In the Clinic: Evidence Based Management of Infections Daniel Deck, Pharm.D. San Francisco General Hospital

Overview l Community-acquired pneumonia l Upper respiratory tract infections l Urinary tract infections l Skin and Soft-tissue infections

Community-acquired pneumonia

Community Acquired Pneumonia (CAP): definition l At least 2 new symptoms l New infiltrate on chest x-ray and/or abnormal chest exam l No hospitalization or other nursing facility prior to symptom onset Fever or hypothermiaCough Rigors and/or diaphoresisChest pain Sputum production or color changeDyspnea

Diagnosis l Chest radiograph – needed in all cases?  Avoid over-treatment with antibiotics  Differentiate from other conditions  Specific etiology, e.g. tuberculosis  Co-existing conditions, such as lung mass or pleural effusion  Evaluate severity, e.g. multilobar l Unfortunately, chest physical exam not sensitive or specific and significant variation between observers Arch Intern Med 1999;159:1082-7

Microbiological Investigation l Sputum Gram stain and culture  Remains somewhat controversial  30-40% patients cannot produce adequate sample  Most helpful if single organism in large numbers  Usually unnecessary in outpatients  Culture (if adequate specimen 25 PMNs/LPF): antibiotic sensitivities  Limited utility after antibiotics for most common organisms

Etiology l Clinical syndrome and CXR not reliably predictive  Streptococcus pneumoniae 20-60%  Haemophilus influenzae 3-10%  Mycoplasma pneumoniae up to 10%  Chlamydophila pneumoniae up to 10% “Atypicals”  Legionella up to 10%  Enteric Gram negative rods up to 10%  Staphylococcus aureus up to 10%  Viruses up to 10%  No etiologic agent 20-70%

S. pneumoniae l 2/3 of CAP cases where etiology known l 2/3 lethal pneumonia l 2/3 bacteremic pneumonia  Apx. 20% of cases with pneumococcal pneumonia are bacteremic (variable) l Risk factors include Extremes of age Alcoholism COPD and/or smoking Nursing home residence Influenza Injection drug use Airway obstruction *HIV infection

S. pneumoniae – drug resistance ~ 25-35% penicillin non-susceptible by old standard nationwide, but most < 2  g/mL l Using the new breakpoints for patients without meningitis, 93% would be considered susceptible to IV penicillin l Other beta-lactams are more active than pencillin, especially  Ceftriaxone, cefotaxime, cefepime, amoxicillin, amoxicillin-clavulanate

S. pneumoniae – drug resistance l Other drug resistance more common with increasing penicillin minimum inhibitory concentration (MIC)  Macrolides and doxycycline more reliable for PCN susceptible pneumococcus, less for penicillin non- susceptible l Trimethoprim-sulfamethoxazole not reliable l Fluoroquinolones – most S. pneumoniae are susceptible  Clinical failures have been reported l No resistance with vancomycin, linezolid

Risk Factors for Drug-Resistant Pneumococcal Pneumonia l Age 65 years l  -lactam antibiotics within 3 months l Alcoholism l Immunocompromised patients l Multiple comorbidities l Exposure to children in day care centers

Conditions that Increase the Morbidity/Mortality of CAP l COPD l Alcoholism l Leukopenia l Bacteremia l Diabetes mellitus l Renal insufficiency l CHF l CAD l Malignancy l Neurologic disease l Chronic liver disease l Immunosuppression

IDSA Outpatient Empiric Therapy Recommendations Previously Healthy & NO DRSP Risk Factors DRSP Risk Factors or High Level Macrolide Resistance > 25% Macrolide (e.g azithromycin) orDoxycycline 1) Fluoroquinolone* or 2) a β-Lactam # plus a Macrolide or Doxycycline *moxifloxacin, gemifloxacin, or levofloxacin (750mg) # Amoxicillin 1 gm PO tid or Augmentin® XR 2 gm PO bid are preferred. Ceftriaxone, cefpodoxime proxetil, and cefuroxime axetil 500 mg PO bid are alternatives

We love doxycycline l Adult inpatients June 2005 – December 2010 l Compared those who received ceftriaxone + doxycycline to those who received ceftriaxone alone l 2734 hospitalizations: 1668 no doxy, 1066 with doxy l Outcome: CDI within 30 days of doxycycline receipt l CDI incidence 8.11 / 10,000 patient days in those receiving ceftriaxone alone; 1.67 / 10,000 patient days in those who received ceftriaxone and doxycycline Doernberg et al, Clin Infect Dis 2012;55:615-20

Duration of Therapy l 5 days should be the minimum duration of therapy l Patients should be afebrile for hours l No more than 1 CAP-associate sign of clinical instability (T > 37.8ºC, HR >100, RR > 24, SBP < 90, O 2 sat < 90%, pO 2 < 60)

Short-Course Therapy l Defined as less than 7 days of therapy l Short course therapy may reduce side effects, cost, and resistance l Azithromycin has been used for 3-5 days l Ceftriaxone, amoxicillin, and fluoroquinolones have been used for 5 days

Reasons for Inadequate Response to Empiric Therapy l Inadequate Antibiotic Selection l Unusual Pathogens l Complications of Pneumonia l Incorrect Diagnosis l Drug-resistant organisms

Upper Respiratory Tract Infections

Upper respiratory tract infections l Rhinosinusitis  ~13 million outpatient visits per year  Viral causes >>>> bacterial  Minimal to NO benefit from antibiotics given for short duration of disease  Xray/CT not helpful in distinguishing cause

Rhinosinusitis diagnosis Major Criteria l Purulent anterior nasal discharge l Purulent posterior nasal discharge l Nasal congestion or obstruction l Facial congestion or fullness l Facial pain or pressure l Hyposomia or anosmia l Fever (acute disease) Minor Criteria l Headache l Ear pain, pressure, or fullness l Halitosis l Dental pain l Cough l Fever (chronic disease) l Fatigue Need at least 2 major or 1 major and ≥ 2 minor criteria

IDSA guidelines: rhinosinusitis l Antibiotics may be helpful if…. 1.Persistent signs/symptoms > 10 days 2.Severe symptoms  Fever > 39C  Purulent nasal drainage for 3 consecutive days  Facial pain 3.Biphasic illness

IDSA guidelines: rhinosinusitis Recommened l 1 st line therapy = Amoxicillin/clavulante (standard dose)  Consider high dose (XR formulation) with severe disease, elderly, recent antibiotic use or hospitalization l Alternatives: doxycycline, levofloxacin l Treatment duration: 5-7 days Not Recommended Macrolides TMP/SMX Oral cephalosporins Routine MRSA coverage

IDSA guidelines: rhinosinusitis DO l Antibiotic duration 5-7 days l Nasal saline irrigation l Intranasal corticosteroids l Consider changing abx if  Clinically worse at hours  No improvement at 3-5 days DO NOT l Decongestants l Antihistamines l NP swab

GAS pharyngitis l Accounts for 15% of adult sore throat visits l Dx: culture or rapid antigen test l Tx :  1 st line = PCN or amoxicillin x 10 days  Mild PCN allergy = cephalexin x 10 days  Alternatives = clindamycin or clarithromycin x 10 days OR azithromycin x 5 days

Antibiotic allergies: History is key! Past reaction l Source l Timeline: symptoms & meds l Detailed description l Treatment l Concurrent illness l Workup l Other exposure Current reaction l Timeline: symptoms & meds l Labs, histology l Concurrent illness

Algorithm for the use of cephalosporins in patients with reported penicillin allergy Practical management of antibiotic allergy in adults. McLean-Tooke et al, J Clin Pathol 2011;64:

Acute bronchitis l 10 million healthcare visits annually l 80% of patient prescribed antibiotics l 95% of case have a viral etiology l Antibiotics = No clinical benefit plus increased cost, adverse reactions, increased antibiotics resistance

Skin and Soft Tissue Infections

Skin Infection Anatomy Epidermis Dermis Subcut. Fat Fascia Muscle Impetigo Erysipelas Cellulitis Abscess, furuncle, carbuncle Fasciitis Pyomyositis

S. pyogenes Resistance in the U.S Antimicrobial AgentPercent Resistant* Penicillin0.0% Cefdinir0.0% Clindamycin0.5% Erythromycin6.8% Azithromycin6.9% Clarithromycin6.6% Levofloxacin0.05% *Richter SS. Clinical Infectious Diseases 2005; 41:599–608

S. aureus Susceptibilities from Outpatient Wound Isolates Antimicrobial AgentPercent Susceptible* Oxacillin52.0% Trimethoprim-Sulfamethoxazole99.6% Clindamycin86.7% Erythromycin41.5% Tetracycline93.8% Vancomycin100% *

Risk Factors for CA-MRSA l Prior history of MRSA infection l Close contact with person with similar infection l Recent antibiotic use l Reported “spider bite” l Outbreaks in IVDU, prisoners, athletes, children, Native Americans

Cellulitis vs Abscess CellulitisAbscess PathogenBeta-hemolytic streptococciStaph aureus (CA-MRSA) TreatmentAntibioticsIncision and Drainage +/- ABX AntibioticsPenicillin (amoxicillin) Cephalosporins (cephalexin) Clindamycin (PCN allergic) TMP/SMX??? TMP/SMX Doxycycline Clindamycin Linezolid $$$ Duration5-10 days; monitor clinical response

Abscess: when to prescribe abx? l Antibiotics may be warranted if  Abscess is large (> 5 cm) or incompletely drained  Significant surrounding cellulitis  Systemic signs and symptoms of infection are present  Patient is immunocompromised  Difficult to drain area (face, hand, genitalia)  Extremes of age

Animal & Human Bite Wounds l One half of all Americans bitten in their lifetime l 80% of wounds are minor, 20% require medical care l Human and cat bites frequently become infected so always require treatment even if not grossly infected l Only 5% of dog bites get infected so treatment indicated if bite is severe, grossly infected, or significant comorbidity (e.g. diabetes)

Bite Wound Treatment l Wound cleaning, irrigation and debridement! l Antibiotics directed against skin flora of patient and oral flora of biting animal/human  Humans (viridans strep, Eikenella, mixed anaerobes)  Dogs (Pasteurella, Capnocytophaga, anaerobes)  Cats (Pasteurella, anaerobes) l Antibiotic Regimens  Oral  Amoxicillin/clavulante 875/125 mg BID  Clindamycin + Fluoroquinolone OR TMP/SMX  IV : Ampicillin/sulbactam 1.5G Q6h

Urinary Tract Infections

Increasing resistance in urinary pathogens l E.coli accounts for ~95% of all cases l TMP/SMX resistance in E.coli > 20% in many parts of the United States l Resultant shift to use of quinolones as first-line empirical therapy over the past years l Quinolones have been associated with “collateral damage”  Increased rates of MRSA  Selection for resistant GNRs including ESBL- producers  Clostridium difficile-associated diarrhea

When to get a culture? l Suspect multidrug-resistant organism  Recent abx  Prior infection or colonization  Recent travel l Suspect pyelonephritis l Follow up cultures unnecessary in patients whose symptoms resolve

2010 IDSA recommended treatment regimens for uncomplicated cystitis First Line Regimens l Nitrofurantoin macrocrystals (Macrobid®) 100 mg BID X 5 days (avoid if early pyelo suspected) l Trimethoprim-sulfamethoxazole 1DS tablet BID X3 days (avoid if resistance prevalence exceeds 20% or if used for a UTI in previous 3 months) l Fosfomycin trometamol 3 grams x 1 dose (lower efficacy than some other agents, avoid if early pyelo suspected) Second Line Regimens l Ciprofloxacin 500 mg BID x 3 days (resistance prevalence high in some areas) l Oral β-lactams (including amoxicillin/clavulante, cefdinir, cefaclor, cefpodoxime, cephalexin (less data); avoid ampicillin or amoxicillin alone; lower efficacy than other available agents, treat for 3 to 7 days) Gupta K et al. Clin Infect Dis. 2011;52(5):

What is fosfomycin? l Phosphonic acid derivative that inhibits cell wall synthesis l Activity against many gram positive and gram negative organisms l In U.S., only oral salt available as a powder sachet dissolved in water  High concentration in the urine l Usual dose 3g x 1 (single dose)  Can also consider 3g every other day x 3 doses or 3g q 72 hrs. x 14 days  3g packet costs about $50

Treatment of cystitis: Back to the future Nitrofurantoin (Macrobid®) PROS l As effective as TMP/SMX l Minimal drug resistance l Low propensity for collateral damage CONS l Blood levels not sufficient to treat early pyelonephritis l Avoid in pts with CrCl < 50 ml/min l Nausea, headache (similar adverse effect rate as TMP/SMX) l Rare pulmonary hypersensitivity Fosfomycin trometamol PROS l Clinical efficacy similar to TMP/SMX l Low propensity for collateral damage l Single dose therapy CONS l Microbiologic efficacy lower than TMP/SMX and nitrofurantoin l Not sufficient to treat early pyelo l Susceptibility testing not routinely performed l Diarrhea, nausea, headache (similar adverse effect rate as nitrofurantoin)

Other oral options for cystitis due to resistant organisms l Amoxicillin-clavulanate (susceptible ESBL-producing E. coli) l Nitrofurantoin Fosfomycin references: l Falagas et al, Lancet Infect Dis 2010;10:43-50 l Neuner et al, Antmicro Agents Chemother 2012;56:

Asymptomatic Bacteriuria l Do not screen if no symptoms are present  Except in pregnancy  Other special situations l Do not prescribe antibiotics!  Relative Risk ~3x for recurrence of symptomatic bacteriuria when asymptomatic patients receive antibiotics

Final Questions? l Contact Info l Extension: l SFGH “As real as it gets”