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.
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.
Related Topics
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