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Mortality RateAppropriate vs Inappropriate Therapy

0

5

10

15

20

25

30

35

M o r t a l i t y r a t e %

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

0

1

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours

L o g N o . V a i a b l e O r g

a n i s m s

Drug A

A+B

Drug B



Antagonistic Effect

01

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours


a n i s m s

Drug A

A+B

Drug B



Additive (Indifferent) Effect

01

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours


a n i s m s

Drug A

A+B

Drug B



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 highrate 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 ofthe drug dose sufficient to reduce dose-

related toxicity



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 localizedhost 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

0

10

20

30

40

50

6070

80

90

100

Penicillin alone Penicillin and

chlortetracyline

Mortality rate

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 forminsoluble precipitates and hence lose

activity

• Mixing ticarcillin or carbenicillin withaminoglycosides results in the inactivation

of the aminoglycosides



Specific Antimicrobial

Combinations



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 Sep;25(9):972-7



Double -LactamsDouble -lactam regimen compared to an

aminoglycoside/ -lactam regimen as empiric antibiotictherapy 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

D bl L t



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 thancombination beta-lactams

Ann Intern Medicine 1991 Dec;1;115(11):849-59



-Lactam & AminoglycosidesMonotherapy versus -lactam-aminoglycoside combination

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

• Combination therapy has no advantage overtreatment with an appropriate beta-lactam

drug in nonneutropenic patients with gram-

negative bacteremia

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



Monotherapy VS Combination TherapyCeftazidime VS Tobramycin/Ticarcillin in NAP

88%83%

0%

10%

20%

30%

40%

50%

60%70%

80%

90%

100%

% o r f s u c c e s s

Ceftazidime Tobramycin/Ticarcillin

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



Fink, AAC 1994;38;547

Monotherapy for Severe

Pneumonia

• Multicenter, double-blind trial (n=405)

– Randomized to:

• Ciprofloxacin 400 mg q8h or

• Imipenem/cilastatin 1000 mg q8h



Monotherapy For Severe PneumoniaDevelopment 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 & 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 Feb;17(2):103-7



-Lactam & QuinolonesComparison of bactericidal activity of trovafloxacin

and ciprofloxacin, alone and in combination withcefepime, 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 beta-



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



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 betweencefazolin and vancomycin

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



Conclusion

• Combination antibiotics has clear cut (as

well as borderline) indications

• Inappropriate use of antimicrobialcombinations may have deleterious effect

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