This is a fairly common topic, but it is such an important one, that the emphasis can not be reduced. The coming era will see different classes of antimicrobials, and they will replace the old ones, why ? because of resistance. The microbes have been on this planet before us and they are going to be here for a much longer time than us whether we like it or not. It’s no surprise that the mechanisms these tiny creatures develop outclasses us everytime.
We will cover this chapter in parts due to its high volume.
It can be natural or acquired, development of resistance may be due to single step mutation ( as observed with streptomycin and rifampicin) or multi step mutation
(erythromycin, tetracycline and chloramphenicol ).
It can be via – Conjugation, Transduction, Transformation.
Conjugation– it is due to physical contact between bacteria and is responsible for multidrug resistance. Chloramphenicol and Streptomycin resistance is developed through this.
Transduction– it is a transfer of a resistance gene through bacteriophage- a virus that can kill a bacteria or consume it. eg- staph aureus
Transformation– It is a transfer of resistance gene through the environment and is not very significant clinically. eg- penicillin G.
Resistance once acquired becomes prevalent due to selection pressure of a widely used antimicrobial agent- i.e antimicrobials allow resistant organisms to grow preferentially.
Mechanisms of resistance
Decreased affinity for the target- eg pneumoccocci and staphyloccocci may develop altered penicillin binding proteins
Altered metabolic pathway– sulfonamides resistant organisms start utilizing preformed folic acid in place of synthesizing it from PABA.
Elaboration of the enzymes which inactivate the drug– eg beta lactamases (pencillins and cephalosporins), chloramphenicol acetyl transferases (chloramphenicol) and aminoglycoside inactivating enzymes (aminoglycosides).
Decreased drug permeability– when there is a loss of specific channels there can be a decrease in the movement of the drug molecules, aminoglycosides and tetracyclines attain much lower drug concentrations in the resistant organisms than in the sensitive organisms.
Efflux pump – this mechanism can cause active extrusion of the drug from the resistant organisms (tetracyclines, erythromycin, fluoroquinolones)
Another reason to worry is when there is an appearance of infection as a result of antimicrobial therapy, the broad spectrum antibiotic can kill the normal flora and fauna found in the body. This can lead to another series of infectious episodes. (tetracyclines, aminoglycosides, clindamycin, chloramphenicol) . This is more commonly seen in immunocompromised patients,. Oropharynx, intestine, respiratory and genitourinary tracts are common sites for the development of new infection.
Some frequent organisms involved are –
1- Candida Albicans
2- Clostridium difficile
4 – Proteus and psuedonomas.
An enhanced action of Warfarin can also be observed due to more anticoagulant effects, which is because of decreased formation of Vitamin K.
Concentration Dependent Killing and Time Dependent killing
- CDK means killing is high when the ration of peak concentration to minimum inhibitory concentration is high. These drugs produces better action when a large single dose is used than a daily divided doses into small portions eg- aminoglycosides, fluroquinolones
- TDK- Time dependent killing, so this would mean , antimicrobial action depends on the length of time the concentration remains above the MIC. Multiple doses are preffered in this time of action, so Vancomycin and Beta- lactams exhibit this type of actions. Macrolides and Clindamycin also exhibit this effect but they are used as static drugs.
- Post antibiotic effect – Most of the antibiotics have a long post antibiotic effect for gram positive bacterias, this effect causes the organism to grow after a lag period, so it means that the effect of the antibiotic remains after the minimum inhibitory concentration. Antibiotics which inhibit dna synthesis, or protein synthesis can show this effect. One common example is Rifampicin prolongs the PAE of isoniazid, due to this reason Isoniazid can be given thrice weekly when given in combination with rifampicin in short course chemotherapy of tuberculosis ( it needs to be administered daily if used alone ).
So the points to be noted are –
- Beta Lactams
Time dependant inhibitory activity
- Macrolides Clindamycin
Prolonged PAE against gram negative bacteria