Antimicrobial Therapy: Potentiated Sulfas and "-phenicols" Flashcards
Folate - background
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
Sulfonamides:
Absorption
Most are well absorbed PO
Sulfonamides:
Distribution
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
Sulfonamides:
Metabolism
Hepatic metabolism primary by acetylation – except dogs who may form reactive metabolites causing immune-like reactions
Sulfonamides:
Elimination
Some renal elimination produces effective concentrations for UTIs
Sulfonamides:
- 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
Sulfonamides:
Spectrum
- 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
Sulfonamides:
Resistance
- 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
Sulfonamides:
Sulfadiazine
- PO
- May have most renal elimination, but others still effective for UTI
- Approved for horses with trimothoprim
- ~$5/dose at cost for horses
Sulfonamides:
Sulfadimethoxine
- 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
Sulfonamides:
Sulfamethoxazole
- PO
- Human approved with trimethoprim, more commonly used because less expensive
- Horses:
- ~$0.90/dose
Trimethoprim:
Absorption
well absorbed PO
Trimethoprim:
Distribution
Lipophilic and penetrates protected environments well
Weak base
Moderate protein binding
Trimethoprim:
Metabolism
primarily hepatic metabolism
Trimethoprim:
Elimination
Some renal elimination in urine to be effective though
Trimethoprim:
Bacteriostatic
when used alone
Trimethoprim:
Combination
to trimethoprim / sulfonamide is typically bactericidal
Trimethoprim:
Spectrum
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
Ormetoprim / Sulfadimethoxine
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
Sulfonamide:
Adverse Effects
Dogs
- 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
Sulfonamides:
Adverse Effects
Any species
- 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
Clinical Uses:
Trimethoprim / Sulfa
- 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
Pyrimethamine:
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
Pyrimethamine:
Mechanism
inhibition of dihydrofolate reductase, but more specific for protozoa than bacteria
Pyrimethamine:
Absorption
Well absorded PO
Pyrimethamine:
Distribution
Distributes well even into protected environments
Pyrimethamine:
Metabolism
Primarily undergoes hepatic metabolism
Pyrimethamine:
Elimination
Small amounts eliminated in urine
Pyrimethamine:
Adverse Effects
anemai in addition to sulfonamide adverse effects
“-Phenicols”
- Chloramphenicol, Florfenicol
- Chloramphenicol prohibited from use in all food animals
- Typically Bacteriostatic
- Inhibits 50s ribosome
“-Phenicols”
Spectrum
- 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
“-Phenicols”
Absorption
Chloramphenicol well absorbed PO, florfenicol vairable
“-Phenicols”
Distribution
the drugs have little to moderate plasma protein binding
Chloramphenicol distributes well to protected tissues, florfenicol not so well
“-Phenicols”
Metabolism / Elimination
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
“-Phenicols”
Resistance
Enzymatic inactivation of chloramphenicol
Florfenicol may be more resistant to inactivation
Chloramphenicol
- 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
Chloramphenicol:
Adverse Effects
- 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
Florfenicol
- 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
