Volume 47 | Issue 1 Article 7

1985 A Basic Overview of and Their seU in Small Animal Medicine Janel Ames Iowa State University

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Recommended Citation Ames, Janel (1985) "A Basic Overview of Penicillins and Their sU e in Small Animal Medicine," Iowa State University Veterinarian: Vol. 47 : Iss. 1 , Article 7. Available at: https://lib.dr.iastate.edu/iowastate_veterinarian/vol47/iss1/7

This Article is brought to you for free and open access by the Journals at Iowa State University Digital Repository. It has been accepted for inclusion in Iowa State University Veterinarian by an authorized editor of Iowa State University Digital Repository. For more information, please contact [email protected]. A Basic Overview of Penicillins and Their Use in Small Animal Medicine

by Janel Ames*

There are many factors to consider when Penicillinase-resistant penicillins deciding upon antimicrobial therapy. Some of Penicillinase-resistant penicillins (e. g. them are suspected etiology, host status, organ , naficillin, cloxicillin, dicloxicillin, system affected, and the properties of the drug and ) were developed by adding sub­ being considered. Iv1icrobicidal drugs, such as stituents onto the aromatic ring of to penicillin, are superior to bacteriostatic drugs sterically inhibit beta-Iactamases.2 Methicillin in immunosuppressed patients, severe and/or was the first semisynthetic penicillin devel­ overwhelming infections where rapid action is oped but is poorly absorbed orally due to gas­ required, and for long-standing infections to tric acid instability, and is not very potent. All eliminate the pathogen, preventing carrier of the later developed drugs in this group are states or relapses. 1 well absorbed orally except for naficllin. All of Due to the thick of and these are effective against Gram-positive beta­ their capability of concentrating solutes, bac­ lactamase producing bacteria. 4 teria have a high intracellular osmolality. is a recently developed penicil­ Penicillin causes cell wall defects by inactivat­ linase-resistant penicillin which is active ing bacterial transpeptidase, which prevents against almost all Gram-negative bacteria ex­ the maintenance of an osmolar gradient, cept Pseudomonas. Because of this, it is effective causing formation of spheroblasts, cell lysis, in treating coliform infections, especially en­ and death. 1 teritis and mastitis. It is poorly absorbed Many penicillins have been developed. orally, but when administered parenterally it They can be divided into; natural penicillins, has an unusually long half-life in humans.s semi-synthetic penicillins such as penicil­ linase-resistant penicillins, broad spectrum Broad-spectrum penicillins (amino-) penicillins, and antipseudomonas The broad spectrum penicillins (e. g. ampi­ and extended spectrum penicillins (See table cillin, , and ) are a very one). important group of drugs due to their activity against both Gram-positive and some Gram­ Natural penicillins negative organisms. They are, however, sus­ Natural penicillins (e. g. penicillin G, peni­ ceptible to penicillinase. This group is stable cillin V, and phenethicillin) were some of the in gastric acid, and therefore effective orally. original penicillins produced. They have a Amoxicillin and have equal activ­ limited range of activity and are highly sus­ ity, but an10xicillin is absorbed better orally ceptible to beta-lactamases which are pro­ and has more rapid action. 2 Hetacillin is inac­ duced by many staphylococci and Gram­ tive as it exists in a preparation, but is n10re negative bacteria. They are also inactivated stable in gastric acid then amoxicillin and am­ by gastric acid. These are efficacious only 2 picillin' and therefore it is absorbed best. Af­ against Gram-positive bacteria. ,3 ter it enters the circulation, it is metabolized * Ms. Ames is a second-year student in the College of to ampicillin and becomes active. Amoxicillin Veterinary Medicine at Iowa State University. We would like to acknowledge Dr. R. A. Packer for his editorial and ampicillin are two of the most widely used assistance. penicillins because of their wide range of ac-

vol. 47) No. 1 33 4 TABLE ONE: Properties of penicillin derivatives (taken from Greene ). Route of Gastric Beta- Generic Trade Adminis- Acid Lactamase Antimicrobial Name Name tration Stability Resistance Spectrum NATURAL PENICILLINS Penicillin G Many PO, 1M, Poor to fair (20%), No Narrow (gram-positive IV food decreases organisms) Penicillin V Many PO Good (60%) No Narrow (gram-positive organisms) Phenethicillin Many PO Good No Narrow (gram-positive organisms) BETA-LACTAMASE- RESISTANT PENICILLINS Methicillin Staphcillin, Celbenin 1M, IV Poor Yes Narrow (gram-positive beta-lactamase- producing organisms) ISOXAZOLYL PENICILLINSt Unipen, Nafcil 1M, IV Variable (not Yes Narrow (gram-positive, recommended for beta-lactamase- oral use) producing organisms) Tegopen PO Good Yes Narrow (gram-positive, beta-lactamase - producing organisms) Veracillin, Pathocil, PO Good (50%), food Yes Narrow (gram-positive Dynapen decreases (30 %) beta-lactamase- producing organisms) Oxacillin Prostaphlin, Bactocil PO, 1M, Good Yes Narrow (gram-positive, IV beta-lactamase- producing organisms) AMINOPENICILLINStt Ampicillin Many PO, 1M, Good (40%), food No Extended (gram-positive IV decreases cocci, some gram- negative organisms) Amoxicillin Omnipen PO, 1M Excellent (75 %) No Extended (gram-positive cocci, some gram- negative organisms) Hetacillin Hetacin PO Good (40%) No Extended (gram-positive cocci, some gram- negative organisms) ANTIPSEUDOMONAS PENIC1LLINS§ Pyopen, Geopen 1M, IV Poor No Greater against gram- negative organisms, Pseudomonas, anaerobes Ticar 1M, IV Poor No Less active than penicillin G on gram-positive organisms EXTENDED-SPECTRUM PENICILLINS Mezlin 1M, IV Poor No Greater against gram- negative organisms Pipracil 1M, IV Poor No Greater against gram- negative organisms PO =oral; 1M =intravenous; IV =intravenous t Also includes flu cloxacillin and floxacillin. ttAlso includes , cyclacillin, , , and . §Also includes , indamylcarbenicillin, , and carfecillin.

34 Iowa State University Veterinarian tivity and their ability to produce good plasma skin lesions and pyodermas. The use for soft concentrations, although at similar dosages tissue, urinary, and respiratory infections in they are less effective than crystalline penicil­ humans indicates that the use in small ani­ 1S lin G. Other derivatives in this group are mals may spread in time. S bacampicillin, cyclacillin, epicillin, pivampi­ is also an excellent example of cillin, and talampicillin. 4 this class of drugs because it is an irreversible Antipseudomonas and Extended-spectrum beta-Iactamase inhibitor, yet provides no use­ penicillins ful activity. Its main difference Antipseudomonas penicillins (e.g. carbeni­ when compared to is the two cillin and ticarcillin) are more active against to five-fold decrease in potency. S Pseudomonas and some anaerobes. They are in­ Methicillin and cloxacillin can also provide activated by beta-Iactamases and gastric acid. protection for beta-lactam rings. They com­ Their activity is increased when aminoglyco­ pete for the penicillinase allowing a second "protected" antibiotic (e. g. penicillin G or am­ side are also given. 4. 7 Penicillanic acid sulfone (sulbactam), 6-ha­ picillin) to exert its antibacterial effect vir­ lopenicillanic acids, 6-acetyl methylene peni­ tually unhindered. 6 There are four n1ain cri­ cillanic acid, and naturally occurring clavu­ teria that are met by these two drugs. They lanic acid, olivanic acids, and are as follows: 1) Their action is primarily due are beta-Iactamase inhibitors that can Dotenti­ to beta-Iactamase inhibition, 2) The "protec­ ate the penicillin antibiotics. Clavula~ic acid tor" drug has a much greater affinity for the is an ideal exampIe of this group. It is a po­ penicillinase than the "protected" drug, 3) tent, irrreversible inhibitor of beta-Iactamase There is little or no hydrolysis of the "protec­ of staphylococci and many Gram-negative tor" drug by the penicillinase, 4) The "protec­ bacteria. It closely matches its antibiotic tor" drug shows no antibacterial activity at the partners, especially amoxicillin, (see figure 1) effective protection concentration. and has little antibacterial activity of its own Staphylococcal penicillinase has a low affin­ that might interfere with the action of the in­ ity for methicillin. Therefore, it is not effective tended primary antibiotic. The minimum in­ in protection of other penicillins from this 6 hibitory concentration required for amoxicil­ penicillinase. lin is markedly reduced when used with Since most penicillins are excreted in the cloxacillin against beta-lactamase producing urine, the blocking analog can be isolates. Clavulanic acid's wide range of effec­ given simultaneously to increase penicillin tiveness makes it a useful potentiator of many serum levels. This offers yet another alterna­ penicillins. This combination is effective in tive method to increase the efficacy of the the treatment of dog and cat staphylococcal penicillins. Although many types of combination therapy may sound promising, and often are very effective, great care must be taken to en­ sure that the substances used together will be

Benzylpenlcilhn ••~~~~~~~?ll'll.a.- _ advantageous. For example, penicillins

Nafcllhn should never be mixed with blood serum or other proteinaceous fluids or with'other a~ti­ Oxacllhn CloxaCillin biotics before they are administered. Penicil­ Temocllhn lins are antagonistic in vivo with ~::~~~7,hn I •••__•••••~~m..-__ and chloramphenicol. Penicillins are some­

Clavulanate what unpredictable when combined in potentiated amoxycillin therapy with , novobiocin, and TlCarcllhn lincomycin. No antagonism is seen with sul­ Clavulanate potentiated fonamides. There is possible synergism when ticarcillin penicillins are used with aminoglycosides, 4 Figure 1. Effect of clavulanate potentiation , and . Deleterious on the antibacterial spectrum of amoxicillin and drug interactions may have their effect by al­ ticarcillin. Taken from: Wishart, David F.: Re­ tering the body's metabolism, , dis­ cent Advances in Antimicrobial Drugs: The tribution, or protein binding of one or both Penicillins.JAVMA 185:1107, 1984. drugs. 4

VOL. 47, No. 1 35 Clinical usage of penicillins cause of high urine concentrations of the drug In the interest of providing a practical out­ due to renal excretion. Because of the short look on the clinical use of penicillins, several half-life of the drug and the renal excretion it organ systems and some common problems is important to only allow the patient to uri­ and solutions will be discussed next. Although nate immediately prior to the next treatment. it is far from a complete guide, it provides a Recurrent infections can be avoided by insti­ basic introduction to the use of the penicillins. tuting a long-tern~ low-dose therapy. 10.16 The foremost problem in treating upper When dealing with canine skin infections respiratory diseases is the large number of Staphyloccus intermedius is the pathogen most commensal bacteria present. Because of this it commonly found. Because of the penicillinase may be very difficult to decide if there is a production by the majority of isolates, beta­ bacterial infection that needs to be treated. lactamase-resistant penicillins are usually the Next, one must decide which is' the causative first choice for tre~tment if a penicillin is to be agent, or agents. Pathogenic upper respira­ used. Drugs from other classes of antibiotics tory infectors include staphylococci, bordetel­ such as erythromycin and lincomycin, are of­ lae, and mycoplasmas. Penicillin is often a ten more effective. Oxacillin has been good choice for therapy here because of its described as an excellent drug for the treat­ penetration of the nasal mucous membranes. ment of canine pyodermas. If penicillins are Ampicillin can be effectively used to prevent used, drainage of abcesses, removal of foreign secondary infections in cases where the prob­ bodies, and debridement of damaged tissues lem may be neoplasia, fungal infections, or must be done to promote bacterial growth, trauma to the mucosa. 8 without which these drugs are quite ineffec­ In the treatment of lower respiratory tract tive. 11 Anaerobic infections can be treated infections, in addition to the usual factors one with ampicillin or carbenicillin. 16 must use in choosing an antibiotic, such as Feline abcesses normally respond well to in­ susceptibility of the organisms, one must also jected procaine penicillin G and benzathine consider the permeability of the alveolar penicillin. If oral therapy is desired, ampicil­ membranes, and the normal tracheobronchial lin and amoxicillin are good choices. 11 flora such as streptococci, staphylococci, Pas­ A special problem is encountered in cases of turella multocida) and Klebsiella . Dis­ gastroenteritis, because of the high concentra­ ease states are commonly caused by Klebsiella) tion of the natural microbial flora present. Achromobacter; Pseudomonas) and E. coli. Larger, Overabundance of one of several species of highly lipid-soluble antibiotics that contain a bacteria is not necessarily indicative of its benzene ring generally penetrate bronchial se­ etiolgical importance. Some bacteria that are cretions more easily. When also considering often seen as specific infectors where anti­ cost and toxicity, ampicillin and amoxicillin biotic therapy is indicated are Yersinia enteroco­ can be considered as a first choice therapy for litica) Campylobacter jejuni) and Salmonella spp. 12 most lower respiratory tract infections. 9 Since these are better treated by non-penicil­ Complete urinalysis from urine collected by lin antibiotics, the issue will not be persued cystocentesis is a quick and reliable way to further here, but it should be emphasized that diagnose urinary tract infection. Tentative any systemic antimicrobial can alter the GI identification of the etiologic agent can come flora and removal of beneficial bacteria can quickly after inoculating blood agar and Mac­ give pathogens an easy route to infection. Any Conkey agar. Primary pathogenic bacteria antimicrobial used, especailly for gastrointes­ seen are Proteus mirabilis) spp., tinal disease, must be selective. alpha-hemolytic streptococci, Pseudomonas Carbenicillin and ticarcillin are used, al­ spp., E coli) Klebsiella spp., and Enterobacter though infrequently, in ophthalmic disease. spp. Susceptibility tests for all species of bac­ These act with gentamycin against Pseudo­ teria present must be done initially, and fre­ monas. Ampicillin, amoxicillin, and hetacillin quently after therapy has begun, due to the are sometimes used for intraocular infections rapid transfer of resistance within bacterial because of their effectiveness against many populations. Penicillins such as ampicillin are different bacteria and their ability to cross the very effective in cases where susceptibility is blood-ocular barrier. Generally the aminogly­ found (especially versus Proteus mirabilis) cosides have been found to be much more ef­ staphylococci, and streptococci). This -is be- fective for treatment.4,16

36 Iowa State University Veterinarian Penicillin and ampicillin are the preferred tient is severely debilitated not only will the antibiotics in neonatal patients. A primary body's reaction against the microorganism be reason is the abiltiy to sustain low doses for lessened, but the reaction to the drug Inay long periods of time with low probability of also be altered. Reduced absorption, distribu­ excretion and toxicity problems. 16 tion, delivery, metabolism, and excretion may Penicillin and naficillin are possible choices lead to failure of therapy to improve the pa­ in complex orthopedic cases. Pyoarthritis is tient's condition, or worse, debilitating the pa­ commonly caused by species of Staphylococcus) tient even more. Therefore this must be se­ Streptococcus) and Mycoplasma. Due to the in­ riously considered. This also means that flammation all antibiotics readily pass into the supportive therapy must be considered, such capsular fluid. 16 Sensitivity testing will indi­ as fluid replacement and correction of electro­ cate the best choice of therapy. lyte and acid-base balances. In addition this Antimicrobials have become drugs not only includes cleaning of the wound to relieve ob­ of use, but also of abuse. Many clients, and struction, removal of as much as possible of some clinicians, have taken the "give 'em a the invading disease-causing agent, and re­ 4 14 dose of penicillin and call me in the morning" moval of debris. • This will help to restore attitude. Although the disease may appear to normal function and aid in the healing proc­ indicate penicillin therapy, other factors often ess. make the therapy ineffective. One must be A factor that is neglected in a surprising aV/are of many variables concerning the host, nun1ber of cases is the etiologic agent. First the etiologic agent, and the drug. (See figure one must establish that there definitely is a 2). n1icrobiological cause to the disease. Clinical The primary concern when considering the signs are not enough. For example, inflam­ host is the immunological status. Most mation and a febrile state alone are not justifi­ therapy is designed to enhance, not replace, cation for antimicrobial therapy. One must the host's defense mechanisms. When the pa- also consider the possibility of multiple agents

Figure 2: Factors involved in failure of antimicrobial therapy. Adapted from; Greene, Clinical Microbiology and Infectious Diseases of the Dog and Cat, and Roberts, Therapeutic Failures with Antimicrobial Drug Treatment. Host - immunosupression Microorganism - resistance - underlying disease - susceptibility - poor physical condition -virulence - foreign bodies Clinician - presumptive diagnosis - experience, 'best guess' Antimicrobial therapy - poor bio-availability - incorrect dosage - drug interactions - short-term therapy Compliance - non-compliance to therapy by client - management variables Response - foreign bodies - with poor drainage - accelerated elimination -lack of supportive care

Vol. 47) No. 1 37 4 or underlying disease. ,14 Although posItIve REFERENCES identification and susceptibility testing is not 1. Smith, Hillas: Antibiotics in Clinical Practice. 3rd ed. always required, or sometimes even possible, Pitman Medical Publishing Co. Ltd. Kent, England. 1977. it cannot be emphasized enough that this is 2. Huber H. G.: Penicillins. Chapter 49. In Booth, Ni­ the best way to decide upon treatment. One cholas H. and McDonald, Leslie, E. (eds) veterinary must not substitute convenience for accuracy. Pharmacology and Therapeutics. 5th ed. Iowa State Uni­ versity Press, Ames, la. 1982. It has the potential, in the long run, for saving 3. Ball, A. P., GrayJ. A., and Murdoch J. : Antibacterial time and money on unneeded and unhelpful Drugs 1Oday. University Park Press, Baltimore, Md. 1978. therapy, and possibly saving the patient's life. 4. Greene, Craig E: Antimicrobial Chemotherapy. Unfortunately a complete work-up is not al­ Chapter 9. In Greene, Craig E. Clinical Microbiology ways possible. In these cases knowledge and and Infectious Diseases of the Dog and Cat. W. B. Saun­ ders Company, Philadelphia, Pa. 1984. experience must be trusted, and close obser­ 5. Wishart, David F.: Recent Advances in Antimicro­ vation is necessary. bial Drugs: The Penicillins.jAVMA 185:1106-1108. Although superficially it may seem simple 1984. 6. Klatersky, John: Clinical Use of Combination Antibiotics. to decide upon a drug for therapy, it is not. John Wiley and Sons, New York. 1975. Unfortunately just finding a drug that can su­ 7. Stowe, C. M.: Antimicrobial Drug Interaction. jAVMA 185:1137-1141. 1984. press growth of the organism is not enough. 8. Harvey, Colin E.: Therapeutic Strategies Involving Many questions must be asked. For example: Antimicrobial Treatment in the Upper Respiratory What is the bio-availability of the drug? Is it Tract.jAVMA 185:1159-1161. 1984. 9. McKiernan, Brendan C.: Therapeutic Strategies In­ compatible with other drugs being used? volving Antimicrobial Treatment of the Lower Res­ Should short-term or long-term therapy be piratory Tract in Small Animals. jAVMA 185: 1055­ administered? What dosage is appropriate? 1058. 1984. 10. Ling, Gerald V.: Therapeutic Strategies Involving Only when these questions are answered can Antimicrobial Treatment of the Canine Urinary an appropriate drug therapy be decided upon. Tract. jAVMA 185: 1162-1164. 1984. 11. Ihrke, Peter J.: Therapeutic Strategies Involving As time goes by and more is learned about Antimicrobial Treatment of the Skin in Small Ani­ the drugs we use, the possibilities for therapy mals. jAVMA 185:1165-1168.1984. become seemingly endless. Unfortunately 12. Dillon, Ray: Therapeutic Strategies Involving Anti­ microbial Treatment of the Gastro-intestinal Tract in time also becomes a limiting factor, as it is Small Animals. jAVMA 185:1169-1171. 1984. impossible for anyone clinician to learn about 13. Peiffer, Robert L., Cook, Cynthia S., and Moller, them all. Hopefully, though, one can take a Ida: Therapeutic Strategies Involving Antimicrobial Treatment of Opthalmic Disease in Small Animals. few drugs, such as the more popularly used jAVMA 185:1172-1175. 1984. penicillins, and learn them thoroughly. One 14. Roberts, Malcolm C.: Therapeutic Failures with Antimicrobial Drug Treatment. jAVMA 185:1150­ must remember, though, that it is equally, if ) 154. 1984. not more important to learn when not to use a 15. English, P. B.: Plasma Concentration and Disposi­ drug than when to use it. A basis for that tion of Antimicrobial Agents in the Dog. Australian feterinary journal. 60:353-360. 1983. knowledge can be built with time and expe­ 16. Aronson, Arthur L. and Kirk, Robert W.: Antimi­ rIence. crobial Drugs. Chapter 29. In Ettinger, Stephen J. (ed) 1extbook of veterinary Internal Medicine. 2nd ed. W. B. Saunders Company, Philadelphia, Pa. 1983.

38 Iowa State University Veterinarian