This document discusses factors that influence the choice and combined use of antimicrobial agents (AMAs). It notes that empiric therapy is sometimes necessary before laboratory results are available. When selecting AMAs, clinicians must consider the activity of the agent against the suspected organism, site of infection, administration route, metabolism/excretion, treatment duration, frequency, toxicity, cost, and local resistance rates. Combining AMAs can achieve synergism, broaden antimicrobial spectrum, reduce toxicity, prevent resistance emergence, and treat mixed infections, but may also increase adverse effects, resistance, costs, and superinfections if not used rationally.

1. Jagir R. Patel
Assistant Professor
Dept. Pharmacology
Choice and Combined use of AMAs

2. Correlation between AMAs, Host
and Microbes

3. What influences the choice of AMAs
 Activity of agent against proven or suspected
organism
 Site of infection
 Mode of administration
 Metabolism and excretion
 Duration of treatment
 frequency of dose
 Toxicity
 cost
 Local rates of resistance

4. Empiric Therapy
Empiric therapy is when drug therapy is initiated before
laboratory results are available (i.e., before the pathogen is
identified and/or before susceptibility test results are
available).
Empiric therapy is sometimes necessary to save a
patient’s life.
Clinicians make an “educated guess” based on past
experience with the type of infectious disease and the most
effective drugs.
•Clinicians must take a number of factors into
consideration before prescribing antimicrobial agents.

5. Selection of Appropriate AMA

6. Patient related factors

7. Cont.…

8. Organism related considerations

9. Drug factors

10. Cont..

11. Combined use
of
Antimicrobials

12. Chemotherapeutic spectrum
 Narrow spectrum antibiotics:
Chemotherapeutic agents acting only on
limited group of microorganisms are said
to have narrow spectrum.E.g.,isoniazid
is active only against mycobacteria.
 Extended-spectrum antibiotics
Extended spectrum is the term applied to
antibiotics that are effective against gram-
positive organisms and also against a
significant number of gram-negative
bacteria.
 E.g. ampicillinis considered to have an
extended spectrum because It acts against
gram-positive and some gram-negative
bacteria.

13. Broad-spectrum antibiotics
 The term refers to antibiotics that are effective against all or majority of
organisms
 Tetracycline and chloramphenicol
 Administration of broad-spectrum antibiotics can drastically alter the
nature of the normal bacterial flora and precipitate a superinfection of
an organism such as Clostridium difficile, the growth of which is
normally kept in check by the presence of other microorganisms

14. ProphylacticTherapy
The antibiotic given when there is likelihood of microorganisms being
present and used to PREVENT infection
Presurgical antimicrobial prophylaxis-
(a single dose cephalosporin (such as cefazoline) administered within 1
hour before the initial incision)
Antimicrobial prophylaxis in immunocompromised patients-
those with HIV infection, those who are undergoing chemotherapy for
cancer, or those who are receiving immunosuppressive therapy after organ
transplant

15. Cont.…
 Antimicrobial prophylaxis to prevent transmission of communicable
pathogens to susceptible contacts-
 Macrolides can be prescribed to reduce transmission of pertussis,
ciprofloxacin can be given to close contacts of a patient with meningitis
caused by N. Meningitidis
 Antimicrobial prophylaxis before dental and other invasive procedures in
patients susceptible to bacterial endocarditis
 Traumatic injuries with a high probability of infectious complications

16. Rationale for use of Combined drugs
 More than one AMAs are frequently used currently.
 This should be done only with a specific purpose and not blindly in the
hope that if:
 One is good
 Two should be better
 Three should cure almost any infection.
Why?
Due to development of resistance
Or more complex disease conditions

17. Combined Drugs targets
To achieve synergism, additive or antagonistic effect
To reduce severity or incidence of adverse effects
To prevent emergencies of resistance
To broaden the spectrum of antimicrobial spectrum

18. To achieve Synergism
 When two AMA belonging to different class are used together results in
 Synergism(supra additive (A+B)>A+B), additive effect(A+B)= A+B or
Antagonism(A+B)<A+B
 Concept of synergism
 It may manifest in terms of decrease in the MIC of one AMA in presence of
other or MIC of both may be lowered
 If the MIC of both drugs are lowered by 25% then the pair is synergistic
 25-50% are considered as additive
 >50% indicates antagonism
 This may also manifest as more rapid lethal action of combination then either
of individual

19. Cont.…
 synergistic interaction, then the addition
of Drug B to Drug A results in a
significantly lower MIC for Drug A (i.e.,
there is an increase in the potency of
Drug A)
 Additive interaction, addition of
increasing amounts of Drug B to Drug A
results in a linear decrease in the MIC of
Drug A; in this case, each of the two
drugs can be thought of as
interchangeable
 Antagonistic interaction, addition of
Drug B to Drug A does not significantly
lower the MIC of Drug A;

20. Cont.…
 Each combination is unique: the same drugs be synergistic for one organism
and antagonistic for the other
 2 bacteriostatic = often additive action e.g. tetracycline's and
chloramphenicol
 2 bactericidal drugs= frequently additive and sometime synergistic:
Rifampicin+ isoniazid
 Combination of bacteriostatic + bactericidal = synergistic or antagonistic
 If the organism is sensitive to cidal drugs, response to combination is equal
to static drug given alone( apparent antagonism)e.g penicillin + tetracycline
 If organism are less sensitive to bactericidal drug then combination causes
synergistic e.g. rifampicin + dapsone in leprosy

21. To reduce the severity or incidence
of adverse effect
 When two drug posses synergetic effect the dose of both can be reduced
 This is needed for AMA with low dose safety margin which when alone
used produce unacceptable toxicity
 e.g.; amphotericin B+ rifampicin
 Rifampicin enhance action of amphotericin

22. To prevent emergency of resistance
 Mutation conferring to one AMA is independent of that conferring
resistance to other, So using 2 or more AMA is valid primarily for chronic
infections i.e.. Leprosy, HIV etc.
To broaden the spectrum of antimicrobial action
 Treatment of mixed infection: UTI, diabetic foot infection gynecological
infections are mixed infections 2 or more AMA should be used
 Initial treatment of severe infections: for empirical therapy when bacterial
diagnosis is not known drugs covering gram –ve and +ve may be given
together e.g. penicillins + streptomycin
 Topically : AMA which are not used systemically are poorly absorbed from
local site so broad range for grm +ve and –ve should be used e.e neomycin,
bacitracin

23. Disadvantages of antimicrobial
combinations
 They foster a casual rather than rational outlooks in diagnosis of
infection and choice of AMA
 Increases incidence and Variety of adverse effect
 Chances of superinfection
 If inadequate dose of non synergistic drugs are used emergence of
resistance may be promoted
 Increase cost therapy