Pseudomonas aeruginosa Two drugs are superior to one in the treatment of serious Pseudomonal infection. 1. True 2. False 50% 50% Combination Therapy? In general, combination therapy has not been found to be superior to beta-lactam monotherapy in the treatment of P.aeruginosa bacteremia, however, there are some exceptions Aminoglycoside monotherapy is inferior to combination and should only be used in combination with an antipseudomonal beta-lactam Neutropenic patients should receive combination therapy In septic patients, a few days of empiric combination therapy and then monotherapy may be the best option

14 Empirical Treatment of Ceftriaxone/Quinolone-Resistant Gram Negative Infection In order of preference from clinically stable (Top) to septic shock (Bottom): Cefepime or carbapenem monotherapy Piperacillin-tazobactam (or cefepime) plus tobramycin Carbapenem (imipenem or meropenem, but not ertapenem) plus tobramycin The Human Intestinal Microbiome in Health and Disease GI tract houses several trillion microbial cells These organisms represent 9.9 million microbial genes > 1 billion years of mammalian-microbial evolution has led to interdependency (N Engl J Med 2016; 375: 2369) Contributions of GI Microbiota Maturation and continued education of the host immune response Protection against pathogen overgrowth Influence host-cell proliferation and vascularization Regulate intestinal endocrine functions, neurologic signaling, bone density (N Engl J Med 2016; 375: 2369) Contributions of GI Microbiota Provide source of energy biogenesis Biosynthesize vitamins, neurotransmitters, and other compounds Metabolize bile salts React to or modify certain drugs Eliminate exogenous toxins (N Engl J Med 2016; 375: 2369)

15 Proportion of patients developing IBD and antianaerobic antibacterial status Antibiotics and Eczema (Pediatrics 2012; 130: e794) P<0.001 Meta-analysis of observational studies involving children and young adults Pooled OR: 1.41 (95%CI ) associating eczema with antibiotic exposure In addition, a 7% increase in eczema risk for each additional antibiotic course received during 1 st year of life ((Br J Dermatol 2013; 169: ) Antibiotics and Juvenile Idiopathic Arthritis Nested case-control study in children with newly diagnosed JIA Results: o Any antibiotic course: OR 2.1 (95% CI ) o One to two courses: OR 1.7 (95% CI ) o Three to five courses: OR 2.8 (95% CI ) o > Five courses: OR 3.0 (95% CI ) (Pediatrics 2015; 136: e333) Antibiotics and Type 2 Diabetes Retrospective review of combined Danish registries: Increased risk with receipt of antibiotics (OR 1.53 (95% CI ) Increase risk of diabetes with cumulative load of antibiotics Risk up to 15 years before diagnosis (J Clin Endocrinol Metab 2015; Oct;100(10): doi: /jc )

16 Antibiotic Use and Childhood Obesity 163,820 children aged 3-18 yo Antibiotic exposure associated with significant increase in weight More antibiotic prescriptions was associated with increased weight Largest weight gain associated with macrolides (Intern J Obesity 2015; Article preview Oct 21) Zinc for the common cold Meta-analysis RCTs comparing oral zinc with placebo or no treatment 17 trials with 2121 participants Efficacy 1.65 day cold symptoms symptoms in adults but not children Adverse events Bad taste: RR 1.65 (95% CI ) Nausea: RR 1.64 (95% CI ) (Can Med Assoc J 2012; 184: E551-61) Vicks VapoRub Vicks VapoRub works. True or False? 1. True 2. False 50% 50%

17 Vicks Vapo Rub for Cold Symptoms Eligible patients aged 2 to 11 years with symptoms attributed to URIs characterized by cough, congestion, and rhinorrhea that lasted 7 days or longer 138 children randomized to Vicks Vapo Rub, petrolatum, or no intervention Parents massaged into child s neck and chest 30 minutes before bedtime (A) cough frequency, (B) cough severity, (C) severity of congestion, (D) severity of rhinorrhea, (E) child's ability to sleep, (F) parent's ability to sleep, (G) combined symptom score Paul, I. M. et al. Pediatrics 2010;126: