Rationale use of Beta Lactam plus Aminoglycosides in Pseudomonal Infection

Rationale use of B-lactam + Aminoglycosides in Pseudomonal Infections

• 3 potential advantages of combination antimicrobial therapy for Gram negative bacteria suggested:
• an increased likelihood that the infective pathogen will be susceptible to at least one of the components of an empiric combination regimen
• the synergistic effect afforded by the use of two agents,
• protection against emergence of resistance with combination therapy.
• Aminoglycosides + Beta lactam synergistic effect - β-Lactam-mediated disturbance of the cell walls of Gram-negative bacilli facilitates passage of aminoglycosides into the periplasmic space. 
• In vitro –some studies showed combination therapy superior to monotherapy of beta lactam in animal rate models

SUPPORTING EVIDENCE

• Some studies showed no clinical differences when combination therapy is used in nonneutropenic and neutropenic patients.
• If organism is intermediate to beta lactam and susceptible to aminoglycosides, synergy can be assumed. (Antibiotic Guideline)
• MDR Pseudomonas – Ceftolozane/Tazobactam (if susceptible) or Anti-pseudomonal B-lactam PLUS Aminoglycoside if synergy is predicted or confirmed
• BMJ – Treatment for gram negative infection (include Pseudomonas) However, 2 drugs in combination can be used if the infection is in a difficult area to penetrate, such as a lung abscess, an empyema, or an accompanying endocarditis

EVIDENCE NOT SUPPORTING COMBINATION

• Monotherapy with a single antibiotic should be sufficient
• Pseudomonas aueruginosa in early onset HAP – IV Tazosin 4.5g qid or IV Cefepime 2g bd. Monotherapy is recommended for early onset of HAP
• No difference in cure rate when antipseudomonal penicillin + aminoglycosides compared to antipseudomonal penicillin alone from an observational study on Pseudomonal bacteremia
• Prospective study found 2 or more antipseudomonal antibiotics was not superior in survival rate compared to a single agent antipseudomonal.
• Since 1989, studies have shown that results are similar between patients with HAP who have single or combination therapy
• The routine use of an aminoglycoside or another second agent effective against Gram-negative facultative and aerobic bacilli is not recommended in the absence of evidence that the patient is likely to harbor resistant organisms that require such therapy

 SUMMARY

SOURCE  OF REFERENCE	RECOMMENDATION	COMMENTS
National Antibiotic Guidelines 2014 (Malaysia)	IV Tazosin MDR P. aeuruginosa: IVTazosin or IV Cefepime + IV Amikacin	Use monotherapy in early onset HAP Use combination if MDR pathogen is suspected
BMJ	Empiric: 2 antipseudomonal agents Pathogen-directed: Monotherapy with single antipseudomonal agent	Combination can be used if the infection is in a difficult area to penetrate, such as a lung abscess, an emphysema, or an accompanying endocarditis
Antibiotic Guidelines 2015-2016 (John Hopkins Medicine)	MDR : Ceftolozane/Tazobactam (if susceptible) or Antipseudomonal beta lactam + Aminoglycoside (if synergy if predicted or confirmed)	If organism is intermediate to beta lactam and susceptible to aminoglycosides, synergy can be assumed.

• There is no convincing clinical evidence that using two active agents instead of one leads to improved outcomes despite theoretical synergistic activity or decreases the risk of emergent resistance.
• But using two agents for empiric therapy may increase the likelihood that an active agent will be used for a potentially resistant organism, thus associated with better outcomes for serious infections.
• Insufficient evidence showing a benefit of a second agent for continued therapy once pathogens and antimicrobial susceptibilities are known

REFERENCES

1. http://cmr.asm.org/content/25/3/450.full

2.http://bestpractice.bmj.com/best-practice/monograph/720/treatment/step-by-step.html

3. http://www.hopkinsmedicine.org/amp/guidelines/Antibiotic_guidelines.pdf

4. National Antibiotic Guidelines 2014