ASK DIS: Combination of 3rd Generation Cephalosporin + Aminoglycoside in CAP

Current Guidelines:

Tazocin/Cefepime + Amikacin/Ciprofloxacin for MDR P. Aeruginosa only (NAG 14)
Tazocin/cefepime/meropenam + Gentamicin + Azithromycin/Ciprofloxacin/Levofloxacin for ICU pseudomonal cases only (BMJ)
For CAP without pseudomonal involvement commonly used combination is beta lactams + macrolides / fluoroquinolones

Combination Therapy: Rationale

Traditionally, combination antibiotic therapy Gram-negative bacteria has included two agents to which an organism demonstrates in vitro susceptibility, typically a beta-lactam and an aminoglycoside.
Although there are theoretical advantages to combination therapy shown by in vitro and animal studies, clinical data have been conflicting
often justified by one of the following three reasons:

(i) to broaden the empiric coverage provided by two antimicrobial agents with different spectra of activity
(ii) to exploit the synergy observed in vitro between two antibiotic agents compared to one (and hence improve clinical outcomes)
(iii) to prevent or delay the emergence of resistance during antimicrobial therapy

Empiric combination therapy was associated with a decreased 28-day mortality (36% versus 29%; P _ 0.0002) and increases in both mechanical ventilation-free days (Kumar et al)
However, Antipseudomonal penicillins, antipseudomonal cephalosporins, and carbapenems failed to exhibit a benefit with the addition of a second agent (Kumar et al)

Synergy : In Vitro

The combination of a Beta-lactam and an aminoglycoside allows for different mechanisms of bacterial killing
Beta Lactam-mediated disturbance of the cell walls of Gram-negative bacilli facilitates passage of aminoglycosides into the periplasmic space
These studies demonstrated that penicillin enhanced the uptake of aminoglycosides found that treatment with a combination of a beta-lactam and an aminoglycoside is superior to treatment with a beta-lactam alone
In vitro synergy appears to be variably present and strain dependent and varies with different beta-lactam and aminoglycoside combinations
use of newer, broader spectrum beta-lactams, it is unclear if the results of these studies would be different if the studies were repeated.

Synergy: Clinical

While synergistic action between beta-lactams and aminoglycosides has been shown in vitro, clinical evidence to support these data are sparse and conflicting
A prospective cohort study of 200 patients with P. aeruginosa bacteremia (both neutropenic and nonneutropenic patients) was undertaken to compare in vitro susceptibility results with mortality. No significant correlation between in vitro synergy testing (either time-kill or checkerboard) and clinical outcome was demonstrated
in contrast, retrospective study of 444 cases of Gram-negative bacteremia, synergism in vitro was correlated with better clinical responses in patients with neutropenia, shock, and P. aeruginosa infections.

Synergism conclusion

There are discrepancies when comparing in vitro and in vivo studies assessing combination therapy for infections with Gram negative bacteria.

Adverse Reactions

Nephrotoxicity

In a randomized, prospectivestudy of 876 febrile, neutropenic episodes, comparing ceftazidime with piperacillin and gentamicin, the incidence of renal toxicity was significantly higher in the combination therapy group
meta-analyses have shown that monotherapy was protective against nephrotoxicity, ranging from 17% to 70%.
Of concern is that patients with Gram-negative sepsis are often exposed to several nephrotoxins, including intravenous contrast agents, additional antibiotics associated with acute renal injury, and diuretics. They also are often volume depleted and have metabolic acidosis.
The addition of an aminoglycoside to these other agents in critically ill patients could result in synergistically worse nephrotoxicity
Even low-dose gentamicin has been associated with nephrotoxicity

Ototoxicity

Existing data suggest that prolonged therapy for 10 or more days, preexisting renal impairment, and prior treatment with aminoglycosides are risk factors for ototoxicity

Clinical Studies

retrospective observational study examining 410 episodes of P. aeruginosa bacteremia in patients with malignancies over a 10-year period. patients who received an antipseudomonal penicillin plus aminoglycoside did not have a higher cure rate than patients who received only an antipseudomonal penicillin (72% versus 71%)
A prospective, randomized clinical trial comparing ceftazidime monotherapy with ceftriaxone and tobramycin for serious infections with Gram-negative bacteria, including Pseudomonas spp., showed similar mortality between the groups
various meta-analyses are limited by the quality of the included studies. Nonetheless, the majority of meta-analyses did not find a clinical advantage to combination therapy for pseudomonal infections

HAP

found monotherapy to be appropriate for pneumonia developing within 10 days of hospitalization, while a beta-lactam antibiotic in combination with an aminoglycoside
In a randomized, open-label study comparing meropenem to ceftazidime and amikacin in 140 patients with VAP, a satisfactory clinical response was observed in 83% of patients receiving meropenem and 66% of patients receiving ceftazidime-amikacin

Conclusion

Although there are theoretical reasons why combination antimicrobial therapy may be superior to monotherapy for the treatment of infections with Gram-negative bacteria, the clinical data supporting these theories are neither overwhelming nor definitive
On the contrary, meta-analyses that have been conducted exclusively evaluating RCTs demonstrate no difference in clinical outcomes between the two treatment strategies for definitive management of infections with Gram-negative bacteria, but there are well-documented increased toxicities with combination therapy.
This suggests that patients with infections with Gram-negative bacteria are served best by receiving definitive treatment with a single appropriate antibiotic.
It should be noted that combination therapy may have some value in a specific subset of patients with severe sepsis.
Due to increasing prevalence of MDRGN infections, saving the second agent for when actually necessary is vital in the war against antimicrobial resistance

References:

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