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
4
6
8
10 12
14 16
Hours
18 20 22
24
Antagonistic Effect
Log No. Vaiable Organisms
8
7
6
5
Drug A
A+B
Drug B
4
3
2
1
0
2
4
6
8 10 12 14 16 18 20 22 24
Hours
Additive (Indifferent) Effect
Log No. Vaiable Organisms
8
7
6
5
Drug A
A+B
Drug B
4
3
2
1
0
2
4
6
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 doserelated 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