Antibacterial Chemotherapy



Antibacterial Chemotherapy


Craig E. Greene and Dawn M. Boothe


The terms antibiotic, antibacterial, and antimicrobial are often used interchangeably, despite different meanings. Antibiotics are chemicals (e.g., penicillin) produced by organisms (“natural”) intended to suppress other organisms (generally, but not exclusively, bacteria), whereas antimicrobial refers to any compound, whether natural, synthetic, or between, that suppresses microbial growth. Antibacterials target bacteria; antifungals target fungi, and so forth.61 Antibacterials, among the most widely used drugs in veterinary practice, are sometimes administered without adequate documentation that a bacterial infection exists. Although this practice may not immediately harm the patient, routine and irrational use of antimicrobials may have several undesirable consequences. Unrestricted use encourages the selection of resistant strains of bacteria, which subsequently limits the choice of effective agents.135 Long-term treatment with antibacterials may suppress the animal’s resident microflora, thereby allowing overgrowth of more resistant microorganisms.


Care must be taken to not confuse antimicrobial resistance with microbial virulence. The latter addresses the ability of a microbe to cause disease, due to infection (versus mere colonization) that harms the host. Pathogenicity generally depends on the presence of virulence factors (e.g., adhesions, cytotoxins), although notable exceptions occur for the immunoincompetent patient in whom opportunistic commensals, without virulence factors, can cause clinical disease. In general, from an evolutionary premise, increase in antimicrobial resistance has been associated with decreasing virulence of pathogenic bacteria. However, with newer evidence, this generally accepted paradigm has been reconsidered.


The worldwide increase in antimicrobial resistance has paralleled the use of drugs to combat microbial infections in humans and animals.406 For example, in a number of studies of antibacterial susceptibility data over time intervals during the past two decades, increases in prevalence of multiresistant bacteria have been observed.29,204,204 In comparing the intervals of 1990 to 1992 and 2002 to 2003, a significant decrease in susceptibility of canine bacterial isolates to commonly used antimicrobials was observed.26 Selection of bacterial subpopulations with greater antimicrobial resistance than the original population is an inevitable consequence of indiscriminant antibacterial treatment. Selection pressures are highest when bacteria are exposed to suboptimal dosage regimens (i.e., concentrations of drug below the minimum inhibitory concentration [MIC]). The therapeutic aim is to treat for an appropriate time interval at a therapeutically active dose that achieves bactericidal concentrations at the site of infection. Once resistance emerges, selection pressure forces it to remain if antimicrobial use is continued. Therefore, veterinary hospitals must develop protocols that minimize inappropriate and indiscriminate antibacterial use.442,555 Judicious use is essential because there are very few new antibacterial drugs on the horizon with novel mechanisms of action.110 Antimicrobial overuse and development of microbial resistance to effective drugs have become a major concern of the veterinary scientific community. The American College of Veterinary Internal Medicine,379 the American Association of Feline Practitioners (AAFP),12,163 the American Animal Hospital Association,11 and the American Veterinary Medical Association13 have all published consensus statements and guidelines addressing these concerns. One veterinary teaching hospital has published their experiences in implementing antimicrobial oversight.607


Selection of antimicrobials can be empirical or based on susceptibility data for the involved microorganisms. Empirical choices are based on the organ system of involvement, the suspected organisms involved, and a knowledge of the available drugs and their antimicrobial activity. Knowledge of the specific organ system infections can be obtained in Chapters 84 to 92. Unfortunately, the widespread and increasing use of antimicrobials in dogs and cats has caused a parallel increase in the resistance patterns of infectious organisms. Therefore, performance of susceptibility testing and proper interpretation of test data are needed. See Chapters 84 to 92 for the various collection methods, for specimens to be collected of body tissues and fluids, and Chapter 29 and Boothe61 for a discussion of methods of susceptibility testing and interpretation of results. The current chapter and the Drug Formulary in the Appendix, can be used to aid in selecting the proper drug and an appropriate dosage regimen.


Good antimicrobial stewardship begins with critical evaluation as to the need to use antimicrobials in a particular clinical situation. Determining the need includes both identifying whether infection is causing clinical illness and confirming that antimicrobials are indicated for treatment of those clinical signs. Once the need for antimicrobial therapy is confirmed, the next consideration is to match the drug to the implicated organism, such that the most narrow-spectrum antimicrobial might be selected. The final, and equally important, consideration is to design a dosing regimen that is appropriate for the patient. This decision must take into account a multitude of factors presented by the chemotherapeutic triangle: host (e.g., target tissue, impact of inflammation, immunocompetence), microbial (e.g., presence of virulence factors, biofilm, resistance), and drug (e.g., lipophilicity, concentration versus time dependency, adverse events) factors.60 Paramount to successful antimicrobial therapy is resolution of clinical signs. Paramount to judicious use is optimizing the dosing regimen to avoid development of resistance. The two goals are not mutually inclusive.


Antibacterials can be divided into two groups based on their patterns of bactericidal activity: concentration-dependent drugs and time-dependent drugs.62,127 For the concentration-dependent drugs, optimal activity is achieved with high peak-drug concentration compared to the MIC of the infecting microbe. This group comprises the aminoglycosides and quinolones (fluoroquinolones) and, under select circumstances, other drugs. Efficacy of quinolones also is associated with area under the curve (AUC). The highest safe, achievable drug concentration is the most important factor for aminoglycosides and quinolones. Pulse infusion or once-daily dosing is likely to maximize the efficacy of these agents and induce the least amount of bacterial resistance.


Most of the remaining antimicrobials are the time-dependent drugs, which show optimal activity when plasma concentrations of approximately four times the MIC are maintained for 50% to 80% of the dosage interval.562 Drugs of this type are the β-lactams (penicillins, cephalosporins, monobactams, carbapenems), vancomycin, tetracyclines, phenicols, clindamycin, and most macrolides. For tetracyclines, macrolides, and vancomycin, efficacy is related to AUC, which is an index relative to maintaining necessary blood or tissue concentrations. Administration of these drugs by continuous infusion or multiple daily doses would be most efficacious for drugs of these groups with short half-lives.


A postantibacterial effect (PAE) refers to persistent suppression of bacterial growth after exposure to an antimicrobial agent. All antibacterials appear to have this effect with susceptible gram-positive bacteria. With gram-negative bacteria, this effect is noted only with inhibitors of protein or nucleic acid synthesis, such as aminoglycosides, quinolones, tetracyclines, macrolides, chloramphenicol, and rifampin. In some instances, as with quinolones and aminoglycosides, the PAE is longer in vivo because they achieve higher concentrations in leukocytes at sites of inflammation.


Antimicrobial combinations are used widely in veterinary practice, but few instances have occurred in which a synergistic outcome is documented; in many cases, combined use might reduce efficacy or enhance toxicity. Combination therapy may be most indicated for treatment of infections for which the risk of resistance is high. However, several potentially effective combinations exist. β-Lactams act on bacterial cell walls and increase the uptake of aminoglycosides. Cell wall–active agents such as penicillins, cephalosporins, imipenem, and vancomycin have been synergistic with the aminoglycosides streptomycin, gentamicin, and amikacin.2 Agents acting sequentially in a pathway, for example, sulfonamides and diaminopyrimidines (see the later discussion of diaminopyrimidines-sulfonamides), have also been effective and more bactericidal than either drug by itself. Combinations of agents acting on the cell wall, such as aminopenicillin (ampicillin, amoxicillin) together with a cephalosporin (cefotaxime, ceftriaxone) have been more effective against bacteria in vitro and in vivo, presumably because they attach to different binding proteins on the bacterial cell wall. The streptogramins (see the later discussion of streptogramins) consist of two components that act synergistically to inhibit protein synthesis in bacteria. β-Lactamase inhibitors (see the later discussion of other β-lactamase inhibitors) increase the activity and spectrum of β-lactams against various bacteria. Other synergistic antimicrobial combinations include quinolones, macrolides, or tetracyclines with rifampin, especially against persistent intracellular microorganisms in difficult-to-reach areas such as pyogranulomatous lesions or meninges. Presumably rifampin facilitates intracellular penetration of the other drugs. Combinations of quinolones with β-lactams or aminoglycosides may also be beneficial.487 Clinical applications that justify combination therapy include bacterial endocarditis, resistant Pseudomonas infections, meningitis, febrile neutropenia, and Brucella, Helicobacter, and Mycobacterium infections.


Antimicrobial antagonism that is possible in certain circumstances can be avoided. The general advice is that cell wall–inhibiting drugs such as the β-lactams should not be used with bacteriostatic agents such as tetracyclines or chloramphenicol because rapid replication is needed for the cell wall–acting drugs to be effective. Macrolides should not be combined with lincosamides because complete antibacterial cross-resistance develops.


The prophylactic use of antimicrobials to prevent anticipated infections is controversial because of the increased risk of selecting for resistant microorganisms.157 Indiscriminant use of antibacterials may alter the patient’s microbial flora and allow colonization by resistant bacteria. For example, this can occur when concurrent antibacterials and indwelling urinary catheters are used in intensive care patients.404 However, in other instances, prophylactic administration has been beneficial, such as when infection is anticipated from contamination of otherwise sterile tissues. These cases include contaminated wounds after trauma, surgical procedures when contamination is expected, surgery in immunosuppressed patients, and during surgical procedures involving prolonged exposure of healthy tissue to air. Antibacterials may also be indicated prophylactically before major dental procedures and high-risk medical conditions, including diabetes mellitus, hyperadrenocorticism, immunosuppressive or cancer chemotherapy, and chronic bronchopulmonary disease. In humans undergoing cancer chemotherapy, prophylactic quinolone administration for neutropenia decreased the rate of development of infections; however, when infections occurred, they were caused by highly resistant microoganisms.37 For further discussion of prophylactic antimicrobials in traumatic and surgical wounds, see Surgical and Traumatic Wound Infections, Chapter 53.


This chapter presents a review of the general properties of antibacterial drugs by pharmacologic groups. Information on specific antibacterial drugs used in dogs and cats can be found in the Drug Formulary in the Appendix at the end of this book. Because of space limitations, a discussion of general principles of antibacterial chemotherapy has been omitted here. Further coverage of antibacterial drug resistance and prophylaxis is in Chapter 93. Dosage charts for the administration of antibacterial drugs in treating bacterial infections of various organ systems are provided in Chapters 84 through 92.



β-Lactam Drugs


This group of drugs, which includes penicillins, cephalosporins, monobactams, and carbapenems, acts by disrupting bacterial cell wall synthesis. These drugs are most effective when organisms are reproducing rapidly because of the high rate of cell wall formation. The most common mechanism of bacterial resistance to β-lactams is production of the enzyme β-lactamase, which damages the β-lactam ring of these compounds. More than 300 uniquely different enzymes have been described. Combination of penicillins with a β-lactamase protector (e.g., clavulanate or sulbactam) improves efficacy and thus broadens the spectrum of the penicillin toward susceptible organisms that have acquired resistance through β-lactamase production. Cephalosporins are generally more resistant to β-lactamases produced by Staphylococcus species, but are more susceptible to those produced by anaerobic organisms.620 More problematic are the emerged extended-spectrum β-lactamases, which target most third-generation drugs, but not the second-generation drug cefoxitin, or clavulanate or carbapenems.104 Extended-spectrum β-lactamases are not generally detected by routine susceptibility methods.23 Genes for β-lactamase, encoded on bacterial chromosomes or plasmids, may spread within and among these populations of bacteria. An increasing number of staphylococci have a modified penicillin-binding protein in their cell walls with a reduced affinity for all β-lactam drugs. These organisms have been classified as methicillin-resistant types and make up a majority of nosocomial isolates from patients in human hospitals. Methicillin resistance in Staphylococcus aureus (MRSA) and Staphylococcus pseudintermedius (MRSP) is indicated by the presence of the mecA gene, which encodes a mutation in PBP2a, thus reducing its affinity for the β-lactam ring, rendering the organism resistant to all β-lactams.69,320 Detection of MRSA or MRSP on susceptibility generally is based on resistance to oxacillin, which is more stable than methicillin in disks used for testing. Although it is community-acquired MRSA strain USA300 that appears to be most commonly associated with increased colonization in clinically healthy dogs and cats, it is USA100, most frequently associated with hospital-acquired MRSA infections in humans, that most commonly causes clinical infections in dogs and cats (see Staphylococcal Infections, Chapter 34).171


β-Lactam drugs act synergistically with aminoglycosides by facilitating their entry into bacterial cells; however, they should never be premixed before administration because the aminoglycoside can damage the β-lactam ring. Synergism has been noted when a β-lactam such as ticarcillin has been combined with a quinolone for treating Pseudomonas infections.



Penicillins


Natural Penicillins


Penicillin G (benzyl penicillin) is a naturally occurring bactericidal antibiotic produced by certain molds of the genus Penicillium. It primarily inhibits synthesis of the gram-positive bacterial cell wall, causing osmotic fragility of susceptible bacteria. Penicillin G has three significant therapeutic limitations: it is degraded by gastric acid, which reduces systemic availability after oral administration; it is inactivated by β-lactamases produced by certain staphylococci and many gram-negative organisms; and at usual therapeutic dosages, its spectrum is limited mainly to gram-positive aerobic and facultative anaerobic organisms (Table 30-1). Newer semisynthetic penicillins have been produced to overcome these disadvantages. In general, penicillins are believed to work synergistically with aminoglycosides in vivo.



TABLE 30-1


Properties of Penicillins and Associated β-Lactam Derivativesa






















































































































































































































































Generic Name (Trade Name) Route of Administration Antimicrobial Spectrum
Gastric Acid Stability Staphylococcal β-Lactamase Resistance Gram- Positive Gram- Negative Anaerobic Pseudomonas
NATURAL PENICILLINS
Penicillin G (many) IM, IV − − + − + −
Penicillin V (many) POb + − + − + −
β-LACTAMASE–RESISTANT PENICILLINS
Methicillin (Staphcillin, Celbenin) IM, IV − + + − − −
Nafcillin (Unipen, Nafcil) IM, IV ± + + − − −
Cloxacillin (Tegopen) POb + + + − − −
Dicloxacillin (Veracillin, Pathocil, Dynapen) POb + + + − − −
Flucloxacillin (Flopen, Floxapen) PO + + + − − −
Oxacillin (Prostaphilin, Bactocil) PO, IM, IV + + + − − −
AMINOPENICILLINSc
Ampicillin (many) PO,b SC, IM, IV + − + ± ± −
Amoxicillin (Omnipen) PO, IM + − + ± ± −
Hetacillin (Hetacin) PO + − + ± ± −
EXTENDED-SPECTRUM CARBOXYPENICILLINS
Carbenicillin (Pyopen, Geopen) IM, SC, IV − − ± + + +
Ticarcillin (Ticar) IM, SC, IV − − ± + + +
UREIDOPENICILLINSd
Mezlocillin (Mezlin) IM, IV − − + ++ ± ++
Piperacillin (Pipracil, Pipril) IM, IV − − + ++ ± ++
OTHER β-LACTAMS
Aztreonam (Azactam) IM, IV − ++ − ++ − ++
Imipenem-cilastatin (Primaxin) IV − ++ ++ ++ ++ ++
β-LACTAMASE INHIBITORS
Clavulanate [CA]e PO, IV + ++ − − − −
CA + amoxicillin (Clavulox, Clavamox, Augmentin) PO + ++ ++ ++ + −
CA + ticarcillin (Timentin) IV − ++ ± + + +
Sulbactam [SB]e IV − ++ + ± ± −
SB + ampicillin (Unasyn, Synergistin) IV − ++ + + + +
Tazobactam (TZ)e IV − ++ + + ± ±
TZ + piperacillin (Zosyn) IV − ++ + ++ ± ++


image


IM, Intramuscular; IV, intravenous; PO, by mouth; SC, subcutaneous; −, none; ±, variable; +, good; ++, excellent.


aSee the Drug Formulary in the Appendix for dosages.


bFor best results, administer on empty stomach.


cAlso includes bacampicillin (Spectrobid), cyclacillin (Cyclapen), epicillin, pivampicillin, and talampicillin.


dAlso includes azlocillin (Azlin).


eSusceptibility data indicate efficacy of inhibitor alone, although the drug is not available by itself.


Despite the production of newer derivatives, penicillin G remains the most active drug against many gram-positive aerobic bacteria. Most streptococci, except for enterococci, are susceptible (see Chapter 33). Many gram-positive bacilli and anaerobic bacteria, with the exception of β-lactamase-producing Bacteroides fragilis, are susceptible. Staphylococci are frequently resistant because of β-lactamase production. Procaine penicillin and benzathine penicillin are poorly soluble compounds that slowly dissolve at the site of injection, liberating penicillin G.


Penicillin V (phenoxymethylpenicillin) is an acid-stable derivative that is better absorbed from the alimentary tract, although resulting blood concentrations are much lower than that produced by parenteral administration of the same dose of penicillin G. Therapeutic effects equivalent to those obtained with penicillin V may be achieved at less expense by giving oral penicillin G to fasting animals at four times the usual parenteral dosage.



β-Lactamase-Resistant Penicillins


Methicillin, the first semisynthetic penicillin developed, resists β-lactamase but is inactivated by gastric acid and must be administered parenterally, limiting its clinical usefulness. Similarly, nafcillin has poor systemic availability after oral administration and is usually administered parenterally. The isoxazolyl derivatives (cloxacillin, dicloxacillin, flucloxacillin, oxacillin) can be administered orally with reasonable absorption from the gut and are resistant to staphylococcal β-lactamase but are less active compared with penicillin G against other penicillin G–sensitive organisms. These substances are highly protein-bound drugs, which delays their elimination and maintains high plasma-drug concentrations. However, this protein binding limits penetration of the drug into tissues. Possible indications for these drugs include infections caused by β-lactamase-producing staphylococci, as in pyoderma or osteomyelitis.




Carboxypenicillins


Carbenicillin and ticarcillin have increased activity against gram-negative aerobes, including Acinetobacter, Proteus, Enterobacter, some Klebsiella, and some anaerobes. Ticarcillin is especially active against Pseudomonas. Carboxypenicillins are destroyed by β-lactamase and are less effective against gram-positive organisms. These drugs are generally not well absorbed orally and must be given parenterally for systemic activity, but carindacillin and carfecillin are two esters of carbenicillin that are available for oral administration. The MICs for susceptible organisms are relatively high; therefore, large doses must be administered and the drugs should be given at shorter intervals. Coadministration with an aminoglycoside improves efficacy against Pseudomonas and reduces development of drug resistance. Ticarcillin and ticarcillin-clavulanate have been used successfully in managing canine otitis externa caused by Pseudomonas aeruginosa (see the Drug Formulary in the Appendix and Chapter 84, Otitis Externa).396 Expense generally limits systemic use of carboxypenicillins.




Pharmacokinetics


Absorption and duration of activity of penicillins depend on the dose administered, the vehicle containing the drug, and the solubility of the salt formulation. The potassium and sodium salts are soluble and can be given by the oral, intramuscular, subcutaneous, intravenous, and topical routes, whereas insoluble trihydrates are absorbed less rapidly by oral, intramuscular, and subcutaneous routes. Soluble penicillin derivatives are absorbed from serous and mucosal surfaces but not through unbroken skin. Food in the stomach can adversely affect bioavailability of orally administered penicillins, with ampicillin more impacted than amoxicillin. All penicillins are eliminated by the kidney through active tubular secretion. As a result, soluble penicillin derivatives must be given at least every 4 hours to maintain therapeutic blood concentrations. Probenecid inhibits this rapid elimination. Activity can also be prolonged by delaying release of penicillins from injection sites by placing them in water-insoluble vehicles or combining them with organic salts. Examples are procaine penicillin and benzathine penicillin.


In general, penicillins are widely distributed into most highly perfused tissues, body fluids, and bone. Brain and cerebrospinal fluid (CSF) are exceptions, but concentrations in CSF are higher when meninges are inflamed. Penetration of body fluids and tissues by the highly protein-bound isoxazolyl derivatives is more limited. Dose reduction may not be necessary in patients with renal failure, despite impaired elimination, because of low inherent toxicity and the increased biliary secretion obtained with the semisynthetic penicillins. Potassium-containing penicillins should not be given intravenously to oliguric patients because of the risk of hyperkalemia.


Most aqueous solutions of penicillins are unstable, especially at higher temperatures. They should be maintained at a pH of 5.5 to 7.5 and not added to solutions containing bicarbonate or other alkalinizing ingredients. With the exception of amoxicillin, oral suspensions of penicillins must be kept refrigerated after reconstitution. Consult product label for storage and shelf-life after reconstitution.


Penicillins should never be mixed with blood, plasma, or other proteinaceous fluids or with other antibacterial before administration. They might display in vivo antagonism with tetracycline and chloramphenicol; variable interactions with erythromycin, novobiocin, and lincomycin; no antagonism with sulfonamides; and possible synergism with aminoglycosides, cephalosporins, and polymyxins. Penicillins should not be mixed in the same syringe with aminoglycosides because of potential inactivation of both drugs.



Pharmacodynamics


Dosing schedules for β-lactams have been based on maintenance of blood levels above MIC for all or most of the dosing interval.574 β-Lactams exhibit time-dependent killing. For optimal effect, plasma drug concentrations should exceed the MIC for 50% to, at, or above 80% of the treatment interval so that bacterial cell walls can be disrupted as they form. A bactericidal effect is usually achieved at between one and four times the MIC. Higher doses of β-lactams have often been used for more severe infections, but reaching the MIC may be all that is necessary, and impairment of excretory mechanisms in septic animals may permit use of lower doses.343 Because of their low toxicity, β-lactam doses generally can be increased in order to maintain effective concentrations with minimal risk of adverse reactions. Additional studies on bioactivity and pharmacokinetics in ill and organ-impaired animals will be needed to resolve the dosing schedules for these drugs. Unlike aminoglycosides and quinolones, penicillins and cephalosporins have no PAE on gram-negative bacteria at clinically achievable concentrations. A PAE for certain gram-positive organisms, such as some staphylococci, has occurred. It is the PAE that allows antibacterial concentrations to fall below the MIC for a portion of the treatment interval without impairing efficacy. Nevertheless, for most infections, β-lactams should be administered at a dose and interval sufficient to maintain plasma concentrations high enough to affect the target organism in the tissues of concern. In severe infections with resistant organisms, this action may necessitate constant intravenous infusions.



Toxicity


Toxic reactions are relatively rare with penicillins, and they generally have a high margin of safety. Rapid intravenous infusion or occasional intramuscular injections may cause neurologic signs and convulsions. Hypersensitivity reactions such as hives, fever, joint pain, and acute anaphylaxis have been noted immediately after administration to dogs and cats. Administration of any penicillin derivatives should be avoided in known sensitized animals because of cross-reactivity.


Bleeding has been an important side effect in human patients treated with antipseudomonal and extended-spectrum penicillins. This effect has been attributed to various factors, including delayed fibrin polymerization, suppression of vitamin K-dependent procoagulants, and platelet dysfunction. Acute postoperative (within 5 days) azotemia has been ascribed to administration of nafcillin to dogs during surgery.423


Diarrhea has been a side effect of oral or parenteral therapy with penicillins and is caused by inducing selective alterations in intestinal microflora.217 In experimental studies in dogs, oral administration of recombinant β-lactamase eliminated the intestinal fraction of parenterally administered ampicillin, preserved serum levels of the drug, but prevented alterations of the fecal microflora associated with diarrhea.231



Other β-Lactam Drugs


Monobactams


Aztreonam, the only clinically available member of this group, is resistant to β-lactamase and active against a wide range of aerobic and facultative gram-negative bacteria, including many strains resistant to other drugs. However, it has no useful activity against gram-positive or anaerobic pathogens. Aztreonam is given parenterally and enters many body tissues and fluids of dogs, including the CSF. Adverse effects are minimal and include diarrhea and vomiting. Primary use has been to treat patients with serious gram-negative infections in which resistance or toxicity to aminoglycosides is anticipated.



Carbapenems


This group includes imipenem, panipenem, biapenem, meropenem, and ertapenem. Imipenem is active against most gram-positive and gram-negative aerobes and anaerobes. It is primarily indicated for treatment of infections caused by cephalosporin-resistant members of the family Enterobacteriaceae and some anaerobes. Resistant Pseudomonas isolates have emerged during therapy. Breakdown of imipenem by dehydropeptidase-1 in the kidney and other tissues produces nephrotoxic metabolites and decreases urine concentrations of active drug. Coadministration of cilastatin, a metabolic inhibitor of dehydropeptidase-1, increases drug concentrations in urine and decreases potential nephrotoxicity. Parenteral administration of imipenem-cilastatin is necessary because neither drug is absorbed orally. The dose should be reduced in renal failure. Panipenem is combined with betamipron for the same reason. Biapenem and meropenem are more stable and do not require that any inhibitor be given concurrently. Meropenem pharmacokinetics have been studied in dogs.48 The protein binding of meropenem is such that plasma concentrations parallel those in interstitial fluid.49 Ertapenem has a narrower spectrum of activity than others in this class. The dose should be reduced in renal failure. Adverse effects include nausea, vomiting, diarrhea, phlebitis at the infusion site, fever, and seizures. See the Drug Formulary in the Appendix for further information on each of these drugs.



β-Lactamase Inhibitors


Some naturally occurring β-lactam drugs have low antibacterial activity by themselves but bind irreversibly to and inactivate bacterial β-lactamase. Concurrent administration of these agents increases the activity of penicillins and decreases the in vitro MIC required to inactivate many β-lactamase-producing organisms, such as staphylococci, Escherichia, Capnocytophaga canimorsus, some Proteus and Klebsiella, B. fragilis, Salmonella, and Campylobacter (Table 30-2). Organisms such as Enterobacter, Serratia, Citrobacter, and Pseudomonas remain resistant.



TABLE 30-2


Comparison of Antibacterial Activity of Selected β-Lactam and β-Lactamase Inhibitor Combinationsa










































Penicillin Bacterial Susceptibility
Inhibitor Gram-Positive Gram-Negative Anaerobes Pseudomonas
Amoxicillin Clavulanate + + + −
Ticarcillin Clavulanate ++ ++ +++ +
Ampicillin Sulbactam + + + −
Piperacillin Tazobactam ++ +++ ++ ++


image


+++, Excellent; ++, very good; +, good; −, poor.


aSee the Drug Formulary in the Appendix for further drug information and dosages.



Clavulanate


Clavulanate has weak antibacterial activity against a wide range of organisms but is a potent inhibitor of β-lactamase. It is rapidly absorbed, unaffected by food, and widely distributed in extravascular sites with the exception of the central nervous system (CNS). Clavulanate is excreted rapidly in unchanged form in urine.


An orally administered product combining amoxicillin with potassium clavulanate is licensed for small animal use. This combination is best suited to treat resistant infections caused by members of the family Enterobacteriaceae (except some Pseudomonas spp.) and anaerobes. It is given commonly to treat infections of the skin, lower respiratory tract, soft tissue, middle ear, and sinuses. The primary side effect has been diarrhea. Studies over a 9-year period on bacteria isolated from dogs and cats showed little decrease in relative susceptibility to this drug combination.582 However, evidence indicates increasing resistance at least by Escherichia coli.500 A parenteral formulation of ticarcillin with potassium clavulanate is licensed for human and equine use.





Cephalosporins


The cephalosporins are a group of antibiotics derived chemically from a substance produced by the fungus Cephalosporium acremonium. Several related compounds can also be considered in the cephalosporin group because they have similar antibacterial activity, pharmacology, and indications. This group includes cefoxitin and cefotetan (both cephamycins), loracarbef (a carbacephem), and latamoxef (an oxacephem).


Similar to penicillins, cephalosporins are bactericidal β-lactam antibacterials that inhibit bacterial cell wall synthesis, resulting in osmotic fragility. These drugs are generally more effective than penicillin in penetrating the outer cell walls of gram-negative bacteria and are less susceptible to inactivation by bacterial β-lactamases.


Cephaosporins have been separated into four generations or classes, based on the chronology of discovery, chemical structure, and therapeutic activity. Generally, increasing generations are associated with decreased susceptibility to β-lactamase destruction, although ESBL has affected this distinction. The characteristics of the classes are compared in Table 30-3, and important features of common cephalosporins are presented in Table 30-4. For further information on specific drugs and dosage, see the Drug Formulary in the Appendix.


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Aug 6, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Antibacterial Chemotherapy

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