Penicillins (General Info)
Pharmacology - Penicillins are usually bactericidal against susceptible bacteria and act by inhibiting mucopeptide synthesis in the cell wall resulting in a defective barrier and an osmotically unstable spheroplast. The exact mechanism for this effect has not been definitively determined, but beta-lactam antibiotics have been shown to bind to several enzymes (carboxypeptidases, transpeptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that various beta-lactam antibiotics have for these enzymes (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. Like other beta-lactam antibiotics, penicillins are generally considered to be more effective against actively growing bacteria.
The clinically available penicillins encompass several distinct classes of compounds with varying spectrums of activity: The so-called natural penicillins including penicillin G and V; the penicillinase-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, azlocillin and 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 slightly more active in vitro on a weight basis against many organisms. This class of penicillin has in vitro activity against most spirochetes and gram positive and gram negative aerobic cocci, but not penicillinase producing strains. They have activity against some aerobic and anaerobic gram positive bacilli such as Bacillus anthracis, Clostridium sp. (not C. difficile), Fusobacterium and Actinomyces. The natural penicillins are customarily inactive against most gram negative aerobic and anaerobic bacilli, and all Rickettsia, mycobacteria, fungi, Mycoplasma and viruses.
The penicillinase-resistant penicillins have a more narrow spectrum of activity than the natural penicillins. Their antimicrobial efficacy is aimed directly against penicillinase-producing strains of gram positive cocci, particularly Staphylococcal species and these drugs are sometimes called anti-staphylococcal penicillins. There are documented strains of Staphylococcus that are resistant to these drugs (so-called methicillin-resistant Staph), but these strains have not as yet been a major problem in veterinary species. While this class of penicillins do have activity against some other gram 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 increased activity against many strains of gram negative aerobes not covered by either the natural penicillins or 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 against many anaerobic bacteria, including Clostridial organisms. Organisms that are generally not susceptible include Pseudomonas aeruginosa, Serratia, Indole-positive Proteus (Proteus mirabilis is susceptible), Enterobacter, Citrobacter, and Acinetobacter. The aminopenicillins also are inactive against Rickettsia, mycobacteria, fungi, Mycoplasma, and viruses.
The extended-spectrum penicillins, sometimes called anti-pseudomonal penicillins, include both alpha-carboxypenicillins (carbenicillin and ticarcillin) and acylaminopenicillins (piperacillin, azlocillin, and mezlocillin). These agents have similar spectrums of activity as the aminopenicillins but 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 and sulbactam have been developed to inactivate these enzymes and thus extend the spectrum of those penicillins. When used with a penicillin, these combinations are often effective against many beta-lactamase-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/Indications and Dosage sections for each individual drug.
Pharmacokinetics (General) - The oral absorption characteristics of the penicillins are dependent upon its class. Penicillin G is the only available oral penicillin that is substantially affected by gastric pH and can be completely inactivated at pH’s of less than 2. The other orally available penicillins are resistant to acid degradation but bioavailability can be decreased by the presence of food (not amoxicillin). Of the orally administered penicillins, penicillin V and amoxicillin tend to have the greatest bioavailability in their respective classes.
Penicillins are generally distributed widely throughout the body. Most drugs attain therapeutic levels in the kidneys, liver, heart, skin, lungs, intestines, bile, bone, prostate, and peritoneal, pleural and synovial fluids. Penetration into the CSF and eye only occur with inflammation and may not reach therapeutic levels. Penicillins are bound in varying degrees to plasma proteins and they cross the placenta.
Most penicillins are rapidly excreted largely unchanged by the kidneys into the urine via glomerular filtration and tubular secretion. Probenecid can prolong half-lives and increase serum levels by blocking the tubular secretion of penicillins. Eexcept for nafcillin and oxacillin, hepatic inactivation 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, use penicillins 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 grave illnesses 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 not been firmly established, but neither have there been any documented teratogenic problems associated 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 to procaine penicillin G.
High doses of penicillin G sodium or potassium, particularly in small animals with a preexisting electrolyte abnormality, renal disease or congestive heart failure may cause electrolyte imbalances. Other injectable penicillins, such as ticarcillin, carbenicillin and ampicillin, have significant quantities of sodium per gram and may cause electrolyte imbalances when used in large dosages in susceptible patients.
Adverse Effects/Warnings - Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence.
Hypersensitivity reactions unrelated to dose can occur with these agents and can be manifested as rashes, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymphadenopathy, or full blown anaphylaxis. In humans, it is estimated that up to 15% of patients hypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of cross-reactivity in veterinary patients is unknown.
When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may also alter gut flora, antibiotic-associated diarrhea can occur, as well as selecting out resistant 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 been reported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia.
Some penicillins (ticarcillin, carbenicillin, azlocillin, mezlocillin, piperacillin and nafcillin) have been implicated in causing bleeding problems in humans. These drugs are infrequently used systemically in veterinary species at the present time and the veterinary ramifications of this effect is unclear.
Overdosage/Acute Toxicity - Acute oral penicillin overdoses are unlikely to cause significant problems 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 or additive activity against certain bacteria when used with aminoglycosides or cephalosporins.
Use of bacteriostatic antibiotics (e.g., chloramphenicol, erythromycin, tetracyclines) with penicillins is generally not recommended, particularly in acute infections where the organism is proliferating rapidly as penicillins tend to perform better on actively growing bacteria. In low concentrations, certain penicillins (e.g., ampicillin, oxacillin or nafcillin) may have additive or synergistic 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 increasing serum levels and serum half-lives. High dosages of certain penicillins (e.g., ticarcillin, carbenicillin) have been associated with bleeding; 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 high dosages (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 in patients in renal failure), serum concentrations of aminoglycosides may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recommended that if the assay is delayed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough.
Monitoring Parameters - Because penicillins usually have minimal toxicity associated with their use, 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 and discarded after 14 days.
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