Selected topics in rational antimicrobial usage (Proceedings)

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Selected topics in rational antimicrobial usage (Proceedings)

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Apr 01, 2008

Dr. Alexander Fleming (1928) initiated the 'modern age of medicine' with the discovery of penicillin.

Drs. Fleming, Florey & Chain (1945) were awarded the Nobel Prize in medicine. They received no money for their amazing discovery.

The Four Basic Human Drives

1. To seek food and shelter

2. To seek care and nurture

3. To procreate

4. To administer antibiotics to everything that moves

Beta-lactam antibiotics

  • Penicillin- Procaine penicillin G, Na or K penicillin
  • Synthetic penicillins- ampicillin, amoxicillin, ticarcillin
  • Cephalosporins-

- First generation- cefazolin, cephalexin

-Third generation- ceftiofur, ceftazidime

- Fourth generation- cefepime

o all have extended gm (-) activity

o increased resistance to B-lactamase org.

  • Most infections in horses caused by B-hemolytic strep. (uniformly susceptible to penicillins).

Beta-lactam antibiotics

  • Primary cephalosporin administered to horses is ceftiofur.
  • Advantages include broad spectrum of activity and good safety profile.
  • Several studies have evaluated concentrations (lungs, plasma) and safety of ceftiofur over wide range (1.1mg/kg to 11mg/kg) IM and IV.



Ceftiofur

  • Approved for use in horses for respiratory tract infections(2.2 to 4.4 mg/kg Q24 IM).
  • Higher doses recommended for treating gm (-) (Klebsiella, Salmonella, Enterobacter).
  • Important to maintain concentrations above MIC with gm (-) (No post-antibiotic effect).
  • Unlike other cephlosporins- it is extensively metabolised (desfuroylcetiofur DFC)- primarily excreted in urine
  • In calves w/ tissue chamber infection model; ceftiofur & DFC higher conc in infected chamber
  • Protein bound DFC is reservoir for active drug at site of infection (reduced dosing interval)
  • Protein binding extends effective t ½
  • PK profile; IV vs. IM vs. SQ
  • 99% protein bound (clinically significant)
  • Binds to acute phase proteins (a1-anti-trypsin) which carries bound drug to sites of inflammation
  • Time dependent antimicrobial
  • Label dose is 2.2 to 4.4 mg/kg q 24h IM.
  • Higher doses (5-10 mg/kg) q 12h IV or IM clinically successful in treating septicemic neonates.
  • The IM route of administration + lack of "penicillin rxn's" + broad spectrum of activity = excellent utility in treating polymicrobic infections (pleuropneumonia)

Oral B-lactams?

  • Very poor absorption and bioavailability
  • 2 recent studies in foals; cephalexin and cephadroxil dosed at 30mg/kg PO q 12 hrs was effective

Trimethoprim-Sulfonamide



  • Considered -cidal at high concentrations.
  • Lipophylic and penetrates tissues well (CNS).
  • Broad-spectrum coverage (gm (+), (-) and some anaerobes.
  • Interfere with synthesis of folic acid from PABA with sulfonamides competitively inhibiting PABA.
  • Purulent fluids rich in protein and PABA, this will decrease TMS activity.
  • Good activity against many Strep organisms- although some resistance noted despite susceptibility results.
  • Potentiated sulfas Not recommended for initial treatment of S.equi infections; Verheyen K, Newton J et al. Elimination of guttural pouch infection and inflammation in asymptomatic carriers of Streptococcus equi. Equine Vet J. 2000; 32. 527-532.
  • Excellent GI absorption although reduced substantially by feeding....(delay feeding).
  • Lack of clinical activity against anaerobes.

Potentiated Sulfas

  • t½ =sulfamethoxazole 3.5-5 hrs.
  • t½ =sulfadiazine 3-4 hrs.
  • t½ =trimethoprim 2-3 hrs.
  • BID PO dosing is necessary to attain therapeutic plasma concentrations of trimethoprim (Dowling in Bertone,2004)

Trimethoprim-Sulfonamide

  • Oral formulation containing TMP with sulfadiazine in a 1:5 ratio commonly dosed at 20 to 30mg/kg BID.
  • In horses- rapid elimination of TMP leads to >persistence of sulfonamide and changes optimal ratio. Therefore, potentiated sulfonamides should be dosed BID.

Erythromycin

  • Macrolide; bacteriostatic except at high dosages they are -cidal.; good tissue distribution.
  • Good activity Strep. Staph. Bacteroides, & Rhodococcus.
  • Poor activity E.coli, Pseudomonas, Klebsiella & Salmonella.
  • R. equi pneumonia- 25mg/kg q 6-8 hrs will achieve plasma conc. which exceed MIC.

Azithromycin



  • Pharmacokinetic advance in macrolide arena.
  • High oral bioavailability, large Vd (18.6L/kg) and peritoneal = synovial = serum conc., T½ = 20hrs, conc. in bronchoalveolar cells 15- 170x [serum].
  • Impression; fewer GI issues.
  • Dose;10 mg/kg QD for 5 days then q 48hrs per os.
  • Significant advantage over erythromycin.
  • Cost +/- $50/day
  • Bioavailability =56% in 6 healthy foals
  • BAL concentrations 15-170X serum
  • PELF concentrations 1-16X serum
  • 10mg/kg QD PO for 5 days then reduced to every other day (suggested)
  • (Jacks, 2001)

Newer Macrolides

  • Broader spectrum than erythromycin.
  • Clarithromycin- more effective than azithromycin against R.equi in vitro. Improved efficacy in severe R.equi pneumonia as compared to erythro or azithromycin. (Giguere ACVIM 2003)
  • Dosage= 7.5mg/kg BID + rifampin (higher incidence of diarrhea?)

Clarithromycin

  • Oral bioavailability =57.3% +/- 12.0%
  • 7.5 mg/kg BID PO provides serum, pulmonary epithelial lining and bronchalveolar cells of foals above MIC for R. equi isolates during entire 12 hr period
  • Determined in 6 healthy foals
  • (Womble, 2006)