Choice of an Antimicrobial Agent

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Chapter: Essential pharmacology : Antimicrobial Drugs: General Considerations

After having established the need for using a systemic AMA in a patient by assessing that the condition is due to a treatable (mostly bacterial) infection, and that it is not likely to resolve by itself or by local measures (antiseptics, drainage of pus, etc) only, one has to choose a drug from the large number available.



After having established the need for using a systemic AMA in a patient by assessing that the condition is due to a treatable (mostly bacterial) infection, and that it is not likely to resolve by itself or by local measures (antiseptics, drainage of pus, etc) only, one has to choose a drug from the large number available. The choice depends on the peculiarities of the patient, the infecting organism and the drug.


Patient factors


1. Age may affect kinetics of many AMAs. Conjugation and excretion of chloramphenicol is inefficient in the newborn: larger doses produce gray baby syndrome. Sulfonamides displace bilirubin from protein binding sites—can cause kernicterus in the neonate because their bloodbrain barrier is more permeable. The t½ of aminoglycosides is prolonged in the elderly and they are more prone to develop VIII nerve toxicity. Tetracyclines deposit in the developing teeth and bone—discolour and weaken them—are contraindicated below the age of 6 years.


2. Renal And Hepatic Function Cautious use and modification of the dose of an AMA (with low safety margin) becomes necessary when the organ of its disposal is defective (see box).



3. Local Factors The conditions prevailing at the site of infection greatly affect the action of AMAs.


(a) Presence of pus and secretions decrease the efficacy of most AMAs, especially sulfonamides and aminoglycosides. Drainage of the abscess reduces the population of the causative bacteria, suppresses anaerobes by exposure to oxygen, and improves diffusion of the antibiotic into the abscess.


(b) Presence of necrotic material or foreign body makes eradication of infection practically impossible.


(c) Haematomas foster bacterial growth; tetracyclines, penicillins and cephalosporins get bound to the degraded haemoglobin in the haematoma.


(d) Lowering of pH at the site of infection reduces activity of macrolide and aminoglycoside antibiotics.


(e) Anaerobic environment in the centre of an abscess impairs bacterial transport processes which concentrate aminoglycosides in the bacterial cell, rendering them less susceptible.


(f) Penetration barriers may hamper the access of the AMA to the site of infection in subacute bacterial endocarditis (SABE), endophthalmitis, prostatitis. However, trimethoprim and fluoroquinolones attain high concentration in prostate due to ion trapping.


4. Drug Allergy History of previous exposure to an AMA should be obtained. If a drug has caused allergic reaction —it has to be avoided in that patient, e.g. drug of choice for syphilis in a patient allergic to penicillin is tetracycline.

βlactams, sulfonamides, fluoroquinolones and nitrofurantoin frequently cause allergy.


5. Impaired Host Defence Integrity of host defence plays a crucial role in overcoming an infection. Pyogenic infections occur readily in neutropenic patients, while if cellmediated immunity is impaired (e.g. AIDS), infections by low grade pathogens and intracellular organisms abound. In an individual with normal host defence, a bacteriostatic AMA may achieve cure; while intensive therapy with cidal drugs is imperative in those with impaired host defence (conditions given on p. 672) or when the organisms are protected by a barrier—as in SABE. Even then complete eradication of the organism may not occur.


6. Pregnancy All AMAs should be avoided in the pregnant because of risk to the foetus. Penicillins, many cephalosporins and erythromycin are safe, while safety data on most others is not available. Therefore, manufacturers label ‘contraindicated during pregnancy’. Tetracyclines carry risk of acute yellow atrophy of liver, pancreatitis and kidney damage in the mother. They also cause teeth and bone deformities in the offspring. Aminoglycosides can cause foetal ear damage. Animal studies indicate increased risk to the foetus, especially with fluoroquinolones, cotrimoxazole, chloramphenicol, sulfonamides and nitrofurantoin. Though metronidazole has not been found teratogenic, its mutagenic potential warrants caution in its use during pregnancy.


7. Genetic Factors Primaquine, nitrofurantoin, sulfonamides, chloramphenicol and fluoroquinolones are likely to produce haemolysis in G6PD deficient patient.


Organism-Related Considerations


Each AMA has a specific effect on a limited number of microbes. Successful chemotherapy must be rational and demands a diagnosis. However, most of the time, definitive bacteriological diagnosis is not available before initiating treatment. Bacteriological testing is time consuming, expensive and appropriate samples of infected material for bacteriology may not be obtainable. A clinical diagnosis should first be made, at least tentatively, and the likely pathogen guessed. The following line of action may be taken:


1. Clinical Diagnosis Itself Directs Choice Of The AMA The infecting organism and its sensitivity are not variable, e.g. syphilis, chancroid, diphtheria, tetanus, plague, cholera, trachoma thrush, tuberculosis, lobar pneumonia, leprosy, amoebiasis, herpes simplex, etc.


2. A Good Guess Can Be Made from the clinical features and local experience about the type of organism and its sensitivity: tonsillitis, otitis media, boils, vaginitis, urethritis; the most appropriate specific AMA should be prescribed and the response watched for. A gram stained smear examination of infected material may help to aid the choice.


3. Choice To Be Based On Bacteriological Examination No guess can be made about the infecting organism or its sensitivity, e.g. bronchopneumonia, empyema, meningitis, osteomyelitis, urinary tract infection, wound infection, etc. In these situations, an AMA should be selected on the basis of culture and sensitivity testing; but this may not be always possible.


a) Bacteriological services not available: empirical therapy to cover all likely organisms with a broadspectrum drug like fluoroquinolone, tetracycline or a combination such as penicillin + streptomycin or gentamicin + a cephalosporin may be used (with metronidazole if anaerobes are suspected). Further therapy is modified on the basis of clinical response; but hasty and arbitrary changes in therapy should be avoided.


b) Bacteriological services available, but treatment cannot be delayed: as in serious infections like meningitis, septicaemias, etc., specimens for bacteriological examination should be sent and empirical therapy started provisionally as in (a). In case of inadequate response, the AMA should be changed later in the light of bacteriological findings.


c) Bacteriological services are available and treatment can be delayed for a few days: as in chronic urinary tract infection; it is better to wait for the culture and sensitivity report; start definitive therapy thereafter.


Bacteriological Sensitivity Testing


This is generally done by diskagar diffusion method using standardized concentrations of antibiotics based on clinically attained plasma concentrations of these. As such, they serve only as guides and cannot be blindly extrapolated to the clinical situation in every patient and for every organism. Broth cultures with breakpoint concentration (concentration that demarcates between sensitive and resistant bacteria) of antibiotics probably yield more reliable results. Breakpoint concentrations are based on clinically attainable serum concentrations of the antibiotic.


Minimum inhibitory concentration (MIC), i.e the lowest concentration of an antibiotic which prevents visible growth of a bacterium determined in microwell culture plates using serial dilutions of the antibiotic is more informative, but not estimated routinely.


Minimum bactericidal concentration (MBC), of the antibiotic is determined by subculturing from tubes with no visible growth. If the organism is killed, no growth will occur; but if it was only inhibited in the parent culture—it will grow on subculturing in antibioticfree medium. MBC is the concentration of the antibiotic which kills 99.9% of the bacteria. A small difference between MIC and MBC indicates that the antibiotic is primarily bactericidal, while a large difference indicates bacteriostatic action. MBC is not used to guide selection of antibiotics in clinical practice.


Post-antibiotic effect (PAE) After a brief exposure if the organism is placed in antibioticfree medium, it starts multiplying again, but after a lag period which depends on the antibiotic as well as the organism. This lag period in growth resumption is known as ‘post-antibiotic effect’ and is the time required for re-attainment of logarithmic growth. A long PAE has been noted with fluoroquinolones, aminoglycosides and βlactam antibiotics.


Drug Factors


When any one of a number of AMAs could be used to treat an infection, choice among them is based upon specific properties of these AMAs:


1. Spectrum Of Activity: For definitive therapy, a narrow-spectrum drug which selectively affects the concerned organism is preferred, because it is generally more effective than a broad-spectrum AMA, and is less likely to disturb the normal microbial flora. However, for empirical therapy, often a broad-spectrum drug has to be used to cover all likely pathogens.


2. Type Of Activity: Many infections in patients with normal host defence respond equally well to bacteriostatic and bactericidal AMAs. But several acute infections resolve faster with a cidal than a static drug, because the cidal drug directly reduces the number of bacteria at the site of infection, while the static drug only prevents increase in their number. Many bactericidal drugs exert prolonged post-antibiotic effect so that maintenance of drug level continuously above the MIC is not essential. With bacteriostatic AMAs the bacteria start multiplying quickly when drug level falls below the MIC, resulting in relapse of infection.


A bactericidal antibiotic is clearly superior to bacteriostatic one in treating patients with impaired host defence, life-threatening infections, infections at less accessible sites (SABE) or when carrier state is possible (typhoid).


3. Sensitivity Of The Organism: assessed on the basis of MIC values (if available) and consideration of postantibiotic effect.


4. Relative Toxicity: Obviously, a less toxic antibiotic is preferred, e.g. a βlactam over an aminoglycoside or erythromycin over clindamycin.

5. Pharmacokinetic Profile: For optimum action the antibiotic has to be present at the site of infection in sufficient concentration for an adequate length of time. This depends on their pharmacokinetic characteristics. Most antibiotics are given at 2 to 4 halflife intervals—thus attaining therapeutic concentrations only intermittently. For many organisms, aminoglycosides and fluoroquinolones produce ‘concentration-dependent inhibition’—inhibitory effect depends on the ratio of peak concentration to the MIC; the same daily dose of gentamicin produces better action when given as a single dose than if it is divided into 2–3 portions. On the other hand, βlactams, glycopeptides and macrolides produce ‘time-dependent inhibition’—antimicrobial action depends on the length of time the concentration remains above MIC; division of daily dose has better effect. However, the doses should be so spaced that the surviving organisms again start multiplying and a cidal action is exerted.


Penetration to the site of infection also depends on the pharmacokinetic properties of the drug. A drug which penetrates better and attains higher concentration at the site of infection is likely to be more effective. The fluoroquinolones have excellent tissue penetration—attain high concentrations in soft tissues, lungs, prostate, joints, etc. Ciprofloxacin and rifampin have very good intracellular penetration. Cefuroxime, ceftriaxone, chloramphenicol, ciprofloxacin attain high CSF concentration. On the other hand, penicillins and aminoglycosides penetrate poorly into CSF unless meninges are inflamed. Ampicillin, cephalosporins and erythromycin attain high biliary concentration.


6. Route Of Administration: Many AMAs can be given orally as well as parenterally, but aminoglycosides, penicillin G, carbenicillin, many cephalosporins, vancomycin, etc. have to be given by injection only. For less severe infections, an oral antibiotic is preferable; but for serious infections, e.g. meningitis, spreading cellulitis, septicaemias, a parenteral antibiotic may be chosen.


7. Evidence Of Clinical Efficacy: Relative value of different AMAs in treating an infection is decided on the basis of comparative clinical trials. Optimum dosage regimens and duration of treatment are also determined on the basis of such trials. Reliable clinical trial data, if available, is the final guide for choice of the antibiotic.


8. Cost: Less expensive drugs are to be preferred.


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