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Systematic review

Effect of using aminoglycosides for treatment of sepsis

Systematically review of the evidence on the treatment effects and harms of any antibiotic regimen with an aminoglycoside versus any antibiotic regimen without an aminoglycoside for sepsis in adults.

Systematically review of the evidence on the treatment effects and harms of any antibiotic regimen with an aminoglycoside versus any antibiotic regimen without an aminoglycoside for sepsis in adults.


Key message

Sepsis is a potentially dangerous or life-threatening medical condition, usually caused by a bacterial infection. In Norway, sepsis is usually treated with antibiotics, and a typical regimen could be to use a narrow-spectrum antibiotic, for example a beta lactam antibiotic such as benzylpenicillin in combination with a highly potent, broad-spectrum antibiotic, such as an aminoglycoside.   

Our aim was to systematically review the evidence on the treatment effects and harms of any antibiotic regimen with an aminoglycoside versus any antibiotic regimen without an aminoglycoside for sepsis in adults.

We searched for systematic reviews, and included one systematic review that met our inclusion criteria. Based on this review which assess the clinical efficacy of beta lactam antibiotic monotherapy versus combination therapy (beta lactam + aminoglycoside-regimens) for sepsis, our main findings are:

 

  • The pooled estimate for any nephrotoxicity showed a 66 % reduction in the risk of any nephrotoxicity using beta lactam monotherapy compared with combination therapy (RR= 0.34; 95% CI [0.25, 0.46]). The quality of the evidence is low.
  • The pooled estimate for serious adverse events showed a statistically non-significant difference between beta lactam monotherapy and combination therapy (RR= 1.06; 95% CI [0.58, 1.91]). The quality of the evidence is low.
  • The pooled estimate for overall mortality showed a statistically non-significant difference between beta lactam monotherapy and combination therapy  (RR= 0.89; 95% CI [0.74, 1.08]). The quality of the evidence is low.
  • The pooled estimate for treatment failure showed a statistically significant difference between beta lactam monotherapy and combination therapy in favor of monotherapy (RR= 0.84; 95% CI [0.72, 0.97]). The quality of the evidence is moderate.

 

The pooled evidence provided in this systematic overview, are from studies done in different settings, with different patient-groups/diagnosis, different pathogens, with different regimens (doses, intervals, length of treatment). All included studies were conducted between the years 1973 and 2006 and contains only regimens comparing beta lactam monotherapy versus aminoglycosides in combination with beta lactams. Treatment failure is defined as it was in the primary studies, and hence a mixture of definitions are included. These definitions and the interpretation of the definitions might have been assessed differently by the different study authors and might have influenced the results for treatment failure.

These aspects are important to be aware of when considering this evidence for making treatment recommendations in Norway.

Summary

Background

Sepsis is defined as a clinical condition that reflects a systemic inflammatory response to infection. In serious cases, sepsis can cause organ dysfunction and death. In Norway, the standard treatment for sepsis is empirical antibiotic treatment based on the diagnostic of the etiologic agent, the expected antibiotic sensitivity, as well as pharmacodynamic- and kinetic considerations. A typical regimen could be to use a narrow-spectrum antibiotic in combination with a highly potent, broad-spectrum antibiotic, such as an aminoglycoside.  

Objective

To prepare an overview of systematic reviews considering the clinical effectiveness of antibiotic regimens with aminoglycosides compared to a regimen without aminoglycosides for treatment of sepsis according to a few pre-specified outcomes.

Method

We have conducted this overview of systematic reviews in accordance with the Handbook for the Norwegian Knowledge Center for the Health Services.

We performed a systematic search for literature and two review authors reviewed all citations to identify relevant publications according to pre-specified criteria. We retrieved full text copies of all potentially eligible publications and assessed whether these publications should be included based on our inclusion criteria. We assessed the methodological quality of potentially relevant systematic reviews using a checklist for systematic reviews. All assessments were conducted and agreed upon by two of the review authors working independently. One review author extracted data from the included systematic reviews for studies dealing with sepsis and entered and analyzed data using the Review Manager software. Another review author verified the data and analyses. We applied the GRADE method to assess overall quality of the evidence for each outcome.

Results

The literature search for systematic reviews on the effect of treatment of sepsis using aminoglycosides, was conducted in September 2013 and updated in April 2014. We identified 1434 references in total. After reading titles and abstracts, we considered 8 references possibly eligible and we read them in full text. Only one systematic review met our inclusion criteria, a recently updated Cochrane review written by Paul 2014 that compared beta lactam monotherapy versus beta lactam and aminoglycoside combination therapy in patients with sepsis. The Cochrane review authors designated studies that included patients with severe sepsis as “sepsis” and we have based our analyses on the 42 studies designated as sepsis and conducted in adults. Trials are pooled independent of type of beta lactam antibiotic used in the study arms.

Our main findings are:

The pooled estimate for any nephrotoxicity showed a 66 % reduction in the risk of any nephrotoxicity using beta lactam monotherapy compared with beta lactam-aminoglycoside combination therapy (RR= 0.34; 95% CI [0.25, 0.46]). The quality of the evidence is low.

The pooled estimate for serious adverse events showed a statistically non-significant difference between beta lactam monotherapy and beta lactam-aminoglycoside combination therapy (RR= 1.06; 95% CI [0.58, 1.91]. The quality of the evidence is low.

The pooled estimate for overall mortality showed a statistically non-significant difference between beta lactam monotherapy and beta lactam-aminoglycoside-combination therapy (RR= 0.89; 95% CI [0.74, 1.08]),

The quality of the evidence is low.

The pooled estimate for treatment failure showed a statistically significant difference between beta lactam monotherapy and beta lactam-aminoglycoside-combination therapy in favor of monotherapy (RR= 0.84; 95% CI [0.72, 0.97]. The quality of the evidence is moderate.

Discussion

The main results are that using a combination therapy of beta lactam and aminoglycoside may lead to more nephrotoxicity and probably leads to more treatment failure compared to using beta lactam monotherapy. Our report is based on data from one systematic review produced within the Cochrane Collaboration, Paul 2014. The Cochrane review included studies with hospitalized patients with sepsis acquired in the community or in the hospital. Sepsis were defined as clinical evidence of infection plus evidence of systemic response to infection. The included patients might be a mixed group of patients with more or less severe sepsis depending on the definition and inclusion criteria in the original articles. The Cochrane review did not perform analysis on a sub-group of patients with septic shock.

We were not able to identify systematic reviews of high methodological quality evaluating the effect of aminoglycosides-regimen other than in combination with beta lactam antibiotic for sepsis treatment.

A limitation with our work is that we do not know how the patients were followed up during treatment with aminoglycosides. In the Norwegian guideline on sepsis treatment, it is recommended to always evaluate the risk of acute renal failure, monitor the serum level of aminoglycosides and avoid concomitant use of nephrotoxic drugs. Lack of such thorough follow up might have led to more nephrotoxicity or other failures in the included trials than will be the case today.

The decisions and monitoring of sepsis treatment are very complex processes, demanding frequent evaluations during the course, and is also dependent on available equipment and settings. The pooled evidence provided in this systematic overview, are from studies done in different settings, with different patient-groups/diagnosis, different pathogens, with different regimen (doses; intervals; length of treatment). These aspects are important to be aware of when considering this evidence for treatment recommendations in Norway.

Conclusion

The results presented in this review indicate that beta lactam-aminoglycoside combination therapy may increase the risk of nephrotoxicity compared with monotherapy. The combination therapy probably leads to more treatment failures compared with beta lactam monotherapy in adult patients. For overall mortality and serious adverse events, there may be little or no difference between monotherapy and combination therapy. The confidence in the estimates for overall mortality, nephrotoxicity and serious adverse events are limited and the true effect may be different from the estimate. We are moderately confident in the effect estimate for treatment failure; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.

The pooled evidence provided in this systematic overview, are from studies done in different settings, with different patient-groups/diagnosis, different pathogens, with different regimens (doses, intervals, length of treatment). All included studies were conducted between the years 1973 and 2006 and contains only regimens comparing beta lactam monotherapy versus aminoglycosides in combination with beta lactams. These aspects are important to be aware of when considering this evidence for making treatment recommendations in Norway.

    About this publication

  • Year: 2015
  • Authors Sæterdal I, Holte HH, Harboe I, Klemp M.
  • ISSN (digital): 1890-1298
  • ISBN (digital): 978-82-8121-939-7