Antibiotics: Principles and Illustrative Cases

Jake Nania, M.D.

Pediatric Infectious Diseases

February 2, 2006

Making wise antibiotic choices

#1 Know what you’re targeting!– Send appropriate diagnostic studies before

antibiotics are started– Empiric Rx based on likely organisms at

suspected site of infection• e.g. Bacterial Meningitis…• READ UP and SEE MORE PATIENTS

– Adjust Rx based on info from the Micro Lab• Gram Stain: should never narrow, only broaden Rx• Culture and susceptibilities

Making wise antibiotic choices#2 Pathogen-specific factors

Know (or look up) susceptibility patterns for suspected organisms:

– Best: Hospital Antibiogram, Pt’s previous cultures– Good: Regional Data (e.g.CDC)– Okay: Published Series of Susceptibility Data

(including the Sanford Guide)– Least Helpful: The guy bringing breakfast to morning

reportKnow agents likely active against bacteria for which

susceptibilities are not usually done– e.g. oral anaerobes…– e.g. Mycoplasma pneumoniae…

Making wise antibiotic choices

• #3 Host-specific factors– How sick or vulnerable = how aggressive– Previous antibiotic history and other risk

factors for resistant organisms– Renal and Hepatic Function, GI absorption

• Ensuring therapeutic levels• Avoiding toxicity

– Previous Allergy or other adverse reactions– Age

• Fluoroquinolones (FQ), if <18 years• Erythromycin, if < 2 weeks

Making wise antibiotic choices

• #3 Host-specific factors (continued)

– Site of infection• Meningitis: clindamycin, macrolides, 1st/2nd gen

ceph, aminoglycosides (AG) not good choices• Endocarditis: bacteriocidal agent(s) needed• Abscesses: AG less active• Biliary tract: PCNs, doxycycline, ceftriaxone, FQs

have high excretion• Bone: FQ, Clinda >PCNs, Ceph, Vanc > AG• Bloodstream: Azithromycin tissue >> blood levels

Making wise antibiotic choices

• Other important factors– Toxicity (e.g. AG oto- and nephrotoxicity)– Cost (someone is paying for it!)– Ease of administration (frequency, palatability,

parenteral vs. oral)

– Avoiding selection of resistance• Narrowest spectrum agent to cover suspected

organism• Having an endpoint in mind• Knowing when to stop

Case 1: Prophylaxis• The patient is a 59 year old male scheduled to

have CABG for advanced coronary disease. He is given mupirocin ointment to apply to his anterior nares for the 5 days leading up to surgery and asked to shower with chlorhexidine soap the night before surgery. As the first incision is made in the OR, a dose of cefazolin is started. After successful surgery, the patient is cared for in the SICU. Cefazolin is continued for 3 days while thoracostomy tubes are in place to prevent infection near the site of the tubes. The patient is eventually discharged from the hospital without an infection related to his stay.

Which are best practice and proven?

– Nasal Mupirocin: – Reduction in SSI shown for S.aureus carriers only (effect diluted

out for entire group in study)

– Chlorhexidine Shower:

Most studies show no effect – Cefazolin in the OR:

The timing was suboptimal. Clear benefit when given in the 30 minutes BEFORE incision

– Cefazolin while chest tubes in place:

Not supported by available data

Antibiotic Prophylaxis – Key Points

• Intuition is not a trustworthy guide

• Guidelines often published, evidence-based– Surgical Site Infection Prevention– SBE Prophylaxis– PCP prevention in compromised hosts

• Question standard practices

• Risk-Benefit– Unaffected patient – prophylaxis must be

justified to outweigh cost and risks of toxicity, induction of resistance

Case 2: Empiric Therapy

• A previously healthy 4 year old girl presents with 2 days of fever (102), wet cough and new onset of right pleuritic chest pain. Exam is significant for RR=40, T=102, O2 sat of 91%, lack of upper resp findings and focal rales in the right base. CXR reveals a streaky RLL infiltrate.

• What empiric antibiotics and why?

Case 2

• Treatable Pathogens of concern:– Pneumococcus– Mycoplasma pneumoniae– S.aureus (including CA-MRSA)– Chlamydophila pneumoniae– GAS– H.flu, M.catarrhalis

Case 2

• Reasonable choices:– cefuroxime (200-240mg/kg/day)– ceftriaxone or cefotaxime

• Kaplan, SL et al. Pediatr Infect Dis J. 2001 Apr; 20(4): 392-6.• Yu, VL et al. Clinical ID. 2003 15 July; 37: 230-237.

– Add a macrolide?• For empiric mycoplasma/chlamydophila coverage• For dual therapy for pneumococcus?

– If serious β-lactam allergy:• Clindamycin, vancomycin, or newer FQs

Empiric Pneumonia Therapy: Key Points

Initial Rx based on likely pathogen & how ill– Outpatient therapy: High-dose oral amoxicillin,

possibly azithromycin or doxycycline– Moderately Ill Inpatient:

• β-lactams remain effective for pneumococcal infections outside CNS; combo therapy?

• In adults:– Dual therapy for community-acquired pneumonia– FQs play much larger role

– Severely Ill Inpatient: Include MRSA coverage

Case 3: Empiric and Definitive Rx

• Hx and Exam: A 9 month old, previously healthy boy presents to the ER with a 12 hour history of poor PO intake, fever to 103, fussiness alternating with sleepiness. He has had a runny nose for 3 days prior to onset of presenting sx. Other family members have cold sx. No significant PMHx, but mom notes that he is “behind on his shots”. HR=140, RR=30, BP=85/39, T=100.2. Exam reveals a somnolent but responsive infant. Ant fontanelle is full. His peripheral capillary refill is about 3 seconds. The rest of the exam is normal.

• You obtain Blood, CSF and Urine for evaluations. CSF is non-bloody and straw colored. Other info pending.

• What empiric antibiotics?

Case 3

• Pathogens of Concern:– Pneumococcus– Meningococcus– Also…

• H.flu (undervaccinated?)

• S.aureus• GAS• Rickettsial – R.rickettsii, Ehrlichia• Salmonella

Case 3

• What to give first?– ceftriaxone/cefotaxime

• How much?– A LOT– Dose: 100 mg/kg/dose (q24 ceftriaxone/q8 cefotaxime)

• When?– NOW!

• After the cephalosporin…?– Vancomycin; Dose: 60mg/kg/day

Case 3

• Work-up of note:– WBC=20.8 (80%N, 14%L, 5%M),Plt=585– CSF WBC=504 (94%N, 4%M), RBC=135– CSF Prot=67, Gluc=6– CSF Gram Stain: 2+PMNs, 2+ GPCs

– CSF and Blood Cx: S.pneumoniae

Case 3• Susceptibility panel of our patient’s

S.pneumoniae isolate:

Penicillin R

Ceftriaxone I

Clindamycin S

Erythromycin S

Vancomycin S

Rifampin S

Case 3

• Definitive Rx:– Ceph3 plus Vancomycin– Plus Rifampin?

• If response to Rx is slow over first days• If steroids given (penetrates even uninflamed meninges)

– If serious β-lactam allergy:• Vancomycin plus Rifampin• ID consult!

Meningitis Case: Key points • In suspected bacterial meningitis/sepsis, treat

ASAP (even before LP if it will be delayed significantly)

• Vancomycin for suspected bacterial meningitis• Know antibiotic penetration for the tissue infected• The dose does matter!

– Even though killing by Vanc and Cephalosporins is time-dependent, high doses needed for CSF penetration

• Ask for help with resistant organisms or serious β-lactam allergy

Take-home Points

• Prophylaxis: consider carefully if benefits outweigh risks and look for evidence

• Selection of an appropriate agent is multi-step process:– Identify possible site(s) of infection– DDx of organisms at that site– Local/Hospital susceptibility patterns– Penetration of agent into site

• Misuse of Antibiotics has Societal Impact

http://home.mdconsult.com/das/book/54675379-2/view/1259

Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases, 6th ed.,2005 Churchill Livingstone Chapter 16 - Principles of Anti-infective Therapy

Update of Practice Guidelines for the Management of Community-Acquired Pneumonia in Immunocompetent Adults Lionel A. Mandell,1 John G. Bartlett,2 Scott F. Dowell,3 Thomas M. File, Jr.,4 Daniel M. Musher,5 and Cynthia Whitney3,a

As Antibiotic Discovery Stagnates ...A Public Health Crisis BrewsBAD BUGS, NO DRUGSwww.idsociety.org