Problems that arise with the use of AMAs

PROBLEMS THAT ARISE WITH THE USE OF AMAs

1. Toxicity

Local Irritancy: This is exerted at the site of administration. Gastric irritation, pain and abscess formation at the site of i.m. injection, thrombophlebitis of the injected vein are the complications. Practically all AMAs, especially erythromycin, tetracyclines, certain cephalosporins and chloramphenicol are irritants.

Systemic Toxicity: Almost all AMAs produce dose related and predictable organ toxicities. Characteristic toxicities are exhibited by different AMAs.

Some have a high therapeutic index—doses up to 100fold range may be given without apparent damage to host cells. These include penicillins, some cephalosporins and erythromycin.

Others have a lower therapeutic index—doses have to be individualized and toxicity watched for, e.g.:

Aminoglycosides : 8th cranial nerve and kidney toxicity.

Tetracyclines      : liver and kidney damage, antianabolic effect.

Chloramphenicol : bone marrow depression.

Still others have a very low therapeutic index—use is highly restricted to conditions where no suitable alternative is available, e.g. :

Polymyxin B       : neurological and renal toxicity.

Vancomycin       : hearing  loss,  kidney damage.

Amphotericin B  : kidney, bone marrow and neurological toxicity.

2. Hypersensitivity Reactions

Practically all AMAs are capable of causing hypersensitivity reactions. These are unpredictable and unrelated to dose. The whole range of reactions from rashes to anaphylactic shock can be produced. The more commonly involved AMAs are—penicillins, cephalosporins, sulfonamides, fluoroquinolones.

3. Drug Resistance

It refers to unresponsiveness of a microorganism to an AMA, and is akin to the phenomenon of tolerance seen in higher organisms.

Natural Resistance: Some microbes have always been resistant to certain AMAs. They lack the metabolic process or the target site which is affected by the particular drug. This is generally a group or species characteristic, e.g. gram-negative bacilli are normally unaffected by penicillin G, or M. tuberculosis is insensitive to tetracyclines.

This type of resistance does not pose a significant clinical problem.

Acquired Resistance: It is the development of resistance by an organism (which was sensitive before) due to the use of an AMA over a period of time. This can happen with any microbe and is a major clinical problem. However, development of resistance is dependent on the microorganism as well as the drug. Some bacteria are notorious for rapid acquisition of resistance, e.g. staphylococci, coliforms, tubercle bacilli. Others like Strep. pyogenes and spirochetes have not developed significant resistance to penicillin despite its widespread use for > 50 years. Gonococci quickly developed resistance to sulfonamides, but only slowly and low-grade resistance to penicillin. However, in the past 30 years, highly penicillin resistant gonococci producing penicillinase have appeared.

Resistance may be developed by mutation or gene transfer.

Mutation

It is a stable and heritable genetic change that occurs spontaneously and randomly among microorganisms. It is not induced by the AMA. Any sensitive population of a microbe contains a few mutant cells which require higher concentration of the AMA for inhibition. These are selectively preserved and get a chance to proliferate when the sensitive cells are eliminated by the AMA. Thus, in time it would appear that a sensitive strain has been replaced by a resistant one, e.g. when a single antitubercular drug is used. Mutation and resistance may be:

Single step: A single gene mutation may confer high degree of resistance; emerges rapidly, e.g. enterococci to streptomycin, E. coli and Staphylococci to rifampin.

Multistep: A number of gene modifications are involved; sensitivity decreases gradually in a stepwise manner. Resistance to erythromycin, tetracyclines and chloramphenicol is developed by many organisms in this manner.

Sometimes mutational acquisition of resistance is accompanied by decrease in virulence, e.g. certain rifampin-resistant staphylococci and low grade penicillin-resistant gonococci have decreased virulence.

Gene Transfer (infectious resistance) from one organism to another can occur by:

Conjugation:  Sexual contact through the formation of a bridge or sex pilus is common among gram-negative bacilli of the same or another species. This may involve chromosomal or extrachromosomal (plasmid) DNA. The gene carrying the ‘resistance’ or ‘R’ factor is transferred only if another ‘resistance transfer factor’ (RTF) is also present. Conjugation frequently occurs in the colon where a large variety of gram-negative bacilli come in close contact. Even nonpathogenic organisms may transfer R factor to pathogenic organisms, which may become widespread by contamination of food or water. Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of E. coli, penicillin resistance of Haemophilus and gonococci and many others have been traced to this mechanism. Concomitant acquisition of multidrug resistance has occurred by conjugation. Thus, this is a very important mechanism of horizontal transmission of resistance.

Transduction: It is the transfer of gene carrying resistance through the agency of a bacteriophage. The R factor is taken up by the phage and delivered to another bacterium which it infects. Many Staph. aureus strains have acquired resistance by transduction. Certain instances of penicillin, erythromycin and chloramphenicol resistance have been found to be phage mediated.

Transformation: A resistant bacterium may release the resistance carrying DNA into the medium and this may be imbibed by another sensitive organism—becoming unresponsive to the drug. This mechanism is probably not clinically significant except isolated instances of pneumococcal resistance to penicillin G due to altered penicillin binding protein, and some other cases.

Resistance once acquired by any of the above mechanisms becomes prevalent due to the selection pressure of a widely used AMA, i.e. presence of the AMA provides opportunity for the resistant subpopulation to thrive in preference to the sensitive population.

Resistant organisms can broadly be of the following three types:

a) Drug Tolerant

Loss of affinity of the target biomolecule of the microorganism for a particular AMA, e.g. resistant Staph. aureus and E. coli develop a RNA polymerase that does not bind rifampin, certain penicillinresistant pneumococcal strains have altered penicillin binding proteins; trimethoprimresistance results from plasmidmediated synthesis of a dihydrofolate reductase that has low affinity for trimethoprim.

Another mechanism is acquisition of an alternative metabolic pathway, e.g. certain sulfonamide resistant bacteria switch over to utilizing preformed folic acid in place of synthesizing it from PABA taken up from the medium.

b) Drug Destroying

The resistant microbe elaborates an enzyme which inactivates the drug, e.g.

i)  β-lactamases are produced by staphylococci, Haemophilus, gonococci, etc. which inactivate penicillin G. The βlactamases may be present in low quantity but strategically located periplasmically (as in gram-negative bacteria) so that the drug is inactivated soon after entry, or may be elaborated in large quantities (by gram-positive bacteria) to diffuse into the medium and destroy the drug before entry.

ii)  Chloramphenicol acetyl transferase is acquired by resistant E. coli, H. influenzae and S.typhi.

iii) Some of the aminoglycoside-resistant coliforms have been found to produce enzymes which adenylate/acetylate/phosphorylate specific aminoglycoside antibiotics.

c) Drug Impermeable

Many hydrophilic antibiotics gain access into the bacterial cell through specific channels formed by proteins called ‘porins’, or need specific transport mechanisms. These may be lost by the resistant strains, e.g. concentration of some aminoglycosides and tetracyclines in the resistant gram-negative bacterial strains has been found to be much lower than that in their sensitive counterparts when both were exposed to equal concentrations of the drugs. Similarly, the low degree penicillin-resistant gonococci are less permeable to penicillin G; chloroquine-resistant P. falciparum accumulates less chloroquine. The bacteria may also acquire plasmid directed inducible energy dependent efflux proteins in their cell membrane which pump out tetracyclines. Active efflux-based resistance has been detected for erythromycin and fluoroquinolones as well.

Cross Resistance

Acquisition of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance. This is more commonly seen between chemically or mechanistically related drugs, e.g. resistance to one sulfonamide means resistance to all others, and resistance to one tetracycline means insensitivity to all others. Such cross resistance is often complete. However, resistance to one aminoglycoside may not extend to another, e.g. gentamicin-resistant strains may respond to amikacin. Sometimes unrelated drugs show partial cross resistance, e.g. between tetracyclines and chloramphenicol, between erythromycin and lincomycin.

Cross resistance may be twoway, e.g. between erythromycin and clindamycin and vice versa, or oneway, e.g. development of neomycin resistance by enterobacteriaceae makes them insensitive to streptomycin but many streptomycinresistant organisms remain susceptible to neomycin.

Prevention Of Drug Resistance

It is of utmost clinical importance to curb development of drug resistance. Measures are:

a)          No indiscriminate and inadequate or unduly prolonged use of AMAs should be made. This would minimize the selection pressure and resistant strains will get less chance to preferentially propagate. For acute localized infections in otherwise healthy patients, symptom determined shorter courses of AMAs are being advocated now.

b)    Prefer rapidly acting and selective (narrow-spectrum) AMAs whenever possible; broad-spectrum drugs should be used only when a specific one cannot be determined or is not suitable.

c)   Use combination of AMAs whenever prolonged therapy is undertaken, e.g. tuberculosis, SABE.

d)         Infection by organisms notorious for developing resistance, e.g. Staph. aureus, E. coli, M. tuberculosis, Proteus, etc. must be treated intensively.

4. Superinfection (Suprainfection)

This refers to the appearance of a new infection as a result of antimicrobial therapy.

Use of most AMAs causes some alteration in the normal microbial flora of the body. The normal flora contributes to host defence by elaborating substances called bacteriocins which inhibit pathogenic organisms. Further, ordinarily, the pathogen has to compete with the normal flora for nutrients, etc. to establish itself. Lack of competition may allow even a normally nonpathogenic component of the flora, which is not inhibited by the drug (e.g. Candida), to predominate and invade. More complete the suppression of body flora, greater are the chances of developing superinfection. Thus, it is commonly associated with the use of broad/extended-spectrum antibiotics, such as tetracyclines, chloramphenicol, ampicillin, newer cephalosporins; especially when combinations of these are employed. Tetracyclines are more prone than chloramphenicol and ampicillin is more prone than amoxicillin to cause superinfection diarrhoeas because of incomplete absorption—higher amounts reach the lower bowel and cause greater suppression of colonic bacteria.

Superinfections are more common when host defence is compromised.

Conditions Predisposing To Superinfections

·          Corticosteroid therapy

·    Leukaemias and other malignancies, especially when treated with anticancer drugs (these are also immunosuppressants and decrease WBC count)

·          Acquired immunodeficiency syndrome (AIDS)

·          Agranulocytosis

·          Diabetes, disseminated lupus erythematosus

Sites involved in superinfection are those that normally harbour commensals, i.e. oropharynx; intestinal, respiratory and genitourinary tracts; occasionally skin.

Superinfections are generally more difficult to treat. The organisms frequently involved, manifestations and drugs for treating superinfections are:

a) Candida albicans: monilial diarrhoea, thrush, vulvovaginitis; treat with nystatin or clotrimazole.

b) Resistant staphylococci: enteritis; treat with cloxacillin or its congeners.

c) Clostridium difficile: pseudomembranous enterocolitis associated with the use of clindamycin, tetracyclines, aminoglycosides, ampicillin, cotrimoxazole; more common after colorectal surgery; the organism produces an enterotoxin which damages gut mucosa forming plaques; metronidazole and vancomycin are the drugs of choice.

a)  Proteus: Urinary tract infection, enteritis; treat with a cephalosporin or gentamicin.

b)  Pseudomonas: Urinary tract infection, enteritis; treat with carbenicillin, piperacillin or gentamicin. To minimize superinfections:

·            Use specific (narrow-spectrum) AMA whenever possible.

·            Do not use antimicrobials to treat trivial, self-limiting or untreatable (viral) infections.

·            Do not unnecessarily prolong antimicrobial therapy.

5. Nutritional Deficiencies

Some of the B complex group of vitamins and vit K synthesized by the intestinal flora is utilized by man. Prolonged use of antimicrobials which alter this flora may result in vitamin deficiencies.

Neomycin causes morphological abnormalities in the intestinal mucosa—steatorrhoea and malabsorption syndrome can occur.

6. Masking Of An Infection

A short course of an AMA may be sufficient to treat one infection but only briefly suppress another one contacted concurrently. The other infection will be masked initially, only to manifest later in a severe form. Examples are:

·          Syphilis masked by the use of a single dose of penicillin which is sufficient to cure gonorrhoea.

·          Tuberculosis masked by a short course of streptomycin given for trivial respiratory infection.