Chemotherapy of Infections

·        Classification.

·        Mechanisms of action.

·        Principles of antimicrobial chemotherapy.

·        Use of antimicrobial drugs.

·        Chemprophylaxis in surgery.

Classification

1.       Antimicrobial: drugs that have antibacterial, antiviral or antifungal activity whether they are of natural or semisynthetic or purely synthetic origin.

2.       Differences between bacterial and human cells:

a.    Cell wall: bacterium has a rigid cell wall that is absent from human cell which maintains its shape and protects it from osmotic damage in water and body fluids.

b.       Ribosomes: bacteria have 70S ribosomes whereas human cells have 80S ribosomes.

c.    Folic acid metabolism: human cell cannot synthesize folic acid whereas some bacteria utilizes para-aminobenzoic acid for the synthesis of folic acid and cannot utilize exogenous source of folic acid.

3.    An ideal antimicrobial drug should possess selective toxicity, i.e. it is toxic to the parasite but not to the host.

4.       Effects on microbes:

a.       Bacteriostatic: those that act primarily by arresting bacterial growth, e.g. tetracyclines and chloramphenicol.

b.       Bactericidal: those which act primarily by killing bacteria, e.g. aminoglycosides, cephalosporins.

c.    Most bacteriostatic drugs are bactericidal at high concentrations.

d.       Bactericidal drugs act most effectively on rapidly dividing organisms; thus a bacteriostatic drug by reducing multiplication, may protect the organism from a bactericidal drug.

Mechanism of action

Principles of Antimicrobial chemotherapy

1.       Make a diagnosis as precisely as possible, defining the:

a.    site of infection.

b.    the organism(s) responsible.

c.    their sensitivity to drugs.

2.       Remove barriers to cure:

a.    lack of free drainage of abscesses.

b.       obstruction in the urinary or respiratory tracts.

3.       Decide whether chemotherapy is really necessary:

a.       acute infections require chemotherapy whilst chronic infections may not.

b.    even some acute infections such as gastroenteritis are better managed asymptomatically than by antimicrobials.

4.       Select the best drug – this involves consideration of:

a.       Specificity: antimicrobial activity of drug should match that of infecting organisms.

b.       Pharmacokinetic factors: ensure the chosen drug is capable of reaching the site of infection in adequate amounts, e.g. by crossing the blood-brain barrier.

c.       Patient: previous allergy or whose routes of elimination may be impaired, e.g. by renal disease.

5.       Administer the drug in optimum dose and frequency and by the most appropriate route(s):

a.       Inadequate dose may encourage the development of microbial resistance.

b.    In general, intermittent dosing is preferred to continuous infusion.

c.       Plasma monitoring can be applied to optimize therapy.

6.       Continue therapy until apparent cure has been achieved; most acute infections are treated for 5 – 10 days.

7.    Test for cure: in some infections, microbiological proof of cure is desirable because disappearance of symptoms occurs before the organisms are eradicated; e.g. urinary tract infection.

8.       Prophylactic chemotherapy:

a.    for surgical and dental procedures should be of limited duration.

b.    it should start at the time of surgery to reduce the risk of producing resistant organisms prior to surgery.

Use of antimicrobial drugs

1.       Choice:

a.       Selection of antimicrobials should be based on identification of the microbe and sensitivity tests.

b.       Choice of antimicrobial follows from the clinical diagnosis.

2.       When the infecting organism is not identified by clinical diagnosis, choice of an antimicrobial may be guided by:

a.       Knowledge of the likely pathogens in the clinical situation.

b.       Simple staining tests: the antimicrobial may be selected in the knowledge that the organism is a Gram-positive or Gram-negative coccus or bacillus.

c.       Modification of treatment can be made later if necessary, in the light of culture and sensitivity tests.

2.       Indications for combinations:

a.       Avoid development of drug resistance especially in chronic infections, e.g. tuberculosis.

b.       Broaden the spectrum of antibacterial activity in a known mixed infection, e.g. peritonitis following gut perforation or where the infecting organism cannot be predicted but treatment is essential before a diagnosis is reached.

c.       Obtain potentiation, i.e. an effect unobtainable with either drug alone, e.g. penicillin plus gentamicin for enterococcal endocarditis.

3.       Selection of agents:

a.    A bacteriostatic drug, by reducing multiplication, may protect the organism from a bactericidal drug.

b.       When a combination must be used blind, it is preferable to use two bacteriostatic or two bactericidal drugs.

4.       Chemoprophylaxis: use of a drug in a healthy person to prevent infection by one organism of uniform susceptibility, e.g. benzylpenicillin against a group A streptococcus.

5.       Categories of chemoprophylaxis:

a.       Prevention of infection: rheumatic fever, recurrent urinary tract infection.

b.       Prevention of opportunistic infections, e.g. due to commensals getting into the wrong place – bacterial endocarditis after dentistry and peritonitis after bowel surgery.

c.       Suppression of existing infection before it causes overt disease, e.g. tuberculosis, malaria.

d.       Prevention of exacerbations of a chronic infection, e.g. bronchitis, in cystic fibrosis.

e.       Prevention of spread amongst contacts: spread of influenza A can be partially prevented by amantadine.

6.       Prophylaxis of bacterial infection can be achieved often by doses that are inadequate for therapy.

7.       Indications for chemoprophylaxis in surgery:

a.    Risk of infection is high because of the presence of large numbers of bacteria in the viscus which is being operated on.

b.    Risk of infection is low but consequences of infection would be disastrous, e.g. insertion of prosthetic joints or heart valves.

c.       Patient is susceptible to infection, e.g. immunocompromised.

8.       Antimicrobials should be given i.v., i.m. or rectally at the beginning of anaesthesia and for no more than 48h:

a.       Colorectal surgery: high risk of infection with E.coli, clostridia and bacteroides which inhabit the gut.

b.       Gastroduodenal surgery: for colonization of the stomach with gut organisms.

c.       Gynaecological surgery: the vagina contains bacteroides, streptococci, coliforms and anaerobes.

d.    Leg amputation: risk of gas gangrene in an ischaemic limb and the mortality is high.

e.       Insertion of prosthetic joints: infection means that artificial joint must be replaced.

Antimicrobial resistance

1.       Mechanism of resistance:

2.       Origin of drug resistance:

a.       Naturally resistant strains: in the course of therapy, the naturally sensitive strains are eliminated and those naturally resistant proliferate and occupy the biological space created by the drug.

b.       Chromosomal mutation: random event and the resultant alteration in bacteria is usually specific for a single drug or class of drugs.

c.       Extrachromosomal: transfer of genes for resistance to one or several antimicrobial drugs via plasmids from other microbes.

3.       Limitation of resistance to antimicrobials:

a.       Avoid indiscriminate use by ensuring that the indication for, the dose and duration of treatment are appropriate.

b.       Using antimicrobial combinations in appropriate circumstances.

c.       Constant monitoring of resistance patters in a hospital or community, and outbreak control to prevent spread of resistant bacteria.

4.       Consequences of resistance:

a.       Choice of antimicrobial agents for treatment of an infection due to resistant strain of bacteria becomes limited.

b.    More toxic and expensive alternative drugs have to be used.