Doses - PENICILLAMINE

Dogs:

For copper-associated hepatopathy:
a) 10 - 15 mg/kg PO bid on an empty stomach. Only effective for long-term use, not foracute copper toxicity. (Twedt and Whitney 1989)]
b) For Bedlington Terriers: Initially at 125 mg q12h PO. If anorexia and vomiting aresignificant problems, start dose at 125 mg daily and increase to 125 mg bid over severaldays. (Hardy 1989)
c) 125 - 250 mg PO 30 minutes prior to feeding. If vomiting occurs, divide daily dosageinto bid-tid. (Cornelius and Bjorling 1988)
For cystine urolithiasis:
a) 15 mg/kg PO twice daily. If nausea and vomiting occur, mix with food or give atmealtime. Some dogs may need to have the dosage slowly increased to full dose inorder to tolerate the drug. (Osborne, Hoppe, and O'Brien 1989)
b) 15 mg/kg PO bid with food (Lage, Polzin, and Zenoble 1988)
For lead poisoning:
a) After initial therapy regimen with CaEDTA and if continued therapy is desired at home, may give penicillamine at 110 mg/kg/day PO divided q6-8h for 1-2 weeks. If vomiting, depression, and anorexia occur, may reduce dose to 33 - 55 mg/kg/day divided q6-8hwhich should be better tolerated. (Mount 1989)
b) As an alternate or adjunct to CaEDTA: 30 - 110 mg/kg/day divided qid for 7 days; mayrepeat after 7 days off therapy. If vomiting occurs, may give dimenhydrinate at 2 - 4mg/kg PO 1/2 hour before penicillamine dose. (Grauer and Hjelle 1988b)

Cats:

For lead poisoning:
a) After initial therapy with CaEDTA and if blood lead is greater than 0.2 ppm at 3-4weeks post-treatment, may repeat CaEDTA or give penicillamine at 125 mg q12h POfor 5 days. (Reid and Oehme 1989)
Monitoring Parameters - Monitoring of penicillamine therapy is dependent upon the reason forits use; refer to the references in the Dose section above for further discussion on the diseases andassociated monitoring of therapy.
Client Information - This drug should preferably be given on an empty stomach, at least 30minutes before feeding. If the animal develops problems with vomiting or anorexia, three remedieshave been suggested. 1) Give same total daily dose, but divide into smaller individual doses and givemore frequently. 2) Temporarily reduce the daily dose and gradually increase to recommendeddosage. 3) Give with meals (will probably reduce amount of drug absorbed).
Dosage Forms/Preparations/FDA Approval Status/Withholding Times - Veterinary-Approved Products: None

Human-Approved Products:

Penicillamine Oral Titratable Tablets 250 mg (scored); Depen® (Wallace); (Rx)Penicillamine Oral Capsules 125 mg, 250 mg; Cuprimine® (Merck) (Rx)
PENICILLINS (GENERAL INFORMATION)

Pharmacology

Penicillins are usually bactericidal against susceptible bacteria and act by inhibiting mucopeptide synthesis in the cel wall resulting in a defective barrier and an osmoticallyunstable spheroplast. The exact mechanism for this effect has not been definitively determined, butbeta-lactam antibiotics have been shown to bind to several enzymes (carboxypeptidases, transpeptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved withcell wall synthesis. The different affinities that various beta-lactam antibiotics have for theseenzymes (also known as penicillin-binding proteins; PBPs) help explain the differences in spectrums of activity the drugs have that are not explained by the influence of beta-lactamases. Likeother beta-lactam antibiotics, penicillins are generally considered to be more effective againstactively growing bacteria.
The clinically available penicillins encompass several distinct classes of compounds with varyingspectrums of activity: The so-called natural penicillins including penicillin G and V; thepenicillinase-resistant penicillins including cloxacillin, dicloxacillin, oxacillin, nafcillin and methicillin; the aminopenicillins including ampicillin, amoxicillin, cyclacillin, hetacillin and bacampicillin; extended-spectrum penicillins including carbenicillin, ticarcillin, piperacillin, azlocillinand mezlocillin; and the potentiated penicillins including amoxicillin-potassium clavulanate, ampicillin-sulbactam, and ticarcillin-potassium clavulanate.
The natural penicillins (G and K) have similar spectrums of activity, but penicillin G is slightlymore active in vitro on a weight basis against many organisms. This class of penicillin has in vitroactivity against most spirochetes and gram positive and gram negative aerobic cocci, but notpenicillinase producing strains. They have activity against some aerobic and anaerobic gram positivebacilli such as Bacillus anthracis, Clostridium sp. (not C. difficile), Fusobacterium and Actinomyces. The natural penicillins are customarily inactive against most gram negative aerobicand anaerobic bacilli, and all Rickettsia, mycobacteria, fungi, Mycoplasma and viruses.
The penicillinase-resistant penicillins have a more narrow spectrum of activity than the naturalpenicillins. Their antimicrobial efficacy is aimed directly against penicillinase-producing strains ofgram positive cocci, particularly Staphylococcal species and these drugs are sometimes called antistaphylococcal penicillins. There are documented strains of Staphylococcus that are resistant tothese drugs (so-called methicillin-resistant Staph), but these strains have not as yet been a majorproblem in veterinary species. While this class of penicillins do have activity against some othergram positive and gram negative aerobes and anaerobes, other antibiotics (penicillins and otherwise)are usually better choices. The penicillinase-resistant penicillins are inactive against Rickettsia, mycobacteria, fungi, Mycoplasma, and viruses.
The aminopenicillins, also called the "broad-spectrum" or ampicillin penicillins, have increasedactivity against many strains of gram negative aerobes not covered by either the natural penicillinsor penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus.
Like the natural penicillins, they are susceptible to inactivation by beta-lactamase-producing bacteria(e.g Staph aureus). Although not as active as the natural penicillins, they do have activity againstmany anaerobic bacteria, including Clostridial organisms. Organisms that are generally notsusceptible include Pseudomonas aeruginosa, Serratia, Indole-positive Proteus (Proteus mirabilisis susceptible), Enterobacter, Citrobacter, and Acinetobacter. The aminopenicillins also are inactiveagainst Rickettsia, mycobacteria, fungi, Mycoplasma, and viruses.
The extended-spectrum penicillins, sometimes called anti-pseudomonal penicillins, include bothalpha-carboxypenicillins (carbenicillin and ticarcillin) and acylaminopenicillins (piperacillin, azlocillin, and mezlocillin). These agents have similar spectrums of activity as the aminopenicillinsbut with additional activity against several gram negative organisms of the family
Enterobacteriaceae, including many strains of Pseudomonas aeruginosa. Like the aminopenicillins, these agents are susceptible to inactivation by beta-lactamases.
In order to reduce the inactivation of penicillins by beta-lactamases, potassium clavulanate andsulbactam have been developed to inactivate these enzymes and thus extend the spectrum of thosepenicillins. When used with a penicillin, these combinations are often effective against many betalactamase-producing strains of otherwise resistant E. coli, Pasturella spp, Staphylococcus spp,
Klebsiella, and Proteus. Type I beta-lactamases that are often associated with E. coli, Enterobacter, and Pseudomonas are not generally inhibited by clavulanic acid.

Uses, Indications

Penicillins have been used for a wide range of infections in various species.
FDA-approved indications/species, as well as non-approved uses, are listed in the Uses, Indicationsand Dosage sections for each individual drug.
Pharmacokinetics (General) - The oral absorption characteristics of the penicillins are dependentupon its class. Penicillin G is the only available oral penicillin that is substantially affected bygastric pH and can be completely inactivated at pH's of less than 2. The other orally availablepenicillins are resistant to acid degradation but bioavailability can be decreased by the presence offood (not amoxicillin). Of the orally administered penicillins, penicillin V and amoxicillin tend tohave the greatest bioavailability in their respective classes.
Penicillins are generally distributed widely throughout the body. Most drugs attain therapeuticlevels in the kidneys, liver, heart, skin, lungs, intestines, bile, bone, prostate, and peritoneal, pleuraland synovial fluids. Penetration into the CSF and eye only occur with inflammation and may notreach therapeutic levels. Penicillins are bound in varying degrees to plasma proteins and they crossthe placenta.
Most penicillins are rapidly excreted largely unchanged by the kidneys into the urine viaglomerular filtration and tubular secretion. Probenecid can prolong half-lives and increase serumlevels by blocking the tubular secretion of penicillins. Eexcept for nafcillin and oxacillin, hepaticinactivation and biliary secretion is a minor route of excretion.

Contraindications, Precautions, Reproductive Safety

Penicillins are contraindicated in patients who have a history of hypersensitivity to them. Because there may be cross-reactivity, usepenicillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics(e.g., cephalosporins, cefamycins, carbapenems).
Do not administer systemic antibiotics orally in patients with septicemia, shock, or other graveillnesses as absorption of the medication from the GI tract may be significantly delayed or diminished. Parenteral (preferably IV) routes should be used for these cases.
Penicillins have been shown to cross the placenta and safe use of them during pregnancy has notbeen firmly established, but neither have there been any documented teratogenic problemsassociated with these drugs. However, use only when the potential benefits outweigh the risks.
Certain species (snakes, birds, turtles, Guinea pigs, and chinchillas) are reportedly sensitive toprocaine penicillin G.
High doses of penicillin G sodium or potassium, particularly in small animals with a preexistingelectrolyte abnormality, renal disease or congestive heart failure may cause electrolyte imbalances.
Other injectable penicillins, such as ticarcillin, carbenicillin and ampicillin, have significant quantitiesof sodium per gram and may cause electrolyte imbalances when used in large dosages insusceptible patients.

Adverse Effects, Warnings

Adverse effects with the penicillins are usually not serious and havea relatively low frequency of occurrence.
Hypersensitivity reactions unrelated to dose can occur with these agents and can be manifested asrashes, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymphadenopathy, or full blown anaphylaxis. In humans, it is estimated that up to 15% of patientshypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of crossreactivity in veterinary patients is unknown.
When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because thepenicillins may also alter gut flora, antibiotic-associated diarrhea can occur, as well as selecting outresistant bacteria maintaining residence in the colon of the animal (superinfections).
High doses or very prolonged use has been associated with neurotoxicity (e.g., ataxia in dogs).
Although the penicillins are not considered to be hepatotoxic, elevated liver enzymes have beenreported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia.
Some penicillins (ticarcillin, carbenicillin, azlocillin, mezlocillin, piperacillin and nafcillin) havebeen implicated in causing bleeding problems in humans. These drugs are infrequently usedsystemically in veterinary species at the present time and the veterinary ramifications of this effect isunclear.
Overdosage, Acute Toxicity - Acute oral penicillin overdoses are unlikely to cause significantproblems other than GI distress, but other effects are possible (see Adverse effects). In humans, very high dosages of parenteral penicillins, especially in patients with renal disease, have induced
CNS effects.

Drug Interactions

In vitro studies have demonstrated that penicillins can have synergistic oradditive activity against certain bacteria when used with aminoglycosides or cephalosporins.
Use of bacteriostatic antibiotics (e.g., chloramphenicol, erythromycin, tetracyclines) withpenicillins is generally not recommended, particularly in acute infections where the organism isproliferating rapidly as penicillins tend to perform better on actively growing bacteria. In lowconcentrations, certain penicillins (e.g., ampicillin, oxacillin or nafcillin) may have additive orsynergistic effects against certain bacteria when used with rifampin, but there is apparent antagonism when the penicillin is present in high concentrations.
Probenecid competitively blocks the tubular secretion of most penicillins, thereby increasingserum levels and serum half-lives.
High dosages of certain penicillins (e.g., ticarcillin, carbenicillin) have been associated withbleeding; they should be used cautiously in patients receiving oral anticoagulants or heparin.
Drug/Laboratory Interactions - Ampicillin may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). Tests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by ampicillin.
When using the Jaffe reaction to measure serum or urine creatinine, cephalosporins in highdosages (not ceftazidime or cefotaxime), may falsely cause elevated values.
In humans, clavulanic acid and high dosages of piperacillin have caused a false-positive direct
Combs' test.
As penicillins and other beta-lactams can inactivate aminoglycosides in vitro (and in vivo inpatients in renal failure), serum concentrations of aminoglycosides may be falsely decreased if thepatient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It isrecommended that if the assay is delayed, samples be frozen and, if possible, drawn at times whenthe beta-lactam antibiotic is at a trough.
Monitoring Parameters - Because penicillins usually have minimal toxicity associated with theiruse, monitoring for efficacy is usually all that is required unless toxic signs or symptoms develop.
Serum levels and therapeutic drug monitoring are not routinely done with these agents.
Client Information - Owners should be instructed to give oral penicillins on an empty stomach, unless using amoxicillin or if GI effects (anorexia, vomiting) occur. Compliance with the therapeutic regimen should be stressed. Reconstituted oral suspensions should be kept refrigerated anddiscarded after 14 days.