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Combination Antibiotics

Mazen Kherallah, MD, FCCP


King Faisal Specialist Hospital &
Research Center

Mortality Rate
Appropriate vs Inappropriate Therapy
35

Mortality rate%

30
25
20
15
10
5
0

Inappropriate therapy

Appropriate therapy

Antimicrob agent Chemother 1997 May;41(5):1127-33

In Vitro Results of Combination


Therapy
Additive (indifferent) effect: the activity of two drugs in
combination is equal to the sum (or a partial sum) of
their independent activity when studied separately
Synergistic effect: the activity of two drugs in
combination is greater to the sum of their independent
activity when studied separately
Antagonistic effect: the activity of two drugs in
combination is less to the sum (or a partial sum) of their
independent activity when studied separately

Synergistic Effect
Log No. Vaiable Organisms

8
7
6
5

Drug A
A+B
Drug B

4
3
2
1
0
2

10 12

14 16

Hours

18 20 22

24

Log No. Vaiable Organisms

Antagonistic Effect
8
7
6
5
4
3

Drug A
A+B
Drug B

2
1
0
2

8 10 12 14 16 18 20 22 24
Hours

Log No. Vaiable Organisms

Additive (Indifferent) Effect


8
7
6
5
4
3

Drug A
A+B
Drug B

2
1
0
2

8 10 12 14 16 18 20 22 24
Hours

Indications for the Clinical Use of


Antimicrobial Combinations
Prevention of the emergence of resistant
organisms
Polymicrobial infection
Initial therapy
Decreased toxicity
Synergism

Prevention of the Emergence of


Resistant Organisms
Decreased resistant mycobacterium
tuberculosis with combination treatment of
Reduction of -lactamase induction with
combination -lactam agents and
aminoglycosides

Polymicrobial Infection
Intraabdominal infection: ciprofloxacin and
metronidazole
Pelvic infection
Mixed aerobic and anaerobic organism
Availability of broad spectrum antibiotics
such as carbapenems and -lactam-
-lactamase inhibitors restrict the use of
combination antibiotics

Initial Therapy
Neutropenic patients: Ceftazidime and
vancomycin
In patients where the nature of infection is
not clear yet: high dose ceftriaxone along
with vancomycin in suspected
pneumococcal meningitis in areas of high
rate of penicillin resistance

Decreased Toxicity
Decrease the toxic drug required for
treatment and thus reduce the dose related
toxicity
No data from clinical trials that establish
without doubt that combination therapy with
different agents permits a reduction of the
drug dose sufficient to reduce dose-related
toxicity

Synergism
Enhanced Uptake of Aminoglycoside when
Combined with -lactam agents

Treatment of enterococcal endocarditis:


ampicillin and gentamicin
Viridans streptococcal endocarditis: penicillin
and gentamicin
Staphylococcal bacteremia: vancomycin and
gentamicin
Treatment of pseudomonas infections: lactam agent and aminoglycosides

Synergism
Inhibition of Sequential Steps

Sulfonamide with trimithoprim


Treatment and prevention of chronic urinary
tract infection, typhoid fever and shigellosis
caused by organisms resistant to ampicillin

Disadvantages of the Inappropriate Use


of Antimicrobial Combination

Antagonism
Increased cost
Adverse effects
Superinfection

Antagonism
Few well-documented clinical examples of
antagonism
Bactericidal agents converts to bacteriostatic
More prominent in immunocompromised
patients or in infections where localized host
defenses may be inadequate such as
meningitis and endocarditis

-lactam - -lactam Antagonism


Induction of B-lactamase by one agent,
renders the second agent ineffective
Enterobacter, Serratia, or pseudomonas
The exact clinical significance of this
phenomenon is not clear

Mortality in Bacterial Meningitis


100
90
80
70
60
50
40
30
20
10
0

Mortality rate

Penicillin alone

Penicillin and
chlortetracyline

Lepper and Dowlling, Arch Intern Med. 1951

Direct Interaction of Drugs


If chloramphenicaol is inadvertently mixed
together with erythromycin in the same
parenteral infusion solution, they may form
insoluble precipitates and hence lose
activity
Mixing ticarcillin or carbenicillin with
aminoglycosides results in the inactivation
of the aminoglycosides

Specific Antimicrobial
Combinations

Double -Lactams

Overview of synergy with reference to double


-lactam combination

Mostly additive effects


Rarely synergistic effect
Sometimes antagonistic effect
Antagonism was seen mainly when treating
enterobacter or pseudomonas infections
DICP 1991 Sep;25(9):972-7

Double -Lactams

Double -lactam regimen compared to an


aminoglycoside/ -lactam regimen as empiric antibiotic
therapy for febrile granulocytopenic cancer patients

In vitro synergism was demonstrated in 73%


Antagonism was not seen
Outcome and nephrotoxicity were similar
Incidence of secondary infection was higher
in double -lactam group
Support Care Cancer 1993 Jul;1(4):186-94

Double -Lactams
-lactam antibiotic therapy in febrile granulocytopenic
patients. A randomized trial comparing cefoperazone plus
piperacillin, ceftazidime plus piperacillin, and imipenem
alone

Double beta-lactams therapy was as effective


as imipenem alone
Superinfections occurred more often in the
double beta-lactam group
Cost of imipenem alone was lower than
combination beta-lactams
Ann Intern Medicine 1991 Dec;1;115(11):849-59

-Lactam & Aminoglycosides

Monotherapy versus -lactam-aminoglycoside combination


treatment for gram-negative bacteremia: a prospective,
observational study

Combination therapy has no advantage over


treatment with an appropriate beta-lactam
drug in nonneutropenic patients with gramnegative bacteremia

Antimicrob agent Chemother 1997 May;41(5):1127-33

-Lactam & Aminoglycosides

Evaluation of bactericidal activity of cefpiromeaminoglycoside combination agaist pseudomonas aeruginosa


strains with intermediate sensitivity to cefpirome and in
various phenotypes of beta-lactam resistance

Combination of cefpirome and


aminoglycosides is bactericidal and showed
synergistic effect

Pathol Biol (Paris) 1997 May;45(5):420-3

Monotherapy VS Combination Therapy

% or f success

Ceftazidime VS Tobramycin/Ticarcillin in NAP


100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%

88%

Ceftazidime

83%

Tobramycin/Ticarcillin

Rapp et al, Pharmacology 1984;4:211-215

Monotherapy for Severe


Pneumonia
Multicenter, double-blind trial (n=405)
Randomized to:
Ciprofloxacin 400 mg q8h or
Imipenem/cilastatin 1000 mg q8h

Fink, AAC 1994;38;547

Monotherapy For Severe Pneumonia


Development of Resistance on Therapy
Pathogen

Cipro

Imipenem

All organisms

9%

11%

Pseudomonas
aeruginosa

33%

53%

Fink, AAC 1994;38;547

Bacteremia due to P. aeruginosa


Antibiotic Rx

Combined
Mono
Mortality rates

Pneumonia

7/20 (35%)

7/8 (88%)

Critically ill

18/37 (47%)

11/12 (92%)

All patients

38/143 (27%)

20/43 (47%)

Hilf, Am J Med 1989:87;540

HAP due to P. aeruginosa


Mortality high (>50%)
Monotherapy inadequate
High rate of failure or relapse
Emergence of resistance

Aminoglycoside plus B-lactam


Rationale:
Synergy in vitro
Improved survival
Prevent emergence resistance

HAP due to P. aeruginosa


Empirical therapy
Combine 2 active drugs:
B-lactam+aminoglycoside
B-lactam+quinolone

-Lactam & Quinolones

Activity of gatifloxacin and ciprofloxacin in combination with


other antimicrobial agents

Combination effect of quinolones and


macrolides, aminoglycosides, beta-lactams,
and vancomycin was only additive
(indifferent) against staphyloccocus aureus,
E. coli, pseudomonas aeruginosa,
enterococcus feacalis and streptococcus
pneumoniae
Int J Antimicrob Agents. 2001 Feb;17(2):103-7

-Lactam & Quinolones

Comparison of bactericidal activity of trovafloxacin


and ciprofloxacin, alone and in combination with
cefepime, against P. aeruginosa
Activity of trovafloxacin against p.
aeruginosa showed synergistic effects when
combined with beta-lactam agent

Chemotherapy 2000 Nov-Dec;46(6):383-9

Quinupristin-dalfopristin combined with betalactams for the treatment of experimental


endocarditis due to Staphylococcus aureus
constitutively resistant to macrolide-lincosamidestreptogramin B antibiotics
Synergistic effect
Q-D-beta-lactam combinations might be
useful for the treatment of complicated
infections caused by multiple organisms,
including MRSA
Antimicrobial agents Chemother 2000 Jul;(7):1789-95

In vitro synergistic effect of double and triple


combinations of beta-lactams, vancomycin,
and netilmicin against MRSA strains
Synergistic effect was found between
imipenem and vancomycin and between
cefazolin and vancomycin

Antimicrobial agents Chemother 2000 Nov;(11):3055-60

Conclusion
Combination antibiotics has clear cut (as
well as borderline) indications
Inappropriate use of antimicrobial
combinations may have deleterious effect