More than one AMAs are frequently used concurrently. This should be done only with a specific purpose and not blindly in the hope that if one is good, two should be better and three should cure almost any infection.
COMBINED USE OF ANTIMICROBIALS
More than one AMAs are frequently used concurrently. This should
be done only with a specific purpose and not blindly in the hope that if one is
good, two should be better and three should cure almost any infection. The objectives
of using antimicrobial combinations are:
Every AMA has a specific effect on
selected microorganisms. Depending on the drug pair as well as the organism
involved, either synergism (supra-additive effect), additive action, indifference
or antagonism may be observed when two AMAs belonging to different classes are
used together.
Synergism may manifest
in terms of decrease in the MIC of one AMA in the presence of another, or the
MICs of both may be lowered. If the MIC of each AMA is reduced to 25% or less,
the pair is considered synergistic, 25–50% of each is considered additive and
more than 50% of each indicates antagonism. Thus, a synergistic drug sensitizes
the organisms to the action of the other member of the pair. This may also
manifest as a more rapid lethal action of the combination than either of the
individual members. Synergistic prolongation of post-antibiotic effect has also
been demonstrated for combinations of βlactams with aminoglycoside and by addition of
rifampin to a variety of antibiotics.
Every combination is unique; the same drugs may be synergistic
for one organism but antagonistic for another. However, general guidelines are:
a) Two bacteriostatic agents are often additive, rarely
synergistic, i.e. combination of tetracyclines, chloramphenicol, erythromycin,
etc. A sulfonamide used with trimethoprim is a special case where supraadditive
effect is obtained because of sequential block in folate metabolism of certain
bacteria (Ch. No. 50). The combination often exerts cidal action, while the individual
components are only static.
Another special
example is the combination of a βlactamase inhibitor clavulanic acid or
sulbactam with amoxicillin or ampicillin for βlactamase producing H. influenzae, N. gonorrhoeae and other
organisms.
b) Two bactericidal drugs are frequently additive and sometime
synergistic if the organism is sensitive to both, e.g.:
· Penicillin/ampicillin + streptomycin/gentamicin or
vancomycin + gentamicin
for enterococcal SABE. Penicillins by acting on the cell wall may
enhance the penetration of the aminoglycoside into the bacterium.
· Carbenicillin/ticarcillin + gentamicin for Pseudomonas infection, especially in
neutropenic patients.
· Ceftazidime + ciprofloxacin for Pseudomonas infected orthopedic
prosthesis.
· Rifampin + isoniazid in tuberculosis.
In the above cases,
the combination produces faster cure and reduces the chances of relapse by more
complete eradication of the pathogen.
c) Combination of a bactericidal with a bacteriostatic drug may be synergistic or antagonistic depending on the organism. In general
(i) If the organism is highly sensitive
to the cidal drug—response to the combination is equal to the static drug given
alone (apparent antagonism), because cidal drugs act primarily on rapidly
multiplying bacteria, while the static drug retards multiplication. This has
been seen with penicillin + tetracycline/chloramphenicol on pneumococci which
are highly sensitive to penicillin. Pneumococcal meningitis treated with
penicillin + tetracycline had higher mortality than those treated with
penicillin alone. Penicillin + erythromycin for group A Streptococci and nalidixic acid + nitrofurantoin for E. coli have also shown antagonism.
(ii) If the organism
has low sensitivity to the cidal drug—synergism may be seen, e.g.:
• Penicillin +
sulfonamide for actinomycosis
• Streptomycin +
tetracycline for brucellosis
• Streptomycin +
chloramphenicol for K. pneumoniae infection
• Rifampin + dapsone
in leprosy.
Thus, wherever possible,
synergistic combinations may be used to treat infections that are normally
difficult to cure. Full doses of individual drugs are given for this purpose.
This is possible only if the combination is synergistic so that the doses can be
reduced. This is needed for AMAs with low safety margin, which when used alone
in effective doses, produce unacceptable toxicity, e.g.
·
Streptomycin + penicillin G for SABE due to Strep. faecalis.
· Amphotericin B + rifampin or minocycline: the
latter drugs are not themselves antifungal, but enhance the action of
amphotericin B.
· Amphotericin B + flucytosine: a shorter course
is needed, specially for cryptococcal meningitis, than when amphotericin is
used alone.
Mutation conferring
resistance to one AMA is independent of that conferring resistance to another.
If the incidence of resistant mutants of a bacillus infecting an individual for
drug P is 10–5 and for drug Q is 10–7, then only one out of 1012 bacilli will
be resistant to both. The chances of its surviving host defence and causing a
relapse would be meagre.
This principle of
using two or more AMAs together is valid primarily for chronic infections
needing prolonged therapy; has been widely employed in tuberculosis, leprosy
and now adopted for H. pylori, HIV as
well. It is of little value in most acute and shortlived infections. However,
rifampin given with ciprofloxacin prevents Staph.
aureus resistance to the latter.
This is needed in:
(a) Treatment Of Mixed Infection Bronchiectasis, peritonitis, certain
urinary tract infections, brain abscesses, diabetic foot infection, bedsores,
gynaecological infections are mostly mixed infections. Often, aerobic and anaerobic
organisms sensitive to different drugs are involved. Obviously two or more AMAs
have to be used to cover the pathogens. Drugs should be chosen on the basis of
bacteriological diagnosis and sensitivity pattern (known or presumed), and
should be employed in full doses. Clindamycin or metronidazole are generally
included to cover anaerobes. It may sometimes be possible to find a single
agent effective against all the causative organisms.
(b) Initial
Treatment Of Severe Infections For empirical therapy, since
bacterial diagnosis is not known; drugs covering gram-positive and gram-negative
(in certain situations anaerobes as well), e.g. penicillin + streptomycin;
cephalosporin or erythromycin + an aminoglycoside ± metronidazole or clindamycin,
may be given together. Rational combinations improve the certainty of curing
the infection in the first attempt, but should be continued only till
bacteriological data become available. When the organism and its sensitivity has
been determined, severity of infection is in itself not an indication for
combination therapy. Combinations should not be used as a substitute for accurate
diagnosis.
(c) Topically
Generally, AMAs which are not used systemically, are
poorly absorbed from the local site and cover a broad range of gram-positive and
gram-negative bacteria are combined for topical application, e.g. bacitracin,
neomycin, polymyxin B.
1. They foster a casual rather than rational outlook
in the diagnosis of infections and choice of AMA.
2. Increased incidence and variety of adverse
effects. Toxicity of one agent may be enhanced by another, e.g. vancomycin +
tobramycin and gentamicin + cephalothin produce exaggerated kidney failure.
3.
Increased chances of superinfections.
4.
If inadequate doses of non-synergistic drugs
are used —emergence of resistance may be promoted.
5. Increased cost of therapy.
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