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Empiric Antibiotic Therapy Antibiotics • The appropriate use of empiric antibiotics is central to medical practice. • The goals of empiric antibiotic regimens are: – To provide adequately broad coverage to treat an infection before the culprit organism is identified. – To use a sufficiently narrow spectrum of coverage so that antibiotic resistance and adverse drug reactions are minimized. – Review previous cultures and sensitivities – Always remember, the cornerstone of effective infectious treatment is good source control. -David Butler, MD, Infectious Disease UCSD Antibiotics • Today we will discuss: – Specific regimens by organ system – Organisms to be worried about Major infections in internal medicine • Pneumonia • Meningitis and encephalitis • Urinary tract infections • Cellulitis and other soft tissue infections • Fever in the neutropenic patient “The captain of the men of death” • Pneumonia is the sixth-leading cause of death in the US • 4,000,000 cases/year in ambulatory patients • More than 600,000 admissions/year – ~14% mortality among inpatients – Likely higher in elderly inpatients Common organisms • Streptococcus pneumoniae – most commonly identified cause of pneumonia across the board. • Haemophilus influenzae and parainfluenzae – second most common organisms in some studies; more common in smokers. • Mycoplasma pneumoniae and Chlamydophila pneumoniae– frequent pathogens among otherwise healthy people, often present atypically. • Legionella pneumophila – also considered an “atypical” organism, may be transmitted via fomites. • Moraxella, Streptococcus pyogenes (GAS). Other organisms • Pseudomonas aeruginosa • Coccidioides immitis • Staphylococcus aureus • Klebsiella pneumoniae, E. coli, other GNRs • Mycobacterium tuberculosis • Pneumocystis jiroveci • Anaerobes: Bacteroides, Peptostreptococcus • Viruses Pneumonia: Guidelines • ATS and IDSA guidelines for pneumonia recommend initial empiric therapy based on patient status and risk factors. • Patient categories based on clinical status, comorbidities, and risks for infection with: – penicillin- and multidrug-resistant pneumococci (MDRSP) – enteric Gram-negative organisms – Pseudomonas aeruginosa Pneumonia: some random thoughts • Antibiotics within 4-8 hours • If someone is sick enough to be admitted, start with two drugs. • Use intravenous therapy up front. • Always get blood cultures beforehand. • Consider sputum cultures if feasible. • Remember the “red flags”: – Multilobar disease, effusions, upper lobe disease, mediastinal lymphadenopathy, cavitary lesions. – Again don’t write pneumonia and effusion in the same note without a tap procedure note soon to follow Community-acquired pneumonia: regimens • Ceftriaxone and azithromycin – Ceftriaxone: 3rd generation cephalosporin (β-lactam) • • • • Good coverage of S. pneumoniae, H. influenza, Moraxella. Use higher doses in patients <50 years old: 2 g IV q24h. Allergic reactions in PCN-allergic patients rare (3-5 %). “Fun-fact” reaction: biliary sludging. – Azithromycin: macrolide • • • • Covers the “atypicals”: Mycoplasma, Chlamydophila, Legionella Reasonable pneumococcus coverage but resistance increasing. Less GI upset than erythromycin. Probably not suitable as outpatient monotherapy in San Diego. Respiratory Fluoroquinolones • Moxifloxacin, Levofloxacin, and gatifloxacin (off the market). • Inhibitors of DNA gyrase. • Broad coverage of pneumococcus, Gramnegatives, atypicals. • Limited activity against Pseudomonas, Staphylococcus. • Ciprofloxacin has limited Gram-positive coverage but is better for Pseudomonas. • No anaerobic coverage. Fluoroquinolones • Moxifloxacin and Levofloxacin are good monotherapy choices for CAP patients who can be treated as outpatients. • Moxifloxacin (Avelox) is the quinolone of choice at NMCSD – Do not have to dose based on renal function – DOES NOT cover UTI • Consider using with ceftriaxone for initial inpatient therapy. • Overuse is breeding resistance. • Adverse reactions of note: – – – – QT prolongation (may be more of a concern with moxifloxacin). Achilles tendon rupture (cipro) Hypo/hyperglycemia, especially with gatifloxacin (which is why it’s off the market). Relatively contraindicated in children. Pneumonia: additional considerations • Consider aspiration risk in patients with alcohol/drug abuse, dementia, stroke. – Cover anaerobes with piperacillin/tazobactam. • Piperacillin/tazobactam (Zosyn™) – – – – Anti-pseudomonal penicillin with β-lactamase inhibitor. Broad coverage (Gram-positive, Gram-negative, anaerobes). Moderate but less-than-fantastic staphylococcal coverage. Indicated in hospital-acquired pneumonias: • Usual dose 3.375 g IV q6h, but 4.5 g IV q6h if concerned for Pseudomonas. • High sodium load (over 2 grams/day at usual doses). • Combine with moxifloxacin or levofloxacin for atypical coverage, ciprofloxacin or aminoglycosides for Pseudomonas. Pneumonia: additional considerations • Why don’t patients get better? – Nosocomial infections with MSSA, MRSA (50% of all S. aureus) – Complicated pleural space – Fungal infections (esp. coccidioidomycosis) – Tuberculosis – Other infections – Consider PCP in the immunosuppressed or with HIV risk factors Pneumonia summary • Community-acquired – Ceftriaxone 1-2 g IV q24h PLUS – Azithromycin 500 mg IV/PO q24h – Moxifloxacin 400 mg IV/PO q24h – Levofloxacin 750 mg IV/PO q24h • Hospital-acquired – Pip/Tazo 3.375-4.5 g IV q6h – +/- Vancomycin or Linezolid for MRSA coverage • Anaerobes – Pip/Tazo 3.375g IV q6h Meningitis and encephalitis • CNS infections are common admitting diagnoses. • Common organisms: – Enteroviruses, HSV, maybe arboviruses? – Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae (rarer) – Mycobacteria, Coccidioides, Cryptococcus in special situations. CSF evaluation • If possible, perform LP on side and get opening pressure especially if considering fungal or MTB • Cell count with differential – tube 1 and 4 • Protein, glucose • Gram stain and culture • Enterovirus and HSV PCR – ensure the ER sent it (makes you feel warm and fuzzy if you don’t think it’s bacterial) • Consider AFB and fungal cultures, cocci serology, crypto antigen if indicated. • Save extra CSF and hand-deliver samples to the lab. • For God’s sake, save extra CSF and hand-deliver samples to the lab. Empiric treatment of meningitis • Generally healthy adults: – Ceftriaxone 2 g IV q12h – Vancomycin 15 mg/kg IV q12h, could talk to pharmacy about q8 hour dosing if young healthy patient (Troughs 15-20) • For coverage of MDRSP until cultures available or negative. • Probably does not cause renal impairment alone. – Consider dexamethasone 0.15mg/kg IV q6h with first dose for confirmed or highly-suspected bacterial meningitis continue for 48-96 hours. • If patients are elderly, immunosuppressed, pregnant, or alcoholic, add ampicillin 2 g IV q4h for coverage of Listeria monocytogenes. • If encephalitis is a concern, add HSV coverage with acyclovir 10 mg/kg IV q8h. – Remember to maintain adequate urine output (15cc/kg/day). Extra thoughts on meningitis • In patients with more insidious presentations and markedly elevated CSF protein, consider: – Coccidioidal meningitis • Lymphocytic pleocytosis in the CSF with elevated protein. • Initial treatment with at least fluconazole 800 mg PO q24h – lifelong therapy indicated if diagnosis confirmed. – Cryptococcal meningitis • Always high on the differential in HIV. • India ink stain good for quick diagnosis although CSF antigen is probably a better test. • Treated with ampho B and flucytosine initially. – Tuberculous meningitis • Especially in subacute patients with appropriate travel/exposure history. • Probably should be talking with ID if you’ve reached this point. Neurological infections summary • Start with ceftriaxone 2 g IV q12h and vancomycin 15 mg/kg IV q12h. • Add ampicillin 2 g IV q4h if immunosuppressed, >50 years, or alcoholic. • Acyclovir 10 mg/kg IV q8h if encephalitic. • Fluconazole 800 mg PO q24h (at least) if cocci is a major concern. – Remember LFT monitoring when using azoles. Pyelonephritis • Clinically presents with CVA tenderness, fever, and pyuria in most patients. – May be more subtle in the elderly and immunosuppressed. • Urinalysis and culture are mandatory and should be obtained prior to antibiotics in the hospitalized patient. • Common organisms: – Escherichia coli – Other GNRs: Proteus, Enterobacter, Klebsiella, Providencia – Enterococcus faecalis and faecium Urine Gram stain • For some mysterious reason, urine is the one body fluid not routinely stained by the lab. – Call 2-9234 and ask for a Gram stain. • Gram-negative rods – E. coli, other Enterobacteriaciae. – Start with a quinolone (cipro, levo) – moxi not effective. – Alternatives: ceftriaxone 1-2 g IV q24h, gentamicin 5 mg/kg IV q24h. • Gram-positive cocci – Group B strep, Enterococcus, Staphylococcus saprophyticus. – Treat with ampicillin 2 g IV q4h once confirmed -> might start with vancomycin empirically. – Consider vancomycin in patients with Foleys or recent hospitaliztion. – Note that E. faecium=VRE (approx 10%) -> rare at NMCSD. – S. aureus in the urine = bacteremia/endocarditis until proven otherwise. Complicated UTIs • Persistent fever on appropriate antibiotics for 72 hours: obtain renal ultrasound to rule out perinephric abscess. • Renal obstruction, renal transplant, indwelling catheters: – Consider additional coverage for Pseudomonas, Enterobacter, Acinetobacter. – Pip/tazo may be appropriate for broader coverage • Candiduria may be treated with short courses of oral fluconazole. – I don’t generally advocate treating candiduria in an asymptomatic patient, but treatment may be warranted if the patient is febrile or otherwise symptomatic with pyuria on UA. • E. faecium may represent VRE – this would be treated with linezolid 600 mg PO/IV q12h, but don’t treat all enterococci empirically as though they’re VRE. – Nausea, diarrhea, and thrombocytopenia are all common side effects of linezolid. Pyelonephritis summary • E. coli and other GNRs are most common and respond well to quinolones in general. • Suspect Enterococcus if GPCs are found on Gram stain. – Vancomycin 15 mg/kg IV q12h or ampicillin 2 g IV q4h (if sensitive). – Consider vancomycin in the recently hospitalized – E. faecium may be VRE – would treat with linezolid or daptomycin in most cases. • Consider Pip/tazo in complicated UTIs. – Pip/tazo will cover E. faecalis (if sensitive). • 14 days of total therapy is generally recommended, especially in β-lactambased regimens. Cellulitis and soft-tissue infections • Staphylococcus aureus and Streptococcus pyogenes (group A β hemolytic streptococci - GABHS). – GABHS tends to evolve more rapidly and may have regional lymphadenopathy and lymphatic streaking on exam. • Admissions usually for failure of outpatient treatment. – Think MRSA, especially in patients from MCRD and NSWC. • Initial regimens: – Vancomycin 15 mg/kg g IV q12h – If MSSA or streptococci are confirmed: • Nafcillin or oxacillin 2 g IV q4h • Cefazolin 1 g IV q8h • Clindamycin 900 mg IV q8h Special considerations • Necrotizing fasciitis – – – • Consider when pain is intense or rapidly progressive. Early surgical consultation and debridement. Antibiotics are only an adjunct to surgery: • Clindamycin 900 mg IV q8h AND • Unasyn 3 g IV q6h OR Pip/Tazo 3.375 g IV q6h AND • Vancomycin 15 mg/kg IV q12h (dose for troughs 15-20). Diabetic foot infections – – – Generally polymicrobial (GPCs, GNRs, anaerobes). Empiric coverage: • Pip/Tazo 3.375 g IV q6h • Clindamycin 900 mg IV q8h and ciprofloxacin 400 mg IV q12h • Concider Augmentin as outpt therapy with close follow-up Duration of therapy depends on tissue viability and the presence/absence of osteomyelitis. Fever in neutropenia • Temperature ≥38.3C x 1 or ≥38.0C for > 1 hour • Absolute neutrophil count <500 (or <1000 and expected to be less than 500 in the next 24 hours) – Total WBCs x (% PMNs + % bands) • Numerous causes, specific etiology may not be isolated. – – – – – Pneumonia: pneumococcus, Klebsiella, E. coli, Pseudomonas. Urinary tract: E. coli, Proteus, Klebsiella, Enterococcus Mucositis: S. viridans Indwelling catheters: S. aureus, coagulase-negative staphylococci, Candida. Viruses, invasive fungal pathogens, non-infectious sources of fever. Initial empiric management • Thorough history and physical exam, including oral cavity, indwelling lines, perirectal region. • Blood and urine cultures, chest radiograph, sputum if available. – Separate cultures from catheter sites. – Fungal isolators. • Initial antibiotics: – Pip/Tazo 4.5 g IV q6h and tobramycin 5mg/kg IV q24 – Cefepime 2 g IV q8h – Aztreonam 2 g IV q6-8h and vancomycin 1-1.5 g IV q12h if PCN-allergic. – Add vancomycin to patients if suspicious of Gram-positive UTIs, catheter infections, mucositis, or prior MRSA infections. • Other regimens (e.g., Pip/Tazo alone, meropenem alone) appear effective; institutions will vary in their “routine” regimen. • Don’t forget aggressive fluid resuscitation in the septic patient. Additional notes • Consider adding metronidazole 500 mg IV q6h if highly suspicious of an anaerobic infection OR if C. difficile is a concern (oral metronidazole preferable for C. difficile). • Empiric antivirals generally not indicated, but acyclovir 10 mg/kg IV q8h appropriate if vesicular or ulcerated lesions are noted on exam. • If no improvement after 3-5 days of broad-spectrum antibiotics, add antifungals. – Traditional drug of choice: amphotericin B – Today, typically we use caspofungin or voriconazole. • Removal of indwelling catheters mandatory if patient is septic or if S. aureus is isolated from the blood. • Consider echocardiography if bacteremic with a new murmur. Final comments • Get cultures before antibiotics whenever possible. – • Review CHCS frequently for results or check out the lab personally. Remember to adjust dosing for renal insufficiency. – – MDRD algorithm – www.nephron.com Check Sanford for dosage adjustments. • Be familiar with common adverse reactions. • If you’re thinking about using the exotic drugs, you might want to think about consulting ID. • Be aware of the FORBIDDEN LIST OF ANTIBIOTICS THAT REQUIRE I.D. APPROVAL. – Meropenem, Imipenem, Ertapenem, Linezolid, Daptomycin, Synercid, Colistin, Tigecycline Questions