Combined Use of Antimicrobials

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:

1. To achieve synergism

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.

2. To Reduce Severity Or Incidence Of Adverse Effects

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.

3. To Prevent Emergence Of Resistance

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.

4. To Broaden The Spectrum Of Antimicrobial Action

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.

Disadvantages Of Antimicrobial Combinations

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.