To make the selection of most appropriate antimicrobial agent following factors should be taken into account.
1. Pharmacokinetics:
Although the knowledge of in vitro sensitivity test helps to great extent in selecting antibiotic but it is not the only factor to be considered. Actually success of therapy depends upon achieving minimal drug conc. approximately equal to MIC at the site of infection without causing significant toxicity to the host. However there is evidence to suggest that even sub inhibitory drug concentrations are effective because of PALE. Although such observation may explain why some infections are cured even when inhibitory conc. are not achieved. It should be objective of antimicrobial therapy to maintain the antimicrobial drug conc. at site of action during dosing interval.
This can be achieved only by full understanding and following the principles of pharmacokinetics and pharmacodynamics. Thus application of all such principles is essential to achieve success of an antibiotic therapy.
2. EFFECT OF SITE OF INFECTION ON THERAPY:
Adequate levels of antibiotics must reach the site of infection in order to eradicate microorganisms effectively. Natural barriers may hamper the penetration of drugs in certain tissues. The example of such situation can be summarized as under.
(A) Blood Brain Barrier:
If the infection is in CSF, the drug must pass Blood Brain Barrier. Many antibiotics are polar at physiological pH and can cross Blood Brain Barrier poorly. The concentration of Penicillin & Cephalosporin in CSF is only 0.5-5.0% of plasma steady state concentration. However, the integrity of BBB is diminished in the inflammatory condition due to active bacterial infection.
This change (tight junctions cerebral capillary open) leads to a marked increase in the penetration of even polar drugs into CSF. As the condition improves inflammation diminishes and permeability returns to normal. This may occur in presence of some viable microorganisms in CSF. Thus drug dosage should not be decreased till the CSF is presumed or proven to be sterile.
(B) Plasma Protein Binding (PPB):
Almost in majority of cases, penetration of drug into infected loci always depends on passive diffusion. The rate of diffusion is proportional to conc. of free drug (unbound) in the plasma/extra cellular fluid. Thus drug extensively bound to plasma protein may penetrate poorly as compared to unbound drug. Consequently highly plasma protein bound drug may have lesser activity.
(C) Prostate Infection:
Bacterial prostatitis is difficult to cure because many antibiotics fail to cross prostatic epithelium and don’t reach prostatic fluid and tissues. Moreover pH of prosthetic fluid is 6.4 in comparison to plasma 7.4. Thus this factor should be taken into account before selecting the proper antibiotic. Trimethoprim, which is a component of Co-trimoxazole (trimethoprim + sulphamethoxazole), is effective in treating prostatitis.
(D) Maintenance Of MIC At The Site Of Infection:
It sounds reasonable that an attempt may be made to achieve antibiotic activity at the site of infection during the dosage interval. However controversy exists whether the therapeutic effect obtained from relatively constant antibacterial activity is superior to that obtained from high peak conc. followed by periods of sub inhibitory activity. To some extent, it depends upon whether the antimicrobial agent exhibits conc. dependent or time dependent growth inhibition/killing e.g. the activity of B-lactam antibiotics is time dependent where that of aminoglycosides is concentration dependent. Experimental data in animals with Meningitis suggests that the pulse dosing (intermittent dosing) with B-lactam antibiotics is more efficacious (equivalent efficacy from less drug). On the other hand, the data suggests that Aminoglycosides are at least as efficacious and are less toxic, when given in large daily dose in comparison to when given more frequently.
Clinical studies have also shown that continuous administration of aminoglycosides may cause un-necessary toxicity.
The knowledge of status of individual patients and mechanism of elimination of drug is essential to be known in case of drugs causing serious toxicity.
Doses of drug should be carefully adjusted in patients with impaired renal or hepatic functioning. The dose regimen should be strictly determined depending upon whether the drug exhibits time dependent or conc. dependent killing.
3. ROUTE OF ADMINISTRATION:
Whenever possible, oral route is preferred. However, in seriously ill patients, parental administration becomes necessary to achieve plasma therapeutic level without delay. For obtaining maximum therapeutic effectiveness, all the factors governing the choice of route of administration and merits and demerits of the route of administration for the individual drug should be followed strictly.
4. HOST FACTORS OR STATUS OF PATIENT:
Innate host factors which apparently seen not to be related to infection being treated are prime determinants of the type of antimicrobial, its dose regimen and toxicity and expected therapeutic out come. Such factors are as under:
(a) Renal Dysfunction:
Impairment of renal function may lead to the accumulation of those antibiotics, which are mainly eliminated by kidneys. This may results into serious adverse effects if appropriate dose adjustments are not made. Care must be taken in case of using aminoglycosides, Vancomycin or Fluocytosin in patients with renal impairment b/c these drugs are exclusively eliminated by renal mechanism. The number of functional neurons decreases with age and elderly people are especially vulnerable to accumulation of drugs eliminated by kidneys.
(b) Hepatic Dysfunction:
For drugs that are concentrated, metabolized or excreted by liver (Erythromycin, Chloramphenicol, Metronidazole, Tetracycline’s), dose must be reduced in patients with hepatic failure or hepatic dysfunction. In liver cirrhosis the half-life of Rifampin and Isoniazid are prolonged significantly. Infection of the biliary tract or biliary obstruction may cause reduced access of the drugs to the site of infection.
(c) Age:
Hepatic metabolism and renal excretion mechanism are poorly developed in newborn babies especially in premature infants. Improper adjustment in dose in such cases may lead to serious consequence e.g. Gray baby syndrome is caused by Chloramphenicol. Elderly people are also prone to toxic effects of those drugs, which are eliminated by hepatic or renal mechanism since these mechanisms are less functional as compared to adult age.
Developmental factors are also primary determinants of type of antibiotic used. As tetracycline bind avidly to developing teeth and bones, there use in children may lead to retardation of bone growth, discoloration or hypoplasia of tooth enamel. Similarly Fluoroquinolones can accumulate in cartilage of young bones and may retard the growth of cartilage.
Achlorhydria: Decreased secretion of HCl in elderly patients & children may alter the absorption of orally administered antibiotics e.g. increase absorption of penicillin G and decrease absorption of Ketoconazole.
(d) Pregnancy:
Antibiotics easily crosses placental barrier and may effect the fetus e.g. hearing loss in children may be associated with Streptomycin therapy given to the mothers during pregnancy.
Tetracycline administration in pregnant females can affect the growth of bones and teeth of fetus. Pregnancy can also alter the pharmacokinetics of different antibiotics specially females undergoing first time pregnancy.
(e) Lactation:
Drugs administration to lactating mothers may enter the nursing infants via breast milk though the conc. of drug excreted in milk is small but may be adequate to cause serious problems in babies e.g. nalidixic acid (Quinolones) & Sulfonamides secreted in milk may cause hemolysis in children with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides through breast milk may predispose the nursing child to kernicterus.
“Kernicterus” is a condition with severe neural symptoms associated with high level of Bilirubin in the blood.
(f) Drug Allergy:
B-lactam derivatives and their degradation products are notorious for provoking allergic reactions. Patients with history of allergy are more susceptible to allergic reactions thus the patient must be interrogated and tested before prescribing anti microbial.
Drug- induced fever should not be mistaken for a sign of continued infection.
(g) Host Defense Mechanism:
The functional state of host defense mechanism is critical determinants of therapeutic effectiveness of antimicrobial. Both humoral and cellular immunity are important. Frequently infection may be successfully treated with bacteriostatic agents in immuno-competent hosts whereas bactericidal drugs are needed to cure the infection in individuals whose defense mechanisms are impaired e.g. endocarditis, where phagocytic cells are excluded from the infected site and bacterial meningitis, where phagocytic cells are ineffective b/c of lack of opsonins.
The most striking example is of AIDS patient having impaired immune response. The therapy of various opportunistic infections in AIDS patients is usually suppressive but not curative. Most AIDS patients respond to conventional therapy for bacteremia i.e. presence of bacteria in blood, due to salmonella but relapse of infection occurs even after prolonged treatment.
(h) Disorders of Nervous System:
Patients having disorders of nervous system are more vulnerable to the risk of localized or major seizures while taking high doses of penicillin G. Neurotoxicity of B-lactam antibiotics correlates well with high conc. of drugs in CSF and this usually occurs in patients with impaired renal and hepatic functions.
5. LOCAL FACTORS:
Local factors at the site of action may greatly influence the effectiveness of anti microbial in curing the disease.
Pus (consisting of phagocytes, cellulose, debris, fibrin protein, micro organisms) reduces the antibacterial action of aminoglycosides by binding to them. Large accumulation of hemoglobin in infected haematomas can bind to penicillin and tetracycline and may reduce their activity. The acid pH of abscess cavities results in a marked loss of antibacterial action of Aminoglycosides, Erythromycin. However drugs like Chlortetracycline and nitrofurantoin show more activity in such acidic condition. Penetration of antibiotics into infected areas like abscess cavities are impaired b/c the vascular supply is reduced. Successful therapy of abscesses usually requires drainage. The presence of foreign bodies in the infected area is another important factor that decreases the probability of successful therapy. This factor has become extremely important in the present era of prosthetic cardiac valves, prosthetic joints pace makers, vascular prosthesis and various vascular and CNS shunts.
The phagocytic cells perceive the prosthesis as foreign body and in an attempt to phagocytize and destroy them; degranulation of phagocytes occurs. This results in the depletion of intra cellular bactericidal substance. Thus phagocytes become relatively ineffective in killing pathogens. Rather pathogens may live in these cells being protected from most antimicrobial agents furthermore microbes may attach to foreign bodies with help of glycocalyx substrate and microbes embedded in this substrate are relatively resistant to the action of most antibiotics. Infections involving foreign bodies are characterized by frequent relapses and failure even after long-term therapy with long dose. The success in such situation lies in removal of foreign body.
6. COST OF THERAPY:
Very often, several drugs show the similar efficacy in treating an infection but they may vary greatly in cost. Sometimes there are many fold differences in the prices of different brands of the same drug. Thus cost of therapy may be taken into account, after accessing the socioeconomic status of patient, before making the final decision.
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