Combination &De-escalation of

Antibiotics DR GHALEB ALMEKHLAFI

Combination Antibiotics vs. monotherapy

History of Combination Therapy

Mortality rate• Combination therapy (27%)• Monotherapy (47%) (p<0.02)• Monotherapy was often an aminoglycoside

Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in aprospective study of 200 patients. Am J Med 1989 Nov; 87(5):540-5.

“Does combination antimicrobialtherapy reduce mortality in Gram negative

bacteremia? A meta-analysis.”

17 studies• Outcome: mortality• Overall gram negative bacteremia• 0.96 (95%CI 0.70-1.32)• Pseudomonas• 0.50 (95%CI 0.30-0.79)

Safdar N, Handelsman J, Maki DG. Lancet Infect Dis. Aug 2004; 4(8):519-27.

Factors influencing decision

Rationale for Combination Therapy

1. Synergy or additive effect (MDRO)2. Prevention of the emergence of resistant

organisms3. Broad spectrum coverage in certain

situations

In Vitro Results of Combination Therapy

Synergistic: whole is > sum

Additive: whole is the sum

Antagonistic: whole is < sum

Chemical interaction between agents

SynergismEnhanced Uptake of Aminoglycoside when Combined

with -lactam agents

Usually different classes with cidal activity• enterococcal endocarditis: ampicillin and

gentamicin• Viridans streptococcal endocarditis: penicillin and

gentamicin• Staphylococcal bacteremia: vancomycin and

gentamicin• Treatment of pseudomonas infections: -lactam

agent and aminoglycosides

Disadvantages of Combination

• Antagonism• Adverse effects• Super infection• Antimicrobial resistance• Increased cost

Appropriate combination

Antagonism

• When Bactericidal agents with bacteriostatic• More prominent in - immunocompromised patients - in infections where localized host defenses may be inadequate such as meningitis and endocarditis

• combinations of 21 different antibiotics

• strong antagonistic interactions among combinations of bacteriostatic and bactericidal drugs

Conclusion: In contrast to their synergistic effect against carbapenem-resistant A. baumannii isolates, colistin and tigecycline were highly antagonistic to carbapenem-resistant A. baumannii strains isolated from patients with VAP when the drugs were administered together. Therefore, alternative treatment options should be used during the treatment of VAP attributed to A. baumannii.

Antagonism in 80% indifference in 20%

Combination prevent resistance

• Decreased resistant mycobacterium tuberculosis with combination treatment of

• Reduction of -lactamase induction with combination -lactam agents and aminoglycosides

• HIV treatment

Clinical Indications of combination

• Polymicrobial infection• Specific sites(IE, meningitis, pnumonia)• Specific organisms(TB, legionella)• Initial/Empirical therapy for severe

infection• MDRO

Polymicrobial Infection

• Intraabdominal infection: ciprofloxacin and metronidazole

• Pelvic infection• Mixed aerobic and anaerobic organismThe Availability of broad spectrum antibiotics such as carbapenems and -lactam- -lactamase inhibitors restrict the use of combination antibiotics

Initial / Empiric broad spectrum/combination antibiotics

• Severe sepsis (organ impairment / shock)• Hospital Acquired /Health-Care Associated Infection• Multiple co-morbidities• Immunosuppressed• Exposures to multiple broad spectrum antibiotics in

the last 90 days• Recent procedures or patient has devices insitu• Elderly > 65 years• Colonized with MDROs

Important Antimicrobial Combinations

and target organisms

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

meropenem plus ertapenem

Aminoglycoside plus B-lactam

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

“Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and metaanalysis of randomized trials”

64 trials with 7586 patients• No difference in all-cause mortality (0.90, 95% CI 0.77-1.06)• Subset of Pseudomonas infections (426 patients) No difference in all-cause mortality (1.50, 95% CI 0.07-32.84)

Paul M, Benuri-Silbinger I, Soares-Welser K, Levbovici L. BMJ 2004 Mar 20;328(7441):668.

-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 May;45(5):420-3

Anti Pseudomonas

• Antipseudomonal beta lactam

• • Piperacillin• • Ceftazidime• • Cefepime• • Imipenem• • Aztreonam

Aminoglycoside• Tobramycin• Gentamycin• AmikacinOR• Fluoroquinolones• Ciprofloxacin• Levofloxacin

+

Anti P. aeruginosa combination

• Empirical therapy• Combine 2 active drugs:–B-lactam+aminoglycoside–B-lactam+quinolone

HAP due to P. aeruginosa

• Mortality high (>50%)• Monotherapy inadequate–High rate of failure or relapse– Emergence of resistance

Bacteremia due to P. aeruginosaAntibiotic 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

Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem in Patients With Severe

Sepsis: A Randomized Trial

Brunkhorst FM, et al. JAMA. 2012;307:2390-9

triple β-lactam combination meropenem-piperacillin-tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA subspecies

At present colistin and tigecycline remain drugs of choice for MDRAB infections. Tigecycline should not be used in combination with piperacillin-tazobactam for MDR-Ab

• Inhaled colistin as an adjunct treatment for lung infection due to MDR gram-negative bacteria have been found promising in recent studies as well as in meta-analysis.

• Colistin combined with tigecycline did not show good synergistic action

• SYNERGY WITH:rifampicin,carbabenems,levofloxacin

Gram-negative MDR bacteria:Carbapenem-resistant Acinetobacter.and Klebsiella pneumoniae.(SD group: 50 mg every 12 hours) (HD group: 100 mg every 12 hours)

Enterococcus faecalis and Enterococcus faecalis

• All daptomycin containing regimens demonstrated significantly greater kill (decrease in CFU/g) than all linezolid-containing regimens. (p<0.0o1)

Conclusion

• Combination antibiotics has clear cut (as well as borderline) indications

• Inappropriate use of antimicrobial combinations may have deleterious effect

De-escalation

Antimicrobial Stewardship

1.Rapid identification of patients with bacterial infections, while reducing the numbers of patients treated unnecessarily.2.Appropriate empirical treatment selection.3.Using PK–PD characteristics to optimize antimicrobial dosing and administration modalities.4.De-escalation once culture results become available.5.Shortening therapy duration.

What is De-escalation and why?

the practice of changing antibiotics from initial broad spectrum agent to a narrower, more focused spectrum when the pathogen identified. Why?De-escalation is one of the most important strategies in reducing antibiotic resistance and has shown to improve patient outcome.

General principles of de-escalation

Include assessing the need for antibiotics everyday based on:• Clinical improvement• Adequate source control• Appropriate culture and sensitivity results

de-escalation success

• De-escalation is feasible in ~50% of the patients. It is influenced by initial microbiologic results and type of initial antibiotherapy.

Antibiotic De-escalation in the ICU: A Five-Step Policy

• 1.Stopping antibiotics in patients without documented bacterial infection

• 2.Stopping vancomycine or linezolid if no MRSA is identified

• 3.Broad-spectrum beta lactams restricted to infection caused by pathogens only susceptible to these agents

• 4.Switching to Monotheraphy after 3 days• 5.Antibiotics stopped ASAP (after a maximum of 8

days in most cases)

Step #1Stopping Antibiotics in ICU Patients Without Documented Bacterial Infection

• Obtaining specimens for cultures before antimicrobial administration is essential and enable therapy de-escalation

• All antibiotic therapy in the ICU should be re-evaluated on days 2 or 3, based on the clinical course of the disease and microbiological culture results

Step #2 Stopping vancomycin or linezolid if no MRSA is identified

• Vancomycin and linezolid should be stopped if no MRSA is identified• Infections caused by MSSA should

be treated with oxacillin, except in case of allergy

Step #3 Streamlining Antibiotic Therapy Once Culture Results Are Available

• Restrict use of very broad-spectrum agents, such as carbapenems, pip./taz., and cefepime, to infections caused by pathogens only susceptible to these agents:

• Treat infections caused by Enterobacteriaceae with a 3rd-gen. cephalosporin (except ESBL-producing strains and Group 3 GNB)

• Treat P. aeruginosa infections caused by piperacillin-S strains with this specific antibiotic

• Restrict use of ciprofloxacin to pts allergic to ß-lactams.

Step #4Switching to Monotheraphy after 3-5 Days

• Therapy can and should be switched to Monotheraphy in most patients after 3-5 days, provided that:

‒initial therapy was appropriate, ‒clinical course appears favorable, ‒and that microbiological data exclude a very difficult-to-treat microorganism, with a very high in vitro MIC, as it can be observed with some nonfermenting-GNB and/or carbapenemase-producing GNB.

Step #5Shortening Duration of Therapy

• A too long duration of treatment may favor the emergence of MDR or pandrug-resistant strains, exposes to antibiotic toxicity, and increases costs, and NOT necessarily improves outcome

How to carry out de escalation‐1. Target broad spectrum antimicrobials that are used empirically2. Review at : i. 72 hours after antimicrobial initiation or; ii. Once a week review of a specific ward, unit, hospital 3. Identify de escalation opportunities‐ i. Were appropriate cultures taken initially? ii. Has there been any growth from the cultures? iii. If there is no growth, can the antimicrobial be stopped? iv. If there is growth, can the antimicrobial be de escalated‐

Conclusions: As part of a global management of empiric antibiotherapy in an intensive care unit, de-escalation might be safe and feasible in a large proportion of patients.

In the EPIC study• diagnostic results for both bacteria and viruses were

available for 2259 adults • (97%) with radiographic evidence of pneumonia. • A pathogen was detected in 853 of these patients (38%). • Viruses were detected in 27% and• bacteria in 14%.

N Engl J Med 2015;373:415-27

•questions?