pharmacology 3 (antibacterial agents for systemic therapy)

MIC (minimum inhibitory concentration)

The lowest concentration of drug that inhibits visible bacterial growth

MIC90

The concentration of drug that inhibits 90% of the bacteria

MBC (minimum bactericidal concentration)

The lowest concentration of a drug that kills 99.9% of bacteria

Bacteriostatic

Stops bacteria from multiplying; elimination of the infection relies on the host immune response

Bacteriostatic: preferred patients

Immunocompetent, otherwise healthy patients (because clearance depends on the host immune response)

Bactericidal

Kills the bacteria directly

Bactericidal: preferred patients

Immunosuppressed animals and severely ill patients (sepsis, neonates, animals on glucocorticoids, animals on cancer chemotherapy)

Static vs cidal: can an antibiotic be both?

Yes, an antibiotic may be both -cidal and -static; it depends on the dose and on the bacteria

Static vs cidal: caveat

There are exceptions, it’s not black and white; the significance has been questioned recently and is based on human data, not veterinary data

Requirement for -cidal action

Bacteria must be multiplying (replicating) for -cidal actions to occur

Post-antibiotic effect (PAE)

Persistent drug effect after plasma concentrations decline below the MIC/MBC

PAE mechanisms

Decreased virulence of the bacteria, development of abnormal cell wall or septum, increased susceptibility to host defenses, persistence of drug at sites of infection

PAE: which drugs/bacteria

Only occurs with some drugs and is bacteria-dependent

PK-PD relationships

Pharmacokinetic-pharmacodynamic relationships relate drug concentration to the MIC of the pathogen to predict the success of antimicrobial therapy

Pharmacodynamic effect

What happens to the bacteria (the drug’s effect on the pathogen)

PK-PD targets: variability

Vary by class of drug and with each pathogen; meeting the targets increases chance of success, not meeting them increases chance of failure

Cmax

Maximum plasma concentration

AUC

Area under the plasma concentration-time curve; reflects exposure of the animal to the drug

T>MIC

Duration the plasma concentration is above the MIC over 24 hours; the PD target for time-dependent antibiotics

Cmax:MIC

Ratio of the maximum plasma concentration to the MIC; the PD target for concentration-dependent antibiotics

AUC:MIC

Ratio of the AUC0-24 to the MIC; the PD target for concentration/time-dependent antibiotics

Time-dependent antibiotics: PD target

T>MIC

Concentration-dependent antibiotics: PD target

Cmax:MIC

Concentration/time-dependent antibiotics: PD target

AUC:MIC

Antibiotic mechanisms of action: cell wall

Inhibit synthesis or function of the cell wall

Antibiotic mechanisms of action: protein synthesis

Inhibit the 50S ribosomal subunit or the 30S ribosomal subunit

Antibiotic mechanisms of action: nucleic acids

Inhibit synthesis or function of nucleic acids (DNA, folate, electron transport); mammalian cells don’t do well with DNA effects, so this is a toxicity concern

Spectrum of activity

Describes the general activity of an antimicrobial

Narrow spectrum

Activity against a limited subset of bacteria (1-2 of 4 quadrants)

Intermediate spectrum

Activity against 2-3 of 4 quadrants

Broad spectrum

Activity against a wide range of bacteria (all 4 quadrants); may also include mycoplasma, rickettsia, and chlamydia

Four quadrants of antibacterial spectrum

Aerobic gram (+), aerobic gram (-), anaerobic gram (+), anaerobic gram (-)

Spectrum of activity: what it tells you

That the bacteria CAN BE affected by the antimicrobial; individual isolates may still be resistant even though they are part of its spectrum

Why spectra are limited

Large variability in susceptibility within quadrants (Streptococci vs Staphylococci, E. coli vs Pseudomonas), within drug classes (cephalexin vs cefpodoxime, erythromycin vs gamithromycin), and among species (TMS for E. coli in dogs vs horses, Pasteurella in cats vs cattle)

Penicillin spectrum

Gram-positive aerobic and anaerobic bacteria

Penicillin: bacteria we actually use it to treat

Beta-hemolytic Streptococci and Fusobacterium

Penicillin: bacteria it does NOT treat

Staphylococci, Bacteroides fragilis, and gram-negative aerobic bacteria

Learning a spectrum: approach

Know the general spectrum (clinics, boards), think about which bacteria we would actually use the drug to treat, and focus on which bacteria they DO NOT treat

“U” vs “A” rule of thumb

Gram-positive bacteria names end in “us”/”um” (StaphylococcUs, StreptococcUs, EnterococcUs, BacillUs, ClostridiUm); gram-negative names end in “a” (EscherichiA, KlebsiellA, LegionellA, SalmonellA, PseudomonAs)

Facultative anaerobes

Are AEROBES that CAN grow in anaerobic conditions

Facultative anaerobes: susceptibility testing

Cultured and tested for susceptibility in aerobic conditions, so in vitro susceptibility may not equal in vivo susceptibility when anaerobic conditions are present in the patient

Anaerobic spectrum

Refers to obligate anaerobes

In vitro susceptibility test caveat

An “in vitro” test that may not reflect clinical outcome

Additive/indifferent interaction

Combined effect equals the sum of the drugs (2 + 2 = 4); typically used to extend the spectrum and treat multiple bacteria

Additive interaction: example

Horse with pneumonia, culture shows Strep. zooepidemicus (gram +) and E. coli (gram -); treat with penicillin and enrofloxacin

Synergism

Combination enhances activity (2 + 2 = 6); very beneficial and what we hope for

Synergism: trimethoprim/sulfonamide

Static alone, -cidal together

Synergism: amoxicillin/clavulanic acid

Clavulanic acid prevents degradation of amoxicillin by beta-lactamases

Synergism: beta-lactams and aminoglycosides

The beta-lactam increases permeability of the cell to the aminoglycoside

Antagonism

Activity of the combination is less than the sum (2 + 2 = 2); what we worry about

Antagonism: example

Static plus cidal, such as penicillin plus tetracycline

Antagonism: clinical approach

Probably depends on the drug/bug; not necessarily contraindicated, but avoided when possible

Judicious use: first question

Is an antibacterial necessary?

Judicious use: second question

Is a systemic antibacterial necessary?

Judicious use: third question

Is an antibacterial really necessary?

Judicious use: other questions

What is the most appropriate route of administration? Where is the infection? Are there any local factors that may affect antibacterial efficacy?

Route of administration: intravenous

Used for severe illness and fast effect

Route of administration: intramuscular

Used for severe illness when IV is not possible

Route of administration: subcutaneous

Avoid in dehydration

Route of administration: oral

Lower bioavailability and variable absorption; avoid in GI disease (esp. vomiting); drug interactions possible

Route of administration: local options

Topical (eyes, skin, wounds), inhaled (pneumonia), intraarticular/regional limb perfusion (synovial infections)

Route of administration: transdermal

Not recommended for antibacterials

Cultures and topical/local antibacterials

Cultures will underestimate the activity of topical/local antibacterials (local concentrations far exceed plasma concentrations)

Site of infection: typical

For most pathogens the site of infection is the interstitial fluid (ISF); most antibacterials reach therapeutic concentrations in ISF, so cultures should predict success

Protected sites

CNS, eye, prostate, bronchus, testes

Site of infection: exceptions to the rule

Protected sites, intracellular infections, abscesses and granulomas

Exception sites: drug diffusion

Limited drug diffusion to these areas, so plasma concentrations are higher than at the site of infection

Exception sites: effect on cultures

Cultures will overestimate the activity of antibacterials; choose a drug that we know will get to the site

Local tissue factors that reduce antibacterial efficacy

Purulent debris, acidic environment, hemoglobin/hemorrhage, anaerobic conditions/necrotic tissue, decreased blood supply

Local tissue factors: culture limitation

Cultures do not account for local tissue factors

Predisposing/complicating factors

Look for factors that decrease antibacterial efficacy and FIX THEM IF YOU CAN; control these first (examples: inhaled stick in a horse, cancer chemotherapy in a cat which causes immune suppression, metabolic disease in a dog)

Source control principle

If you can drain it, cut it out, or otherwise treat it, do it

Choosing an antibiotic: factors

Availability (formulations), ease of use (client and patient compliance), adverse effects, cost, species

Choosing an antibiotic: known cause, single isolate

Use a narrow-spectrum drug

Choosing an antibiotic: unknown cause or multiple bacteria isolated

Use a broad-spectrum drug (or a combination when multiple bacteria are isolated)

Choosing an antibiotic: severity and immune status

Bactericidal for severe infection or compromised immune system; bacteriostatic acceptable with a functional immune system

Choosing an antibiotic: route options

Oral, parenteral, or topical/local, based on the preferred/most practical route