Antimicrobials Part 2

Pharmacology for Veterinary Technicians

Course: VET 2024

Focus on: Antimicrobials Part 2

Cephalosporins

Classification:

• Type: Beta-lactam antimicrobials, which are characterized by their beta-lactam ring structure.

• Classified by Generations: Cephalosporins are divided into several generations based on their spectrum of activity, pharmacokinetic properties, and resistance to beta-lactamase enzymes.

• Common Prefix: Most cephalosporins begin with "ceph" or "cef," such as cephalexin and cefazolin.

Resistant Mechanism:

• Cephalosporins are susceptible to hydrolysis by beta-lactamase enzymes, particularly cephalosporinases, which can inactivate the antibiotic and reduce its effectiveness.

Mechanism of Action (MOA):

• The action of cephalosporins is similar to that of penicillin; they primarily function by inhibiting bacterial cell wall synthesis, which leads to cell lysis and death of the bacteria.

First Generation Cephalosporins

Examples:

1. Veterinary Uses:

   • Cephadroxil (Cefa-dropsⓇ): Often used for treating skin and soft tissue infections in dogs and cats.

   • Cephapirin (Cefa-LakⓇ/Cefa-DriⓇ): Typically employed in bovine medicine to treat mastitis.

2. Human Products:

   • Cephalexin (Keflex®): Available for both human and veterinary use; effective against a variety of infections and common in skin and soft tissue treatments.

   • Cefazolin (Kefzol®): Often utilized as a surgical prophylactic to prevent infections during surgeries.

Product Information:

• Cephalexin: Formulated in 500 mg tablets; dosage and administration may vary based on the specific type of infection and the patient's condition.

2nd and 3rd Generation Cephalosporins

2nd Generation:

• Generally not used in veterinary medicine due to limited efficacy against resistant bacteria.

3rd Generation:

• Primarily injectable forms. Example includes:

  • Ceftiofur (Naxcel®): Used in large animals for respiratory infections and has a long half-life; effective in treating various conditions due to its extended activity.

  • Cefpodoxime (Simplicef®): An oral option that is effective for skin infections in dogs.

  • Cefovecin (Convenia®): Long-acting injectable that provides extended coverage against common bacteria for up to 14 days in cats and dogs.

  • Cost Considerations: Many human-grade products exist and are often significantly more expensive for veterinary usage.

Pharmacokinetics of Cephalosporins

Absorption:

• Most cephalosporins are unstable in gastric acid, necessitating parenteral administration. Exception: Cephalexin is stable in stomach acid, making it suitable for oral administration but still has its effectiveness potentially reduced by food intake; consult drug inserts for specifics regarding administration.

Distribution:

• Cephalosporins are widely distributed in body tissues, achieving high tissue concentrations; however, they have limited penetration in the cerebrospinal fluid (CSF) and do not readily cross the blood-brain barrier, affecting treatment of central nervous system infections.

Metabolism:

• Primarily hepatic metabolism occurs with generally minimal impact on liver function, suggesting that dose adjustment is often unnecessary in hepatic impairment unless otherwise specified.

Excretion:

• They are excreted predominantly unchanged via renal filtration and active secretion in renal tubules, resulting in high concentrations of the drug in the urine. Many cephalosporins may also be found in milk after systemic administration, necessitating attention to withdrawal times in food animal applications.

Cephalosporins - Precautions

Hypersensitivity Reactions:

• Potential for hypersensitivity reactions similar to penicillins, although the incidence of these reactions is generally lower. It is advisable to avoid administering cephalosporins to animals that have a known hypersensitivity to penicillins due to risks of cross-reactivity.

Possible Reactions:

• Include fever, rashes, eosinophilia, and severe allergic reactions such as anaphylaxis.

Cephalosporins – Side Effects

Superinfection:

• The use of first-generation oral cephalosporins may lead to superinfections due to the overgrowth of non-susceptible pathogens.

Efficacy Reduction:

• Co-administration with bacteriostatic drugs, like chloramphenicol, can reduce the efficacy of cephalosporins, as these antibiotics require actively dividing bacterial populations to exert their effects.

Common Oral Side Effects:

• Include vomiting, anorexia, and diarrhea, which may be dose-related and require monitoring during treatment.

Questions:

1. What is the Mechanism of Action (MOA) for Cephalosporins?

2. What are three distinguishing characteristics of Cephalosporins?

3. What are important side effects associated with Cephalosporins?

Bacitracins

Caution:

• Bacitracin can be nephrotoxic if used systemically; therefore, its use is limited to topical applications where effectiveness is not compromised.

Usage:

• Commonly incorporated in topical creams and ointments; often utilized in conjunction with polymyxin B and neomycin for synergistic effects.

MOA:

• Similar to penicillin and cephalosporins, bacitracin disrupts bacterial cell wall synthesis but operates through a different mechanism, making it effective against certain resistant strains.

Aminoglycosides

Properties:

• Aminoglycosides are powerful antimicrobials used against serious aerobic gram-negative infections due to their bactericidal properties, particularly potent in severe infections.

Caution:

• Aminoglycosides carry substantial risks for nephrotoxicity (kidney damage) and ototoxicity (ear damage), necessitating careful monitoring during therapy.

Aminoglycosides – Spectrum

Effectiveness:

• Effective exclusively against aerobic bacteria and profoundly ineffective against anaerobic bacteria. Their bactericidal properties make them particularly suitable for severe infections caused by gram-negative organisms.

Bactericidal Properties:

• The action against gram-negative bacteria involves the disruption of protein synthesis at the ribosomal level, effectively killing the bacterial cells.

Aminoglycosides - MOA

Mechanism:

• The aminoglycosides function by impairing the ribosomal machinery necessary for the production of essential proteins within bacterial cells. This mechanism is energy-dependent and requires active transport to reach the target site inside the bacterial cell.

Examples of Aminoglycosides

Common Aminoglycosides:

• Gentamicin, Amikacin, Neomycin, Apramycin, Kanamycin, Tobramycin.

Naming:

• The majority of aminoglycoside antibiotics conclude with the suffixes “micin” or “mycin.” Care should be taken not to confuse them with trade names of various formulations.

Aminoglycosides - Resistance

Cross-resistance:

• Develops between different aminoglycosides, requiring careful selection of therapy in cases of resistance.

Resistance Mechanisms:

• Bacteria can develop resistance through several pathways, including the production of destructive enzymes that inactivate aminoglycosides or an inability to penetrate the bacterial cell wall.

Pharmacokinetics of Aminoglycosides

Absorption:

• Generally administered parenterally; while they can be absorbed into extracellular fluids, oral absorption is often limited due to oral formulations mainly intended for gastrointestinal infections.

Absorption (cont.):

• They can be absorbed well across abraded skin and are often effectively utilized in surgical wound irrigation.

Delivery Methods:

• Aminoglycosides can be delivered via infusion directly into the uterus and bladder with an expectation of minimal systemic absorption.

Pharmacokinetics of Aminoglycosides (cont.)

Distribution:

• Aminoglycosides do not significantly penetrate the blood-brain barrier or ocular tissues, which limits their effectiveness in central nervous system infections and eye diseases.

Transport:

• Active transport enables aminoglycosides to accumulate in the kidneys and inner ears; this accumulation leads to a high risk of nephrotoxicity and ototoxicity, particularly in susceptible populations.

Developmental Risks:

• These drugs cross the placenta, presenting potential risks of causing kidney and ear damage to the developing fetus, enhancing the need for caution in pregnant females.

Excretion:

• Primarily eliminated unchanged via glomerular filtration through the kidneys; due to their hydrophilic nature, most aminoglycosides are not reabsorbed in the renal tubules and are excreted in urine. They possess a short half-life (1-2 hours) attributed to efficient elimination processes.

Cautions for Using Aminoglycosides

Toxicity:

• Aminoglycosides are generally associated with increased toxicity compared to other antibiotics, especially in elderly animals or those with preexisting renal conditions, shock, or dehydration. Monitoring renal function is vital.

Cautions for Using Aminoglycosides (cont.)

Early Signs of Nephrotoxicity:

• Indicators such as casts or proteins visible in urine warrant immediate monitoring; daily urinalysis is often recommended as nephrotoxicity may manifest prior to elevations in BUN and creatinine levels. The process may be potentially reversible with prompt intervention.

Neomycin:

• Noted to have the highest risk for nephrotoxicity, particularly if absorbed systemically; it is most frequently used in topical forms or within the gastrointestinal tract due to limited systemic circulation.

Ototoxicity Risks:

• Aminoglycosides can lead to hearing loss and affect the vestibular system, balance, and coordination, which may not be reversible and necessitates risk assessment before administration especially in at-risk populations.

Passive Diffusion/Concentration Gradient

Drug Movement:

• Administration strategies that allow sufficient plasma concentrations remain essential, as drug movement out of cells occurs via passive diffusion.

Dosage Intervals:

• Sufficient intervals between doses must allow for the establishment of a concentration gradient; administration too frequently may prevent this effective movement from occurring. Continuous IV infusions can inhibit the drug's ability to exert its therapeutic action adequately.

Aminoglycosides – Administration

Administration Insight:

• Single daily doses of aminoglycosides can provide effective bactericidal activity while concurrently reducing the risk of nephrotoxicity. Dosage planning must consider the concentration-dependent nature of these drugs.

Combining Drugs

Combination Caution:

• Combining systemic and topical aminoglycosides can lead to significant toxicity; using the drugs with denuded skin increases absorption risks. Caution is strongly advised when coadministering with other nephrotoxic or ototoxic medications.

Aminoglycosides - Ineffectivity

Limitations:

• Although broad-spectrum, aminoglycosides are ineffective when cellular debris and pus are present, as the binding of the antibiotic to nucleic acid proteins found in debris diminishes drug availability and effectiveness.

Questions:

1. What is the Mechanism of Action (MOA) for Aminoglycosides?

2. What are three distinguishing characteristics of Aminoglycosides?

3. What are important side effects associated with Aminoglycosides?

Quinolones (Fluoroquinolones)

Attributes:

• Quinolones represent a newer generation of potent bactericidal antimicrobials, broadly effective across both gram-positive and gram-negative aerobic bacteria.

Examples:

• Include but not limited to:

  • Enrofloxacin (Baytril®)

  • Marbofloxacin (Zeniquin®)

  • Orbafloxacin (Orbax®)

  • Difloxacin (Dicural®)

  • Pradofloxacin (Veraflox®)

  • Danofloxacin (Advocin®): Specifically approved for use in food animals.

• Human equivalents include Ciprofloxacin and Ofloxacin.

Quinolone - MOA

Mechanism of Action:

• Quinolones work by disrupting essential bacterial DNA function, which leads to bacterial cell death. Their action primarily interferes with the DNA gyrase enzyme, crucial for bacterial DNA replication and function, a mechanism distinct from that found in mammalian cells.

Effectiveness:

• They boast effectiveness against both gram-positive and gram-negative aerobic bacteria, establishing them as valuable therapeutic options in cases of complex infections.

Pharmacokinetics of Quinolones

Absorption:

• Quinolones are readily absorbed orally in species such as dogs, cats, calves, and adult horses; however, ruminants may experience less than 20% bioavailability. The absorption process may also be slightly delayed by the presence of food; hence, parenteral administration routes exist for optimal therapeutic effects.

Pharmacokinetics of Quinolones (cont.)

Distribution:

• A high drug accumulation is typical in tissues such as the kidneys, liver, lungs, bone, joints, and aqueous humor of the eye, as well as the prostate and central nervous system (CNS). This unique distribution pattern supports their efficacy in treating deep-seated infections.

Metabolism:

• Metabolism predominately occurs in the liver, resulting in the generation of various metabolites, notably ciprofloxacin, which is a critical metabolite derived from enrofloxacin.

Macrophage and Neutrophils

Action Mechanism:

• Quinolones are effectively transported to sites of infection via macrophages and neutrophils, which play a crucial role in inflammatory responses; consequently, they are often favored for treating conditions like pyodermas where deep tissue infection is present.

Pharmacokinetics of Quinolones (cont.)

Excretion:

• The kidneys and liver are responsible for the excretion of both metabolized and unmetabolized forms of quinolones, thus careful dose reduction in cases of severe renal impairment is crucial to prevent toxic build-up and associated adverse effects.

Safety and Usage:

• Quinolones are generally considered very safe when used judiciously and under veterinary guidance to prevent unnecessary adverse effects.

Precautions - Quinolones

Adverse Effects:

• Quinolones can be harmful to developing joint cartilage, with potential erosion noted in young animals subjected to therapy before skeletal maturity.

Contraindications:

• Established guidelines recommend avoiding use in specific populations, including:

  • Small/medium-sized dogs <8 months old.

  • Large breed dogs <12 months.

  • Giant breeds <18 months.

  • Cats <12 months.

  • Foals <3 years.

  • Pregnancy caution is advised as these drugs carry the potential risk of fetal cartilage damage, necessitating avoidance during pregnancy.

Seizure Concerns:

• It is recommended to avoid using quinolones in animals that are prone to seizures due to potential increases in seizure incidence during treatment.

Dosage Limit for Cats:

Maximum Dose:

• For cats, it is essential to adhere to a strict maximum dose of 5 mg/kg/day; exceeding this dosage may result in severe and permanent retinal degeneration leading to blindness.

Resistance Issues:

Caution:

• An increasing concern exists regarding the potential for bacterial resistance developing if older drugs are available that can adequately treat infections. Using quinolones unnecessarily contributes to resistance patterns that could render these agents ineffective in the future.

Food Animal Restrictions:

• Due to concerns regarding resistance in human pathogens, extra-label use in food animals is illegal and has been banned in several regions to ensure food safety.

Questions:

1. What is the Mechanism of Action (MOA) for Quinolones?

2. What are three distinguishing characteristics of Quinolones?

3. What are important side effects associated with Quinolones?

Conclusion

• This detailed overview of major antimicrobial classes for veterinary technicians highlights their roles, mechanisms, pharmacokinetics, and crucial precautions that must be taken into consideration when using these medications in clinical practice. Understanding these aspects is essential for ensuring the effective and safe treatment of a variety of bacterial infections in veterinary patients.