09/10: Rational Antimicrobial Therapy

Bacteria that are G+ aerobes/facultative anaerobes

Stay Strong- Entire Cows Live and Culture Positive

• Staphylococcus

• Streptococcus

• Enterococcus

• Corynebacterium

• Listeria

Bacteria that are G+ anaerobes

Stay Strong- Entire Cows Live and Culture Positive

• Clostridium

• Peptostreptococcus

Bacteria that are G- aerobes/facultative anaerobes

Entry Past Many Mighty Hills Perhaps Bad, Hesitate - Before Following

• Enterobacteriaceae/E. coli and friends (Klebsiella, Serratia, Proteus, Enterobacter)

• Pasteurella

• Mannheimia

• Mycoplasma

• Histophilus

• Pseudomonas

• Bordetella

• Haemophilus

Bacteria that are G- anaerobes

Entry Past Many Mighty Hills Perhaps Bad, Hesitate - Before Following

• Bacteroides

• Fusobacterium

Common intracellular bacteria

• TBD: Ehrlichia, Anaplasma, Rickettsia

• Chlamydia

• Rhodococcus

• Lawsonia

MIC

Minimum inhibitory concentration; Lowest concentration that inhibits visible growth

MBC

Minimum bactericidal concentration; Lowest concentration that kills 99% of bacteria

What does it mean if a drug’s MIC and MBC are very different

It is likely that the drug is bacteriostatic

When does it matter if your antibiotic is bactericidal v bacteriostatic

When your patient is immune compromised and simply stopping growth isn’t enough for the patient to handle the infection on their own

As a default, why should you avoid combining bactericidal and bacteriostatic drugs

As a general, most of those combinations are antagonistic

When can you use a combination of a bactericidal and bacteriostatic drug

When it is a combination that is known to be synergistic for certain bacteria

Post-AB effect (PAE)

Even after a drug is eliminated below the MIC, bacterial growth is still inhibited

What happens if an AB does not have a PAE

You need to maintain a tissue concentration >MIC for at least half of the dosing interval

Serum breakpoint AKA breakpoint MIC

The values used to decide whether an isolate is susceptible, intermediately susceptible, or resistant to a certain antibacterial

Factors that influence serum breakpoints

• Population level MIC

• Drug PK

• Clinical trial data

Why is plasma concentration a good evaluation of AB distribution

We assume interstitial fluid has the same concentration as plasma, and as a general can get into tissues

Types of drugs that can get into urine in much higher concentrations

Polar and hydrophilic drugs

Concentration-dependent antibiotic effect

MIC dependent on the intensity of drug exposure

Time-dependent antibiotic effect

MMIC dependent on >50% of dosing interval being above the MIC

Types of resistance

Constitutive or acquired

Ways a bacteria acquires resistance genes

• Conjugation: transfer of plasmids

• Transduction: transfer via bacteriophage

• Transformation: uptake of DNA from the environment

Mechanisms of resistance

• Inactivation of drug

• Decreased intracellular accumulation

• Change the drug target

• Change metabolism

Bacteria most commonly used to assess drug efficacy in dogs

Staphylococcus pseudointermedius

Bacteria most commonly used to assess drug efficacy in cats

Pasteurella multocida

Bacteria most commonly used to assess drug efficacy in horses

Streptococcus equi zooepidemicus

Bacteria most commonly used to assess drug efficacy in cattle

Mannheimia haemolytica (BRD!) and Streptococcus agalactiae (mastitis!)

Bacteria most commonly used to assess drug efficacy in pigs

Mycoplasma hyopneumoniae

Most common mechanism of acquired resistance to beta lactams

• Deactivation via beta lactamase

• Change in target site (penicillin binding protein)

Constitutive resistance to beta lactams

Penicillin and 1st generation cephalosporins are not effective for G- bacteria (they don’t get past the outer cell membrane

Most common mechanism of acquired resistance to aminoglycosides

General adaptive resistance

Constitutive resistance to aminoglycosides

Aminoglycosides require oxygen-dependent transport, and so are ineffective against anaerobes

Most common mechanism of acquired resistance to macrolides

Methylation of binding site on the 50S ribosomal subunit

Constitutive resistance to fluoroquinolones

Anaerobes are inherently resistant (except to pradofloxacin)

Most common mechanism of acquired resistance to TMS

Change in target (folic acid metabolizing enzymes)

How do “highly lipophilic” antifungals differ from “highly lipophilic” antibacterials

Highly lipophilic antifungals may be so highly protein bound as to be almost unable to distribute into barrier restricted compartments. Highly lipophilic antibacterials are much less bound to proteins, better absorbed from the GIT, and can better get into barrier restricted compartments

Highly polar ABs

• Aminoglycosides

• Bacitracin

• Polymyxin B

• Vancomycin

Moderately polar ABs

• Penicillins

• First gen cephalosporins

Moderately lipid soluble ABs

• 3rd gen cephalosporins

• Tetracyclines

• Lincosamides

• Sulfonamides

• Fluoroquinolones

Highly lipid soluble ABs

• Rifampin

• Chloramphenicol

• Doxycycline

• Macrolides

ABs that do not cross the BBB

• Aminoglycosides

• First gen cephalosporins

• Tetracycline

ABs likely to be excreted intact in the urine (good for UTIs)

• Beta lactams

• Aminoglycosides

• Tetracyclines

• Nitrofurantoin

• Polymyxin B

• Fluoroquinolones

• TMS

ABs likely to accumulate in acidic tissues (prostate and mammary)

• Fluoroquinolones

• TMS

• Chloramphenicol

• Imipenem

ABs good for intracellular bacteria

• Tetracyclines

• Chloramphenicol

• Florfenicol

• Erythromycin, azithromycin, clarithromycin

• Tylosin, tilmicosin

• Clindamycin

• Fluoroquinolones

• Rifampin

Primary side effect associated with therapeutic doses of penicillins

Hypersensitivities

Primary side effect associated with therapeutic doses of cephalosporins

Hypersensitivities and GIT disturbance

Primary side effect associated with therapeutic doses of aminoglycosides

• Nephrotoxicity

• Ototoxicity

• Neuromuscular blockade

Primary side effect associated with therapeutic doses of tetracyclines

GIT disturbance and discoloration of teeth

Primary side effect associated with therapeutic doses of chloramphenicol

Bone marrow suppression (especially in humans!)

Primary side effect associated with therapeutic doses of macrolides and lincosamides

Species-specific GIT toxicity and anhidrosis in foals

Primary side effect associated with therapeutic doses of tilmicosin

Cardiotoxicity

Primary side effect associated with therapeutic doses of fluoroquinolones

• Arthropathy (cartilage damage) in growing animals

• Retinal degeneration in cats

Primary side effect associated with therapeutic doses of rifampin

• Stains tears, saliva, and urine red

• Induces P450 enzymes

Primary side effect associated with therapeutic doses of metronidazole

• Carcinogenic/mutagenic

• Neuro disease

• GIT distress

Primary side effect associated with therapeutic doses of TMS

• Teratogenic

• Keratoconjunctivitis sicca in dogs

• GIT distress