Combination Antibiotics

1
Combination Antibiotics

• Mazen Kherallah, MD, FCCP
• King Faisal Specialist Hospital Research Center

2
Mortality RateAppropriate vs Inappropriate
Therapy
Antimicrob agent Chemother 1997 May41(5)1127-33
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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

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Synergistic Effect
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Antagonistic Effect
6
Additive (Indifferent) Effect
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Indications for the Clinical Use of Antimicrobial
Combinations

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

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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

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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

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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

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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

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SynergismEnhanced 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

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SynergismInhibition of Sequential Steps

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

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Disadvantages of the Inappropriate Use of
Antimicrobial Combination

• Antagonism
• Increased cost
• Adverse effects
• Superinfection

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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

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?-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

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Mortality in Bacterial Meningitis
Lepper and Dowlling, Arch Intern Med. 1951
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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

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Specific Antimicrobial Combinations

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Double ?-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
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Double ?-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
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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 Dec1115(11)849-59
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?-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
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?-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
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Monotherapy VS Combination TherapyCeftazidime VS
Tobramycin/Ticarcillin in NAP
Rapp et al, Pharmacology 19844211-215
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Monotherapy for Severe Pneumonia

• Multicenter, double-blind trial (n405)
• Randomized to
• Ciprofloxacin 400 mg q8h or
• Imipenem/cilastatin 1000 mg q8h

Fink, AAC 199438547
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Monotherapy For Severe PneumoniaDevelopment of
Resistance on Therapy
Fink, AAC 199438547
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Bacteremia due to P. aeruginosa
Hilf, Am J Med 198987540
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HAP due to P. aeruginosa

• Mortality high (gt50)
• Monotherapy inadequate
• High rate of failure or relapse
• Emergence of resistance

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Aminoglycoside plus B-lactam

• Rationale
• Synergy in vitro
• Improved survival
• Prevent emergence resistance

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HAP due to P. aeruginosa

• Empirical therapy
• Combine 2 active drugs
• B-lactamaminoglycoside
• B-lactamquinolone

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?-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
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?-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
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Quinupristin-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
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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
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Conclusion

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