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, Gram-negatives, 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-lactam-based 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 q8hAND

• Unasyn 3 g IV q6h OR Pip/Tazo 3.375 g IV q6hAND

• 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