Combination of Antibiotics

Good & Bad

Manaf Alqahtani , MB Bch BAO (Ire) MMM (USA) FACP (USA)
FRCPC (Canada)
Infectious Diseases & Clinical Microbiologist
Royal Medical Services – BDF Hospital
 Acknowledgments

Mazen Kherallah, MD, FCCP

King Faisal Specialist Hospital &
Research Center

NO Potential conflicts of interest

 Mortality Rate
Appropriate vs Inappropriate Therapy

35
30
Mortality rate%

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 their independent activity
when studied separately

• Synergistic effect: the activity of two drugs in

combination is greater to their independent activity
when studied separately

• Antagonistic effect: the activity of two drugs in

combination is less to independent activity when
studied separately
 Synergistic Effect
8

7
Log No. Vaiable Organisms

5
Drug A
4 A+B
3 Drug B

0
2 4 6 8 10 12 14 16 18 20 22 24
Hours
 Antagonistic Effect
8
7
Log No. Vaiable Organisms

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

6
5 Drug A
4 A+B
3 Drug B
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

• 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
 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
Based on Evidence
 Double -Lactams
Overview of synergy with reference to double
-lactam combination
• Mostly additive/indifferent effects
• Rarely synergistic effect
• Sometimes antagonistic effect
• Antagonism was seen mainly when treating
enterobacter or pseudomonas infections
• Mostly studied in cancer patients
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 gram-
negative bacteremia

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

 -Lactam & Aminoglycosides
Evaluation of bactericidal activity of cefpirome-
aminoglycoside 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
Ceftazidime VS Tobramycin/Ticarcillin in NAP

100% 88%
90% 83%
80%
% or f success

70%
60%
50%
40%
30%
20%
10%
0%
Ceftazidime 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
-Failure to achieve bacteriological
eradication
Pathogen Cipro Imipenem

All organisms 9% 11%

Pseudomonas 33% 53%

aeruginosa

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

 Blizotis et al ; CID 2005

8 trials were analyzed, 6 of which used late-generation agents

as monotherapy.

The results showed no difference between monotherapy and

combination therapy in mortality or emergence of resistant
pathogens
 Blizotis et al ; CID 2005
• combination therapy is superior to monotherapy as
the initial empirical approach to Pseudomonas
bacteremia

• completion of therapy with a single effective agent

after susceptibility data are known appears to be
equivalent to continued combination therapy
 Combination Therapy
Still remains controversial

• consensus is that combination therapy is

probably more effective than monotherapy
only for infections with P. aeruginosa and
primarily among patients with bacteremia
and neutropenia
 Combination Therapy
Still remains controversial -2
• Recent consensus ( IDSA & ATS) :
monotherapy with newer agents (quinolones,
late-generation cephalosporins, β-lactam-β-
lactamase inhibitor combinations, or
carbapenems) is preferred for patients with no
risk of infection with drug-resistant organisms
and without severe infection
 My Philosophy in Combination
Therapy
Combination Antibiotic Therapy Against
Susceptible Pathogens
Combination therapy is probably preferable
for treatment of serious infection with
antibiotic-susceptible gram-negative
pathogens, particularly as empirical therapy
for bacteremia due to P. aeruginosa
Example: β-lactam drug plus an aminoglycoside or
quinolone
 My Philosophy in Combination
Therapy
Combination Antibiotic Therapy Against
Highly Resistant Pathogens

• Few Tx options for MDR A. baumannii and

P. aeruginosa
• The polymyxins remain the most
consistently effective agents in vitro against
both A. baumannii and P. aeruginosa
 Conclusion
• Combination antibiotics has clear cut (as
well as borderline) indications
•
• Inappropriate use of antimicrobial
combinations may have deleterious effect
 Enhanced activity of antibiotic combinations against multidrug-resistant Pseudomonas
aeruginosa and Acinetobacter baumannii: in vitro and clinical evidence.

Rahal J J Clin Infect Dis. 2006;43:S95-S99

© 2006 by the Infectious Diseases Society of America