Pharm 10: Introduction to Antibacterial Agents

Antibiotic

“Opposing life”; produced by one organism to suppress the growth of other organisms

Antibacterial drug

Exclusively toxic to bacteria (not viruses, fungi, etc.)

Antimicrobial drug

Drug active against microorganisms (including bacteria, virus, fungus, protozoan)

• The microbe must be sensitive to the drug.

• The drug must come in contact with the microbe.

• The drug must be present in high enough concentrations.

• The drug must be present for a sufficient length of time.

• The drug must not kill the patient.

Essentials for successful antimicrobial therapy

Pharmacodynamic, pharmacokinetic, toxicity, pharmaceutical characteristics

Drug characteristics that impact antimicrobial therapy

Tetracyclins, chloramphenicol, macrolides, lincosamides, sulfonamides, nitrofurans

Examples of bacteriostatic drugs

Bacteriostatic drugs

1. Do not kill the bacteria but make them more vulnerable to the patient immune system

2. Must have normal defense mechanisms for them to work: not good for very young or old animals, immunocompromised, etc,

3. Some can be bactericidal if given in high doses or in combination with other medication

4. Used to be considered as antagonists of bactericidal drugs– inhibiting cell wall targeting drugs from working on non-dividing cells

   1. Not the case for all such combinations

Penicillins, cephalosporins, polymyxins, fluoroquinolones, aminoglycosides

Examples of bactericidal drugs

Bactericidal drugs

1. Kill the bacteria: wall and membrane disruption, DNA interference

   1. Can be bacteriostatic if given in suboptimal doses

   2. More prone to causing mucosal superinfection/dysbiosis (overgrowth of a pathogenic bacteria) because they may kill off normal flora

Aminoglycosides

What are the only protein synthesis inhibitors that can kill bacteria?

Minimal inhibitory concentration (MIC)

The lowest concentration of an antibiotic that prevents visible growth after 18-24 hours of incubation

Minimal bactericidal concentration (MBC)

The minimal concentration of an antibiotic that kills 99.9% of the cells

MIC

Which parameter (MIC or MBC) cannot differentiate between -static and -cidal?

MBC

Which parameter (MIC or MBC) is only applied to -cidal activity?

High

Bacteriostatic MBC/MIC is [low/high].

Low (<4)

Bactericidal MBC/MIC is [low/high].

Breakpoints

Typically only MIC is used with ___.

Concentration-dependent antibiotics

Needs to exceed MIC by as much as possible but does not need that level sustained for a long period of time

Time-dependent antibiotics

Needs only to exceed MIC, but levels need to be sustained for a longer period

Cell wall synthesis inhibitors

Time-dependent antibodies consist of a property associated with ___ (e.g., beta-lactams and vancomycin).

MIC

For time-dependent antibiotics, antibacterial activity continues as long as the plasma concentration is greater than the ___.

Clinical significance: The concentration of these drugs should be maintained above the [same term] for as long as possible between doses

Peak drug concentration (Cmax)

For concentration-dependent antibiotics, the rate and extent of killing increases as the ___ increases (e.g., aminoglycosides, fluoroquinolones, and metronidazole)

Fewer, side effects

For concentration-dependent antibiotics:

1. Longer dosing intervals = [fewer/more] pills per day

2. Reduced drug plasma levels; therefore reduced ___

Post-antibiotic effect (PAE)

1. Some drugs also exhibit a persistent suppression of bacterial growth after limited exposure to an antibiotic, caused by any of the following:

   1. Slow recovery of bacteria after non-lethal damage to cell structures

   2. Persistence of the antibiotic at its binding site

   3. A need for bacteria to synthesize new proteins before growth can continue

2. This can happen with both concentration and time-dependent antimicrobials

3. Usually occurs with protein or DNA synthesis inhibitors

4. Can allow longer dosing intervals

Gram + aerobic, gram + anaerobic, gram - aerobic, gram - anaerobic

Quadrants of bacteria

Broad spectrum antibiotics

1. Affects three or four quadrants and potentially protozoans as well

2. E.g., tetracyclines, imipenem, chloramphenicol, fluoroquinolones

Narrow spectrum antibiotics

1. Affects one or two quadrants only

2. Predominantly gram (+): e.g., older penicillins, macrolides, lincosamides, rifampin

3. Predominantly gram (-): e.g., aminoglycosides, fluoroquinolones

4. Strictly anaerobes: e.g., metronidazole

Pharmacokinetic features (ADME)

1. Absorption

2. Distribution

   1. Extracellular vs. intracellular

   2. Vascular vs. tissue fluids vs. deep tissues, pH issues, blood-brain barrier, etc.

3. Metabolism

   1. Half-life

4. Elimination

   1. Hepatic vs. renal

Pharmaceutical features (practicality of treatment)

1. Dosages

   1. Frequency of dosing required to get drug concentration/time requirement

2. Route

   1. PO, IP, IM, SC, IV, intramammary

3. Formulations

   1. Concentration, extended release

4. Cost

IV

Which route of administration is best for absorbing maximum plasma levels?

PO

Which route of administration is best for long-term therapy and GI infections?

MIC, concentration-dependent

If rate of absorption is too slow, then efficacy can be minimized for organisms with high ___ or for ___ drugs.

Prolonged

Slow-release preparations may never reach therapeutic concentrations due to ___ absorption.

Distribution barrier

Some organs and tissues are difficult to penetrate due to the ___ (brain, CSF, testes, prostate, etc.).

Lipid-soluble

What kind of drug is used for the treatment of intracellular organisms and tissues with a distribution barrier?

pKa, pH

Ionization is based on the ___ of the drug and the __ of the environment.

Ionized vs. un-ionized levels of a drug

What determines intracellular/extracellular distribution?

Cats, kittens

The glucuronidation system in ___ is much slower than in other animals; even slower in ___

Good tissue distribution (usually lipophilic), CNS even without inflammation, poor tissue distribution, good extracellular distribution in blood and fluids

Categories of tissue distribution in drugs

Good oral distribution, bad oral distribution, inactivated with stomach acid

Categories of oral absorption in drugs

Big drop in number of culturable Gram + bacteria from the gut; very big increase in Gram - bacteria

What can happen if an antibiotic that targets Gram + bacteria is given to herbivores?

1. To better understand (and therefore remember) its spectrum of action

2. To understand which antibiotics can be combined and which ones aren’t

3. To understand how it could cause toxic effects in your patient

4. To know which antibiotic to choose empirically (in the absence of sensitivity tests)

5. To know how to navigate resistance profiles

6. To know the best alternative treatment to choose if an antibiotic fails

Why do you need to know the mechanism of action of antibiotics?

Empirical antibiotic therapy

1. Pros: quicker and cheaper

2. Cons:

   1. More likely to have the wrong antibodies

   2. More likely to have the wrong dosage regimen

   3. Potential waste of time

   4. Potential waste of money (especially for larger breeds and species)

   5. Potential selection of resistance

Culture/sensitivity-based antibiotic therapy

1. Pros

   1. Very likely to have the correct antibiotics

   2. Very likely to have the correct dosage regimen

   3. Save time and money if wrong antibiotics had been chosen empirically (especially for larger breeds and species)

2. Cons

   1. Takes >48-72 hours

   2. Cost

   3. 1-2 member(s) of each antibiotics class tested → assumption of similar results with other members

   4. Lab protocol might not perfectly represent reality

Resistant, lack, altered, efflux

1. Some organisms are inherently ___ to an antimicrobial for some reason

   1. They ___ the target or have an ___ target by gaining an escape mechanism (mutation or plasmid-mediated)

      1. Beta-lactamases for B-lactames

      2. DNA gyrase mutations for fluoroquinolones

      3. The drug may not be taken into the microorganism or may be pumped back out by an ___ mechanism

Breakpoint value

MIC value that an organism should not exceed in order to assure clinical success at the recommended dosage

Unique for each microorganism and each drug and their location

Cannot be compared

Determined ahead of time by a national lab on hundreds of isolates of one particular type of bacteria vs. one specific drug