Rational Antimicrobial Therapy
World Small Animal Veterinary Association World Congress Proceedings, 2003
Jill E. Maddison
Royal Veterinary College
London, UK

The goal of antibacterial therapy is to help the body eliminate infectious organisms without toxicity to the host. It is important to recognise that the natural defence mechanisms of a patient are of primary importance in preventing and/or controlling infection. The difficulty of controlling infections in the immunocompromised patients emphasises that antibacterial therapy is supplementary rather than a magic "cure all".

CLASSIFICATION OF ANTIBACTERIAL DRUGS

Antimicrobial drugs can be classified in various ways-by their mechanism action, by the method by which they suppress bacterial growth and by the spectrum of activity.

Mechanism of action

The four major categories of antibacterial agents exert their antibacterial action through:

 Inhibition of cell wall synthesis--penicillins, cephalosporins, bacitracin

 Inhibition of cell membrane function--polymyxins, amphotericin B, imidazoles, nystatin.

 Inhibition of protein synthesis--chloramphenicol, erythromycin, lincomycin, tetracyclines, aminoglycosides

 Inhibition of nucleic acid synthesis--sulphonamides, trimethoprim, quinolones.

Methods of bacterial suppression/killing

Antibacterial agents are often described as bacteriostatic or bactericidal.

Bacteriostatic drugs

Bacteriostatic drugs e.g., tetracyclines, chloramphenicol, sulphonamides temporarily inhibit the growth of an organism but the effect is reversible once the drug is removed. For these drugs to be clinical effective the drug concentration at the site of the infection should be maintained above the minimal inhibitory concentration (MIC) throughout the dosing interval.

Bactericidal drugs

Bactericidal drugs e.g., penicillins, cephalosporins, aminoglycosides cause the death of the organism. The use of bactericidal drugs is indicated in infections that cannot be controlled or eradicated by host mechanisms either because of the nature/site of the infection e.g., bacterial endocarditis, or where the immunocompetence of the host is reduced e.g., patient on immunosuppressive drugs or with immunosuppressive illness such as feline leukaemia virus or feline immunodeficiency virus.

Bactericidal drugs are further classified as time-dependent and concentration-dependent drugs. Time-dependent drugs such as the penicillins and cephalosporins are slowly bactericidal and their concentration should be kept above the MIC throughout most of the dosing interval. Concentration-dependent drugs include the aminoglycosides and fluoroquinolones. For these drugs, the peak concentration achieved (aminoglycosides, fluoroquinolones) and/or the area under the plasma concentration curve (fluoroquinolones) predict antibacterial success.

ANTIMICROBIAL SPECTRUM

Many texts list (appropriately) the bacterial species that are sensitive to various antibiotics-these lists are usually organised by class of antibiotic and are useful if one has identified the species of bacteria or can be reasonably confident of the species most likely to be causing an infection in a patient.

However, often we do not know the bacterial species we wish to treat. It is for this reason that it is often useful to consider the spectrum of antimicrobial action related to broad categories of bacteria. Bacteria can be classed based on their staining properties (gram negative or gram positive or other) and on the environment in which they grow-i.e., aerobic, anaerobic and facultative anaerobic. Combining these factors can give a useful classification which helps select the most appropriate antimicrobial drug when culture and sensitivity information is not available.

The most practical classification (in my opinion) is as follows:

 Gram positive aerobic bacteria (and facultative anaerobes)

 Gram negative aerobic bacteria (and facultative anaerobes)

 Obligate anaerobes--both gram negative and positive

 Penicillinase-producing Staphylococcus

The reason for this grouping is that there are some predictable differences between the sensitivity of gram negative and gram positive aerobic bacteria but there are no predictable difference between gram negative and gram positive anaerobic bacteria. IN addition, due to its ability to produce penicillinase, Staphylococcus can have a very different sensitivity compared with other gram positive aerobic bacteria. We will explore further this later in the lecture.

FACTORS AFFECTING THE SUCCESS OF ANTIBACTERIAL THERAPY

 Bacterial sensitivity

 Distribution to the site of infection (pharmacokinetic phase)

 Favourable environmental conditions (pharmacodynamic phase)

 Client compliance

Client compliance

There is little published data on patient (client) compliance in veterinary medicine but some guidelines exist from human studies and unpublished work. Studies have shown that a substantial proportion of human patients comply poorly with drug therapies prescribed by physicians. Limited observations suggest non-compliance is also prevalent in veterinary medicine: in two canine studies, only 27% of owners gave the prescribed number of doses during short term antibiotic treatment. Underdosing and dosing at sub-optimum intervals were common problems, but overdosing also occurred.

Compliance is influenced by:

 Vet/client communications--failure by the veterinarian to explain why drug is prescribed often results in failure of THE client to appropriately medicate the patient

 Imprecise or illegible dosage instructions

 Physical characteristics of medication e.g., large pills are very difficult to give to cats and small dogs. Brachycephalic breeds may be particularly difficult to pill for an owner.

 Frequency of dosage and duration of therapy

Undesirable consequences of poor compliance include inadequate response to treatment, increased costs and creation of doubts in the mind of the client about the effectiveness of both the drug and the clinician.

Potential difficulties with compliance should be addressed by scheduling administration to suit the owners' routines where possible, deciding with the owners the dosage form they can best manage, demonstrating its use, and providing clear verbal and written instructions.

Human studies have shown that the risk of missed doses increases with treatment complexity. Accordingly, if no therapeutic difference exists between several alternative treatments, the one with the least complex regimen should be chosen. Likewise, additional medications of questionable value are best avoided, because complicated treatment schedules could reduce the owners' ability to comply with the regimens recommended for the more important drugs.

FACTORS INFLUENCING THE CLINICIAN'S CHOICE OF ANTIBACTERIAL DRUG

Key questions

Always consider:

 Is a bacterial infection confirmed or probable?

 Can you predict the type of infection and sensitivity pattern?

 Are there any special considerations re tissue penetration?

 Are there any potential side effects of concern?

 Is a culture and sensitivity indicated?

Nosocomial infections

In veterinary hospitals, nosocomial infection (infection acquired during hospitalisation) by resistant bacteria is an emerging problem although it is not as serious as the current situation in human hospitals. Klebsiella spp, E. coli, Proteus and Pseudomonas spp have been associated most frequently with veterinary nosocomial infections.

Age (young or old), severity of disease, duration of hospitalisation, use of invasive support systems, surgical implants, defective immune responses and previous use of antibacterial agents predispose to nosocomial infections.

The antibacterials with the greatest potential to suppress endogenous flora that normally keep pathogenic enteric bacteria in check are broad spectrum drugs particularly those that are relatively poorly absorbed from the GI tract or are excreted via the bile. These include orally administered broad spectrum penicillins, tetracyclines and chloramphenicol as well as lincosamides (which have a narrow spectrum but are excreted in bile). Antibacterial agents that in general do not have this effect include cephalosporins, aminoglycosides (parenteral), trimethoprim sulphas and sulphonamides.

Prophylactic antibiotics in surgery

 Prophylactic antibiotics in surgery are not indicated for routine, clean surgery where no inflammation is present, the gastrointestinal or respiratory systems have not been invaded, and aseptic technique has not been broken.

 Prophylactic antibacterial therapy is indicated after dental procedures in which there has been bleeding (almost all), patients with leucopoenia (viral, drug induced), contaminated surgery and surgery where either the consequences of infection would be disastrous (orthopaedic) or there is major tissue trauma (major thoracic and abdominal surgery).

 If prophylactic antibacterial agents are used, they should be administered before the procedure so that adequate levels are present in blood and tissue at the time of surgery to achieve maximum effect the drug must be present in the wound at the time of bacterial contamination.

 The prophylactic advantages of antibacterial therapy are minimal if therapy is commenced any later then 3-5 hours after contamination. Intravenous administration 20-30 minutes prior to surgery is currently recommended.

 Therapy is not usually continued for longer than 24 hours postoperatively and in some institutions, a postoperative dose of antibiotic is only administered if the surgery time is greater than 90 minutes.


 

Table 1. Actions and indications of drugs used systemically against bacterial pathogens

Division into bactericidal and bacteriostatic groups is based on in vitro activity. The distinction is not absolute and may vary with drug concentration and bacterial species

DRUG GROUP Action

Individual drugs

Aerobes and facultative anaerobes

Obligate anaerobes

Other

   

Staphylococci producing
ß lactamase

Other Gram Positive
Organisms

Gram Negative Organisms

   

Penicillins

Amoxicillin, ampicillin

--------

xxxx

xx

xxxx

 

bactericidal

Amoxicillin clavulanate

xxxx

xxxx

xxx

xxxx

 

 

Carbenicillin

--------

--------

xxxx

--------

 

 

Cloxacillin, flucloxacillin, oxacillin

xxxx

--------

--------

xx
variable

 

 

Penicillin G
(benzylpenicillin)

--------

xxxx

--------

xxxx

 

 

Penicillin V
(phenoxy
methylpenicillin)

--------

xxxx

--------

xxxx

 

 

Ticarcillin,
Ticarcillin-clavulanate

--------

--------

xxxx

xxxx

 

Cephalosporins,

Cephamycins
bactericidal

Oral cephalosporins
Cefadroxil,
cephalexin

xxxx

xxxx

xx

xx
unpredictable

 

 

Parenteral
group I - cefazolin

xxxx

xxxx

xx

xx

 

 

group II - ceftiofur

xxxx

xxxx

xxxx

xx

 

 

group III - cefoperazone

xx

xx

xxxx

xx

 

 

group IV - cefoxitin

xx

xx

xx

xxxx

 

Aminoglycosides bactericidal

Gentamicin,
(dihydro)streptomycin
kanamycin,
spectinomycin,
tobramycin, amikacin

xxxx (but resistance emerges
during treatment)

--------

xxxx

--------

 

 

DRUG GROUP
Action

Individual drugs

Aerobes and facultative anaerobes

Obligate anaerobes

Other

   

Fluoroquinolones
bactericidal

Ciprofloxacin,
enrofloxacin,
marbofloxacin,
norfloxacin, etc

xxxx

xxxx

xxxx

--------

Mycobacteria,
Brucella,
Mycoplasma,
Chlamydia,
Rickettsia

Lincosamides
bacteriostatic

Lincomycin,
clindamycin

xx variable
resistance

xxxx

--------

xxxx

Toxoplasma
(clindamycin)

Macrolides
bacteriostatic

Erythromycin,
spiramycin,
tylosin

xx variable
resistance

xxxx

--------

xxxx

Mycoplasma

Potentiated
Sulphonamides
bactericidal

Various
sulphonamides with
baquiloprim,
ormetoprim or
trimethoprim

xx

xx

xx

xx

Toxoplasma,
Neospora,
Isospora,
Coccidia

Sulphonamides
alone
bacteriostatic

Sulphadimidine,
sulphamethoxy-

xx

xx

xx

xx

Toxoplasma,
Neospora,
Isospora,
Coccidia

Tetracyclines
bacteriostatic

Doxycycline, oxytetracycline
etc.

xxxx

xx

xx

xx

Mycoplasma,
Rickettsia,
Chlamydia,
Borrelia,
Haemabartonella

Polymyxins
bactericidal

Colistin
(polymyxin E),
polymyxin B

--------

--------

xxxx

--------

 

Miscellaneous

 

 

 

 

 

 

bacteriostatic

Chloramphenicol

xxxx

xxxx

xx

xxxx

Chlamydia,
Rickettsia

bactericidal

Metronidazole

-------

--------

--------

xxxx

 

Division into bactericidal and bacteriostatic groups is based on in vitro activity. The distincition is not absolute and may vary with drug concentration and bacterial species.

Table 2. Physicochemical properties of antimicrobial drugs and effects on tissue distribution

(from Watson, A.D.J., Maddison J.E. and Elliott J. Antibacterial Drugs. In: Canine Medicine and Therapeutics, Gorman N.T. (ed). (1998). Blackwell, pp. 53-72)

Polar (hydrophilic) drugs of low lipophilicity

Drugs of moderate to high lipophilicity

Highly lipophilic molecules with low ionisation

Acids

Bases

Weak acids

Weak bases

Amphoteric

 

Penicillins
Cephalosporins
Beta lactamase
inhibitors

Polymixins
Aminoglycosides

Sulphonamides

Trimethoprim
Lincosamides
Macrolides

Tetracyclines
-tetracycline
-chlortetracycline
-oxytetracycline

Chloramphenicol
Fluoroquinolones
Lipophilic
tetracyclines
-doxycycline
Metronidazole
Rifampin

These drugs:

 Do not readily penetrate "natural body barriers" so that effective concentrations in CSF, milk and other transcellular fluids will not always be achieved.

 Adequate concentrations may be achieved in joints, pleural and peritoneal fluids

 Penetration may be assisted by acute inflammation

 Weak acids (penicillins, cephalosporins) may diffuse into prostate in small concentrations but easily diffuse back to the plasma

These drugs:

 Cross cellular membranes more readily than polar molecules so enter transcellular fluids to a greater extent.

 Weak bases will be ion trapped (concentrated) in fluids that are more acidic than plasma e.g., prostatic fluid, milk, intracellular fluid if lipophilic enough to penetrate (e.g., erythromycin)

 Penetration into CSF and ocular fluids is affected by plasma protein binding as well as lipophilicity-sulphonamides and trimethoprim penetrate effectively whereas macrolides, lincosamides and tetracyclines do not.

 Tetracyclines do not achieve high concentrations in prostate after systemic administration

These drugs:

 Cross cellular barriers very readily

 Penetrate into difficult transcellular fluids such as prostatic fluid and bronchial secretions.

 However chloramphenicol and tetracyclines do not achieve high concentrations in prostate after systemic administration

 All penetrate into CSF except tetracyclines and rifampin

 All penetrate into intracellular fluids

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Jill E. Maddison
Royal Veterinary College
London, UK


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