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General Pharmacology 2 > Antimicrobial Therapy: Potentiated Sulfas and "-phenicols" > Flashcards

Antimicrobial Therapy: Potentiated Sulfas and "-phenicols" Flashcards

1
Q

Folate - background

A

Folate is required as a cofactor fo the synthesis of thymidine, purines, and DNA in many bacteria

Sulfonamides and trimethoprim are competitve inhibitors of separate enzymes for bacterial folate synthesis

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2
Q

Sulfonamides:

Absorption

A

Most are well absorbed PO

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3
Q

Sulfonamides:

Distribution

A

Lipophilic and penetrate protected environments well

weak acids

Moderate to high protein binding

Drug interactions due to protein binding quite unlikely, despite some label claims

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4
Q

Sulfonamides:

Metabolism

A

Hepatic metabolism primary by acetylation – except dogs who may form reactive metabolites causing immune-like reactions

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5
Q

Sulfonamides:

Elimination

A

Some renal elimination produces effective concentrations for UTIs

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6
Q

Sulfonamides:

A
  • PK are drug/species specific, but many have loading doses to immediately achieve effective concentrations
  • Bacteriostatic when used alone
  • Combination of Trimethoprim/sulfonamides is typically Bactericidal
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7
Q

Sulfonamides:

Spectrum

A
  • Gram positve, and gram negative aerobic, T>MIC
    • Pseudomonas, Enterococcus and anaerobes typically RESISTANT
    • Poor activity with cellular debris/pus as folate is present in the environment
  • Additional Spectrum:
    • several parasites of Veterinary importance require folate synthesis
    • Sulfadimethoxine is approved for treating enteritis caused by COCCIDIA
    • Sulfadiazine in combination with pyrimethamine for equine protozoal myeloencephalitis
    • Sulfonamide in combination with pyrimethamine for dogs with Neospora caninum
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8
Q

Sulfonamides:

Resistance

A
  • Mechanisms include decreased cell permeability, target changes adn enhanced bacterial synthesis of PABA
  • Overall it seems the resistance in dogs/cats is low due to use of other antimicrobials
    • TMP/Sulfas used ot be very commonly used, now cephalosporins, fluoroquinolones and amoxicillin/clavulanate are more commonly used
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9
Q

Sulfonamides:

Sulfadiazine

A
  • PO
  • May have most renal elimination, but others still effective for UTI
  • Approved for horses with trimothoprim
  • ~$5/dose at cost for horses
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10
Q

Sulfonamides:

Sulfadimethoxine

A
  • PO, IV
  • approved for use in cattle, cats, dogs, chickens, and turkeys as sole ingredient or in combination with ormetoprim
    • available as an injection - IV use only due to tissue damage, irritioation, residues for IM/SQ
    • For Dairy:
      • read label
      • No ELDU for lactating dairy cattle
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11
Q

Sulfonamides:

Sulfamethoxazole

A
  • PO
  • Human approved with trimethoprim, more commonly used because less expensive
  • Horses:
    • ~$0.90/dose
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12
Q

Trimethoprim:

Absorption

A

well absorbed PO

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13
Q

Trimethoprim:

Distribution

A

Lipophilic and penetrates protected environments well

Weak base

Moderate protein binding

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14
Q

Trimethoprim:

Metabolism

A

primarily hepatic metabolism

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15
Q

Trimethoprim:

Elimination

A

Some renal elimination in urine to be effective though

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16
Q

Trimethoprim:

Bacteriostatic

A

when used alone

17
Q

Trimethoprim:

Combination

A

to trimethoprim / sulfonamide is typically bactericidal

18
Q

Trimethoprim:

Spectrum

A

Gram postive and gram negative aerobic

Pseudomonas, Enterococcus and anaerobes considered resistant

Poor activity with cellular debris / pus as folate is present in the envirnoment

19
Q

Ormetoprim / Sulfadimethoxine

A

Ormetoprim is a veterinary specific drug in combination with sulfadimethoxine

In general, similar as TMP/sulfas with an advantage of once daily dosing for some indications

Adverse effects still due to the sulfa component

20
Q

Sulfonamide:

Adverse Effects

Dogs

A
  • Keratoconjuctivitis sicca
  • Delayed hypersensitivity reactions
    • bone marrow suppression: anemia, thrombocytopenia, neutropenia
    • Polyarthritis, fever, glomerulopathy, skin rash
    • hepatic necrosis
    • Death
    • Doberman pinschers appear to be overrepresented
    • Develop an average of 12 days after start of treatment
  • Hypothryroidism:
    • long-term administration, reversible upon discontinuation, but may interfere with endocrine tests
21
Q

Sulfonamides:

Adverse Effects

Any species

A
  • Cystalluria
    • due to water insolubility of acetyl conjugates, less likely in dogs as they do not make the acetylated metabolite
    • Ensure hydration prior to administration
  • GI Flora alterations, diarrhea
  • Folate antagonism
    • methotrexate inhibits mammalian dihydrofolate reductase
    • Injection site reactions (SQ, IM)
      • need to administer IV
22
Q

Clinical Uses:

Trimethoprim / Sulfa

A
  • Respiratory / pneumonia, UTI, Skin, Joints
  • CNS / Meningitis, prostatitis, bronchitis, ocular infections
  • Coccidia, but many DVMs are using ponazuril instead
  • In general, oral TMP / sulfas are well tolerated by horses and one of the few antimicrobials that can be administered PO
  • Use in dogs, many clinicians now think of TMP/Sulfas combinations as a near “last resort” due to availability of other antimicrobials with less severe adverse effects
    • the rate of severe adverse effects in dogs is low, but are regular and devastating when another reasonable antimicrobial choice is available
    • I only recommend it when C&S indicate there are not other reasonable options
23
Q

Pyrimethamine:

A

FDA approved with sulfadiazine to treat EPM in horses dur to Sarcocystis neurona

Rarely used ot treat Toxoplasma, Neospora, Sarcocystis in small animals, lacks sufficient safety / efficacy data in small animals

Compounding errors have resulted in horse deaths

24
Q

Pyrimethamine:

Mechanism

A

inhibition of dihydrofolate reductase, but more specific for protozoa than bacteria

25
Q

Pyrimethamine:

Absorption

A

Well absorded PO

26
Q

Pyrimethamine:

Distribution

A

Distributes well even into protected environments

27
Q

Pyrimethamine:

Metabolism

A

Primarily undergoes hepatic metabolism

28
Q

Pyrimethamine:

Elimination

A

Small amounts eliminated in urine

29
Q

Pyrimethamine:

Adverse Effects

A

anemai in addition to sulfonamide adverse effects

30
Q

“-Phenicols”

A
  • Chloramphenicol, Florfenicol
    • Chloramphenicol prohibited from use in all food animals
  • Typically Bacteriostatic
  • Inhibits 50s ribosome
31
Q

“-Phenicols”

Spectrum

A
  • Good acitivity agianst gram postive, gram negative and anaerobes
    • methicillin resistant Staphylococcus may be susceptible
    • Some activity against Mycoplasma, Rickettsia, Leptospira, and Chlamydia
      • tetracyclines drug of choice
    • Poor overall activity, but sometimes effective against Enterococcus
    • Variable resistance by Gram negative aerobes
    • poor activty agianst Pseudomonas
32
Q

“-Phenicols”

Absorption

A

Chloramphenicol well absorbed PO, florfenicol vairable

33
Q

“-Phenicols”

Distribution

A

the drugs have little to moderate plasma protein binding

Chloramphenicol distributes well to protected tissues, florfenicol not so well

34
Q

“-Phenicols”

Metabolism / Elimination

A

Chloramphenicol primarily eliminated by hepatic metabolism

A smaller, but effective amount of chloramphenicol is eliminated in the urine as active drug

Florfenicol is eliminated by kidneys as intact drug and by metabolism

35
Q

“-Phenicols”

Resistance

A

Enzymatic inactivation of chloramphenicol

Florfenicol may be more resistant to inactivation

36
Q

Chloramphenicol

A
  • Good PO bioavailabilty, bitter tasting
    • injection on longer widely available, primarily oral dosing
  • Used in dogs, cats, horses, but not the first choice due to potential for human adverse effects
  • Most commonly used when a C&S demonstrates resistance to other antimicrobials
  • It is a toss up in my mind as to which to recommend first in dogs, if the only reasonable bacterial susceptibilities are to TMP/sulfa or chloramphenicol
    • client characteristics, cost, compiance, availability
37
Q

Chloramphenicol:

Adverse Effects

A
  • Nausea, vomiting, Anorexia, Diarrhea
  • Produces a dose/duration reversible suppression of bone marrow in cats >>>> dogs that resolves upon discontinuation
    • In humans, there is an idiopathic irreversible bone marrow suppression, fatal without transplant
    • The prevalence of irreversible suppression in humans is 1 / 24,000 - 1 /40,000
    • ALWAYS have clients wear gloves when administering choramphenicol
    • Cautious use if grinding tablets for horses
      • ideally ground in a hood or with respirator
38
Q

Florfenicol

A
  • Injection, SQ/IM
    • respiratory diesease, foot rot
    • 28d withdrawal time lower IM doses
    • 38d for higher SQ single dose
    • Nuflor gold WDT 44d
    • ELDU in diary not prohibited, but no tolerance set,
      • much longer WDT in cull dairy or veal
    • IMM >/= 5 day milk discard
  • ELDU sheep >42 day WDT
  • Water additive (swine)
    • respiratory disease
  • Feed additive
    • various bacterial infections
  • Otic combinations (dogs)
  • Dogs:
    • poor PO bioavailability and short half-life makes it systemic use problematic
    • NOTE:
      • due to molecular differences, the risk of bone marrow suppression by florfenicol is virtually eliminated - hence the reason it is allowed as a food animal drug

General Pharmacology 2 (17 decks)

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