Title: Combination Antibiotics
1Combination Antibiotics
- Mazen Kherallah, MD, FCCP
- King Faisal Specialist Hospital Research Center
2Mortality RateAppropriate vs Inappropriate
Therapy
Antimicrob agent Chemother 1997 May41(5)1127-33
3In 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
4Synergistic Effect
5Antagonistic Effect
6Additive (Indifferent) Effect
7Indications for the Clinical Use of Antimicrobial
Combinations
- Prevention of the emergence of resistant
organisms - Polymicrobial infection
- Initial therapy
- Decreased toxicity
- Synergism
8Prevention of the Emergence of Resistant
Organisms
- Decreased resistant mycobacterium tuberculosis
with combination treatment of - Reduction of ?-lactamase induction with
combination ?-lactam agents and aminoglycosides
9Polymicrobial 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
10Initial 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
11Decreased 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
12SynergismEnhanced 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
13SynergismInhibition of Sequential Steps
- Sulfonamide with trimithoprim
- Treatment and prevention of chronic urinary tract
infection, typhoid fever and shigellosis caused
by organisms resistant to ampicillin
14Disadvantages of the Inappropriate Use of
Antimicrobial Combination
- Antagonism
- Increased cost
- Adverse effects
- Superinfection
15Antagonism
- 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
16?-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
17Mortality in Bacterial Meningitis
Lepper and Dowlling, Arch Intern Med. 1951
18Direct 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
19Specific Antimicrobial Combinations
20Double ?-LactamsOverview 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 Sep25(9)972-7
21Double ?-LactamsDouble ?-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 Jul1(4)186-94
22Double ?-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 Dec1115(11)849-59
23?-Lactam AminoglycosidesMonotherapy 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 May41(5)1127-33
24?-Lactam AminoglycosidesEvaluation 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 May45(5)420-3
25Monotherapy VS Combination TherapyCeftazidime VS
Tobramycin/Ticarcillin in NAP
Rapp et al, Pharmacology 19844211-215
26Monotherapy for Severe Pneumonia
- Multicenter, double-blind trial (n405)
- Randomized to
- Ciprofloxacin 400 mg q8h or
- Imipenem/cilastatin 1000 mg q8h
Fink, AAC 199438547
27Monotherapy For Severe PneumoniaDevelopment of
Resistance on Therapy
Fink, AAC 199438547
28Bacteremia due to P. aeruginosa
Hilf, Am J Med 198987540
29HAP due to P. aeruginosa
- Mortality high (gt50)
- Monotherapy inadequate
- High rate of failure or relapse
- Emergence of resistance
30Aminoglycoside plus B-lactam
- Rationale
- Synergy in vitro
- Improved survival
- Prevent emergence resistance
31HAP due to P. aeruginosa
- Empirical therapy
- Combine 2 active drugs
- B-lactamaminoglycoside
- B-lactamquinolone
32?-Lactam QuinolonesActivity 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 Feb17(2)103-7
33?-Lactam QuinolonesComparison 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-Dec46(6)383-9
34Quinupristin-dalfopristin combined with
beta-lactams for the treatment of experimental
endocarditis due to Staphylococcus aureus
constitutively resistant to macrolide-lincosamide-
streptogramin 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
35In 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
36Conclusion
- Combination antibiotics has clear cut (as well as
borderline) indications - Inappropriate use of antimicrobial combinations
may have deleterious effect