any substance (natural, semisynthetic, or synthetic) that kills or inhibits the growth of a microorganism, but causes little or no host damage.
A substance produced by a microorganism that, at low concentrations, inhibits or kills other microorganisms. All antibiotics are antimicrobials. Not all antimicrobials are antibiotics. There is little reason to care about the distinction except that bacteria have been developing means to resist antibiotics for millennia...
describes the GENERAL activity of an antimicrobial against bacteria (mostly). Narrow spectrum is usually taken to imply activity against some limited subset of bacteria. Broad Spectrum usually implies activity against a wide range of bacteria (perhaps even all genre) and may imply activity against mycoplasma, rickettsia, and chlamydia. Individual isolates of bacteria may be resistant to an antimicrobial even though they are part of its spectrum.
The classic "4 quadrants of coverage" do not account facultative anaerobes (e.g., E. coli). It is important to remember that facultative anaerobes are not anaerobes, they are aerobes that have the ability to live in an anaerobic environment. We culture them as aerobes, they (mostly) infect patients as aerobes and they respond to therapy as aerobes.
Bacterial growth may be inhibited by some antibiotics even after concentrations fall (and should be ineffective).
Bacteria that survive the first dose of an antibiotic develop adaptive resistance. This resistance is different than either constitutive or acquired resistance that is gene based. This may partially explain the efficacy of pulse dosing of aminoglycoside antibiotics.
We combine antimicrobials for a number of reasons. An honest analysis suggests that we generally combine antimicrobials to increase the spectrum when we are confronted with "infection due to unknown." The following results of such combinations are known to occur:
action of the combination is equal to the sum of the actions of each component.
action of the combination is significantly greater than the sum of the actions of each component.
action of the combination is significantly less than the sum of the actions of each component. Most commonly cited is "bacteriostatic drug inhibits action of bacteriocidal". Usually, bacteriostatic activity is sufficient for cure and you only waste money. Antagonism is only evident (clinically) when the patient is dependent on the antimicrobial for survival or cure.
The "source" of an infection is the biological niche where the bacteria lived prior to emerging as an infection. It is useful to consider the source of any infection as it provides insight as to the kind(s) bacteria that might be present as well as their susceptibility. For example, bacteremia arising in a puppy with a parvoviral infection is most likely caused by bacteria that were part of the enteric flora. As a secondary consideration, it may be that antimicrobial resistance among bacteria from a particular source have been affected by previous exposure to antimicrobials.
Concerns about antimicrobial resistance have recently prompted a reassessment of antimicrobial use by veterinarians. The FDA Center for Veterinary Medicine has added "impact on antimicrobial resistance" to a list of post-marketing surveillance requirements for new antimicrobials. The primary focus has been food animals because of a concern that resistant microorganisms may (and probably do) contaminate the food supply. Companion animal practitioners should anticipate that attention will also be focused on their practices. Even medical doctors have begun to alter antimicrobial prescribing practices. View an article from The Roanoke Times on Sunday, January 23, 2000 at http://cpharm.vetmed.vt.edu/vm8784/ANTIMICROBIALS/newspaper_antibiotics.pdf.
Susceptibility and sensitivity would seem to mean the same thing. However, susceptibility usually refers to the presence of targets of antimicrobial activity within a genre or species of bacteria. "E. coli (referring to all of them) are susceptible to gentamicin." Sensitivity is measure of the concentration of an antimicrobial necessary to demonstrate activity against a particular isolate. "This E. coli isolate (a particular clinical case) is sensitive to (a particular concentration of) gentamicin." Resistance takes on a variety of meanings depending on the context:
Bacteria that do not possess the target of antimicrobial action or possess some intrinsic protection from the antimicrobial are constitutively resistant. Organisms with constitutive resistance are NOT part of the spectrum of the antimicrobial.
Bacteria that acquire (usually from some other bacteria but occasionally by point mutation of chromosomal DNA) the ability to destroy or avoid the antimicrobial or a change in structure of the target of antimicrobial action. This is USUALLY a "concentration dependent" phenomenon. Organisms may acquire resistance but still be part of the antimicrobial's spectrum.
For certain bacteria, we can list specific drugs, doses, and intervals for which we can expect efficacy. This is often based on clinical experience. Nearly all isolates of Corynebacterium, Erysipelothrix, Bacillus, Beta-hemolytic streptococci are susceptible to penicillin G and have remained so since its introduction.
Some strains of bacteria have acquired resistance to almost all antimicrobials. Acquired resistance is also a variable phenomenon depending on the microorganisms ability to express the acquired trait. Therefore, the antimicrobial concentration becomes an important expression of susceptibility. Individual isolates of Enterobacteriaceae, Staphylococci vary in their susceptibility to a variety of antimicrobials. Some bacterial genre are noted for exceptional resistance (e.g., Pseudomonas aeruginosa)
Antibiotic resistance can be categorized in three types:
MIC is the concentration of antimicrobial required to inhibit the growth of a particular bacterial isolate in vitro. Dose regimens in common use generally produce plasma concentrations 2s - 4 x the MIC. Clinically the MIC is used to assign an organism to a susceptibility category (sensitive, intermediate, resistant).
MBC is the concentration required to kill a particular bacterial isolate in vitro. Experimentally, the MBC is usually 2 to 4 x the MIC for the same isolate. MBC is RARELY (if ever) determined clinically.
Quantitative susceptibility data (MICs) for individual isolates (taken from multiple cases) can be pooled. Historical susceptibility data can be sorted by bacterial species, disease, site of infection, etc. This pooled data is used to evaluate the likelihood of success for particular antimicrobials given by specific doses and intervals.
the concentration that will inhibit 50% of the isolates of a given bacterial class
the concentration that will inhibit 90% of the isolates of a given bacterial class (e.g. genre).s (e.g. genre). The numeric subscript may be any percentage historical isolates.
Useful in selection of drugs for suspected organisms or isolates of unknown susceptibility. Selection of drugs that can be administered to produce an MIC90 in the target tissue for the suspected organism should have a higher success rate for a given situation.
View the Veterinary Antimicrobial Decision Support (VADS) Susceptibility demoAll susceptibility testing is essentially a three stage process:
Where do breakpoints come from?
Interpret using published ranges for "susceptible, intermediate, and resistant". Apply INTERPRETATIONS as for agar disk diffusion.
| Figure 3. Tube dilution MIC for ampicillin. A different range is used to interpret the susceptibility of an isolate from soft tissue vs. the urinary tract. Interpretation: Isolate 1 = S for Soft Tissue, S for Urinary Tract; Isolate 2 = I for Soft Tissue, S for Urinary Tract; Isolate 3 = R for Soft Tissue, R for Urinary Tract. |
|---|
as for Tube dilution MIC but only reported as susceptible (sometimes intermediate) or resistant.
| Figure 4. Tube dilution MIC vs Breakpoint wells for ampicillin. The interpretations do not change, only the number of concentrations tested. |
| Figure 5. Break-point MIC wells for three antimicrobials. Breakpoints established for soft tissue infections. Interpretation: Ampicillin = R; Cephalothin = I; Gentamicin = S. |
| Figure 6. Kirby-Bauer susceptibility test. |
Process for determing antimicrobial dose, interval and duration is not based on susceptibility testing directly. Dosing recommendations made by reputable authors in reputable sources of information are our common starting point. THEN the following rough guidelines are applied:
Determine the urgency of therapy. Immunocompromise dictates selection of a bacteriocidal antimicrobial. Remember, though that bacteriocidal activity depends on concentration. The more compromised the host or the more rapid a cure required, the higher the blood and tissue concentrations should be.
Only an imperative consideration for aminoglycoside antibiotics in order to avoid nephro- and oto- toxicities. Bacteriocidal antibiotics are thought to be more effective if organisms are allowed to grow at the end of each dose interval (so a repeated low trough may have GENERAL benefits when cidal antimicrobials are given).
The use of patient pharmacokinetic parameters for aminoglycoside dose calculation is discussed in other sections of these notes. Most antimicrobials are safe enough that USUAL doses produce concentrations that exceed minimum targets and remain safe despite variable pharmacokinetics.
The optimum dose interval would be the sum of "the time required for the most effective kill" + "duration of post-antibiotic effects" + "time for bacterial lag phase". There is no method for calculating the optimum dose interval. It is, however an important theoretical concern which should be considered when you decide among options.
Persist for several hours after removal of some drugs (especially beta-lactams and aminoglycosides). If adequate concentrations were achieved at some point during the dose interval no bacterial growth occurs for some time after concentrations fall below MIC. The true PAE preceeds the normal lag phase required by bacteria to return to log-phase growth.
IF the total duration of antimicrobial therapy is too short, we expect therapeutic failure and re-appearance of infection and its clinical signs. IF the total duration of therapy is too long, we increase the risk of adverse drug events and MAY increase resistance in bacterial populations. When discussing antimicrobial regimens, most authors indicate that the duration of therapy must be "adequate." For many infectious diseases, an old rule "treat 3 days past the end of clinical signs" seems appropriate (not a useful rule for asymptomatic infections). For certain diseases, authors may recommend a negative culture before antimicrobial therapy is discontinued (not a good practice in my opinion). Finally, there is a general tendency to assign durations based on commonly accepted practice and/or clinician experience.
What I know for certain is that we have an unsophisticated view of duration of therapy and very little information to substantiate claims of efficacy for therapies of a particular duration. We have even less information about the impact of therapeutic duration on antimicrobial resistance. I offer the following references (please note they all concern human patients, I am unaware of veterinary studies of the same subject) along with an abbreviated synopsis each:
| Chastre, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in Adults. JAMA 290 (19) 2588-2598, 2003. | No difference in clinical outcome. If patients relapsed, patients receiving shorter duration therapies were less likely to have resistant isolates. |
| Kiyota, et al. Comparison of 1-week vs 2-week triple therapy with omeprazole, amoxicillin, and clarithromycin in peptic ulcer patients with Helicobacter pylori infection: results of a randomized controlled trial. Gastroenterol 34(suppl 11), 76-79, 1999. | No significant difference in clinical outcomes. |
| Villar, et al. Duration of treatment of asymptomatic bacteriuria during pregnancy. Database Syst Rev 2000 (2) CD000491 | Inconclusive (no difference determined but extreme variability) |
| Vinod, et. al. Duration of antibiotics in children with osteomyelitis and septic arthritis. J. Paediatr. Child Health (2002) 38, 363-367. | Most patients studied received long duration therapy (even though short duration therapy was considered "routine"). Short duration patients were said to have done well although statistical comparison was not made. Included no information on antimicrobial resistance patterns. |
| Li, et al. Efficacy of Short-Course Antibiotic Regimens for Community-Acquired Pneumonia: A meta-analysis. The American Journal of Medicine 2007 120, 783-790. | Study indicated equal efficacy for short and long duration therapies. No data was collected relative to antimicrobial resistance. |
| Oral Administration | |
|---|---|
| Availability |
|
| Appropriate Uses | Appropriate for mild to moderate infections but NOT for life threatening infections and NOT for systemic aminoglycoside action |
| Patient pharmacokinetics | Absorption is
always the most variable (as compared to IM, SC) between patients. Even
greater variability is likely with disease states such as enteritis,
motility disorders, GI blood flow disturbances, Liver disease. Oral is only rarely used for ruminants as drugs are metabolized by rumen microflora and only slowly released from the Rumen. Oral is rarely a good route for horses (though it is often used). Amounts of drug unabsorbed may lead to flora alterations and severe GI disease. There are few appropriate dose forms available. |
| Intravenous Administration | |
| Availability | Most activity profiles are available (all aminoglycosides, all tetracyclines, chloramphenicol, macrolides, all representative actions for beta-lactams, most sulfonamides). Some questionable forms exist (48% Tribrissen) |
| Appropriate Uses | Life threatening infections; when intramuscular is contraindicated (due to tissue irritation, severe dehydration, thrombocytopenia, hemostatic disorder, etc.); to avoid injection site residues (food animals); rarely when steady sustained concentrations are desired (by constant intravenous infusion) |
| Patient pharmacokinetics | IV is the most predictable routes. Most iv "bolus" antibiotics should be given over 5 - 30 minutes as peak concentrations may be toxic (or waste drug). Continuous (steady state) infusions no longer in vogue. |
| Intramuscular (IM) / Subcutaneous (SC) Administration | |
| Availability | Most activities are
available. Reasons for SC VS IM may either be regulatory or physiologic
(the drug is irritating, or ambient temperature is cold or animal is
dehydrated). IM route is out if patient is in shock. For either route, the dose form controls rate of release. Simple neutral salts in aqueous vehicles are rapidly released from injection sites. Esters, oily vehicles, procaine salt etc. are slowly released from injection site |
| Appropriate Uses | Life threatening infections (use rapidly absorbed products). Any time oral route is inappropriate (vomiting, absorption affected by GI disease, in ruminants) |
| Patient pharmacokinetics | Concentration profiles for IM and SC are very similar (on average) but SC is more variable. Expect less variability with rapidly absorbed products. The anatomic site influences absorption rate: M. serratus ventralis cervicis > M. biceps > M. pectoralis > M gluteus (decreasing availability - procaine pen G) |
 |  |
 |  |
| Lipid soluble (relatively less water soluble) | |
|---|---|
| Elimination | Hepatic - microsomal or biliary excretion
|
| Distribution | Most distribute to intracellular space.
|
| Absorption |
|
| Variably soluble (Fairly soluble in both water and lipid) | |
| Elimination | Elimination varies with solubility
|
| Distribution | Improves (higher concentrations in cells, CNS, prostate) as lipophilicity increases.
|
| Absorption | Tetracyclines are well absorbed orally, im, and sc. There are "sustained release" dose forms available. Sulfonamides a usually well absorbed orally though some forms are not absorbed well by design. Sulfonamides are usually well absorbed when given by im or sc routes. |
| Poorly lipid soluble (generally high water solubility) | |
| Elimination | Renal (unchanged) and dosing tends to be consistent between species |
| Distribution | usually (and in practical terms) limited to extracellular space. Doses (/kg) are consistant between species and individuals with same % ECF. For aminoglycosides: dose adjustments are made for neonates based on altered ECF. For cephalosporins: some third generation drugs have improved tissue penetration |
| Absorption | For aminoglycosides: virtually no oral absorption (though sufficient absorption still occurs to produce kidney residues with prolonged oral administration). For penicillins: oral absorption is moderate to poor (absorption depends on drug selection). Oral absorption modified more by acid resistance than by lipid solubility. Differences in solubility affect antibacterial activity more than pharmacokinetics. For cephalosporins:oral absorption is variable by generic drug (some are well absorbed, some poorly, some not at all). For all drugs: im, sc absorption is very good, best for neutral salts. For penicillins: products often designed to slow absorption and produce sustained effect by salt formulation (procaine, benzathine). |
Topic Summary (Principles of Antimicrobials)