Combination antibiotic therapy can provide benefits over monotherapy in some situations. Combining antibiotics may result in synergistic effects against certain pathogens like MDROs or additive effects. It may help prevent resistance. However, combinations can also lead to antagonism or increased side effects. Appropriate combinations depend on the infection and organism. De-escalation of antibiotics is important for improving outcomes and reducing resistance. It involves narrowing therapy based on culture results and clinical response. Regular review and stopping antibiotics when no longer needed are key aspects of de-escalation.

1. Combination &
De-escalation of
Antibiotics
DR GHALEB ALMEKHLAFI

2. Combination Antibiotics vs.
monotherapy

3. 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 a
prospective study of 200 patients. Am J Med 1989 Nov; 87(5):540-5.

4. “Does combination antimicrobial
therapy 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.

6. Factors influencing decision

7. Rationale for Combination Therapy
1. Synergy or additive effect (MDRO)
2. Prevention of the emergence of resistant
organisms
3. Broad spectrum coverage in certain
situations

8. In Vitro Results of Combination
Therapy
Synergistic: whole is > sum
Additive: whole is the sum
Antagonistic: whole is < sum
Chemical interaction between agents

9. Synergism
Enhanced 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

10. Disadvantages of Combination
• Antagonism
• Adverse effects
• Super infection
• Antimicrobial resistance
• Increased cost
Appropriate combination

11. 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

12. • combinations of 21
different antibiotics
• strong antagonistic
interactions among
combinations of
bacteriostatic and
bactericidal drugs

13. 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%

14. Combination prevent resistance
• Decreased resistant mycobacterium
tuberculosis with combination treatment of
• Reduction of -lactamase induction with
combination -lactam agents and
aminoglycosides
• HIV treatment

15. Clinical Indications of combination
• Polymicrobial infection
• Specific sites(IE, meningitis, pnumonia)
• Specific organisms(TB, legionella)
• Initial/Empirical therapy for severe
infection
• MDRO

16. Polymicrobial Infection
• Intraabdominal infection: ciprofloxacin and
metronidazole
• Pelvic infection
• Mixed aerobic and anaerobic organism
The Availability of broad spectrum antibiotics
such as carbapenems and -lactam-  -
lactamase inhibitors restrict the use of
combination antibiotics

20. 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

21. Important Antimicrobial
Combinations
and target organisms

23. Double -Lactams
Overview 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

24. meropenem plus ertapenem

26. Aminoglycoside plus B-lactam
• Rationale:
– Synergy in vitro
– Improved survival
– Prevent emergence resistance

27. “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.

28. -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

29. Anti Pseudomonas
• Antipseudomonal
beta lactam
• • Piperacillin
• • Ceftazidime
• • Cefepime
• • Imipenem
• • Aztreonam
Aminoglycoside
• Tobramycin
• Gentamycin
• Amikacin
OR
• Fluoroquinolones
• Ciprofloxacin
• Levofloxacin
+

30. Anti P. aeruginosa combination
• Empirical therapy
• Combine 2 active drugs:
–B-lactam+aminoglycoside
–B-lactam+quinolone

31. HAP due to P. aeruginosa
• Mortality high (>50%)
• Monotherapy inadequate
–High rate of failure or relapse
–Emergence of resistance

32. 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

34. 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

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

40. 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

41. • 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

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

43. 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)

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

45. De-escalation

46. 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.

47. 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.

48. General principles of de-escalation
Include assessing the need for antibiotics
everyday based on:
• Clinical improvement
• Adequate source control
• Appropriate culture and sensitivity results

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

50. 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)

51. Step #1
Stopping 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

52. 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

53. 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.

54. Step #4
Switching 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.

55. Step #5
Shortening 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

56. How to carry out de‐escalation
1. Target broad spectrum antimicrobials that are used
empirically
2. 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

57. 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.

58. 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

60. •questions?