Re-Assessing Renal Dose Adjustments of Antibiotics: Expert Q&A

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For patients with serious infectious diseases, the first 48 hours represent a critical window for antibiotic administration.
For patients with serious infectious diseases, the first 48 hours represent a critical window for antibiotic administration.

For patients with serious infectious diseases, the first 48 hours represent a critical window for antibiotic administration. Various studies have demonstrated worse outcomes in patients with infections who did not receive adequate early antibiotic treatment. In one retrospective cohort study, for example, there was a 7.6% reduction in survival for each hour that effective therapy was delayed following the onset of hypotension in patients with septic shock.1

In addition, a 2010 meta-analysis found increased mortality risk in people with sepsis  who received inadequate treatment in the first 48 hours (odds ratio [OR] 1.60; 95% CI, 1.27-1.86).2 In patients with community-acquired bloodstream infection, adequate therapy within 48 hours was strongly associated with 28-day mortality (OR 0.54; 95% CI, 0.43-0.71).3

For patients with renal impairment, however, dosing is often deferred because of  the potential for nephrotoxicity. According to a new paper published in Clinical Infectious Diseases, this practice may  increase the risk for poor outcomes unnecessarily in patients with acute kidney injury (AKI), as dose adjustment protocols for drugs cleared by the kidney are determined in early-phase pharmacokinetic trials, based on patients with stable chronic kidney disease.4

“Antibiotics do not fit cleanly into this paradigm due to overwhelmingly episodic, rather than chronic, use,” the study authors wrote. “Similarly, renal impairment may be acute, rather than chronic, in a clinically meaningful subset of acutely infected patients, especially those requiring hospitalization.”

Dose adjustments based on early-phase studies may be inappropriate for use in clinical trials for antibiotic approval and for patients with transient AKI. This may be why several  antibiotics approved by the US Food and Drug Administration — ceftolozane/tazobactam, ceftazidime/avibactam, and telavancin — have been linked with reduced clinical response in individuals with moderate renal impairment (baseline creatinine clearance 30- 50 mL/min).4

The review authors analyzed records from 18,500 unique encounters of patients hospitalized with infectious disease diagnoses to test the hypothesis that a significant portion of such patients present with acute vs chronic renal impairment, and that the impairment often resolves within 48 hours.4 The results show that 17.5% of patients had AKI on admission, with a rate that was 2-fold higher in those with admission creatinine clearance or glomerular filtration rate < 60 mL/min[/1.73 m2]. In 57% of patients with AKI, the renal injury resolved within 48 hours.

“The frequency of AKI across these infections and the rapidity with which it resolved in the majority of cases has significant implications for empirical dose reductions for renal impairment,” the study authors concluded.

For further discussion on the topic, Infectious Disease Advisor interviewed one of the authors of the review, Manjunath P. Pai, PharmD, FCP, an associate professor of clinical pharmacy and deputy director of the Pharmacokinetics Core at the University of Michigan; as well as Phyllis Tien, MD, a professor of infectious diseases at the University of California, San Francisco, and staff physician at the San Francisco Veterans Affairs Medical Center.

Infectious Disease Advisor: What are some of the issues pertaining to renal dosing of antibiotics in clinical practice?

Dr Tien: One important issue is being able to recognize that some antibiotics, if not dose adjusted, could have adverse effects. Some antibiotics can lead to renal toxicity, especially if used in conjunction with other drugs. Therefore, knowing when to monitor drug levels and kidney function while on a particular antibiotic is also important.

Dr Pai: Another issue is that there are multiple equations to estimate kidney function for renal dosing of antibiotics, but they require stable creatinine levels. Patients with active infections can have unstable serum creatinine values, which makes estimation of kidney function difficult. Clinicians may be unnecessarily reducing doses in some patients because the estimated kidney function may not be accurate.

Infectious Disease Advisor: How can clinicians avoid inappropriate dosing of antibiotics, and what are additional recommendations for clinicians?

Dr Tien: Careful assessment the patient's history and risk for renal disease, as well as recognizing whether the antibiotic used can be renal toxic is important. Working closely with a pharmacist is essential to ensure correct dosing and monitoring. In clinics or hospitals where there is an electronic prescription ordering system, building reminders or flags about a patient's kidney function and whether there might be potential for renal toxicity into the system is another way to assist clinicians in avoiding inappropriate renal dosing.

Dr Pai: Drug labels for dosing adjustments are based on patients with chronic kidney disease and not acute kidney disease, so care should be applied when reducing antibiotic doses by considering this individual patient-level factor.

Consideration regarding the safety profile of the antibiotic must be done first. If it is not a narrow therapeutic index drug, then dose reduction could be delayed until more information is gained about the stability or instability of kidney function. Within a 48-hour period, most hospitalized patients will have at least 3 measurements of serum creatinine to gain more certainty on the trajectory of kidney function. Delaying dose adjustment for 48 hours is a pragmatic option for antibiotics that are not narrow therapeutic index drugs.

Infectious Disease Advisor: What should be the focus of future research in this area?

Dr Tien: Research is needed to identify more accurate markers of kidney function. Current standard markers to determine kidney function, such as creatinine, are affected by age and muscle mass, and so elderly persons may appear to have low creatinine and thus better kidney function, leading to inappropriate dosing of antibiotics and an increased risk for adverse outcomes.

Dr Pai: Additional studies should evaluate the safety of delaying renal dose adjustment for 48 hours in both wide and narrow therapeutic index drugs.

References

  1. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
  2. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. 2010;54(11):4851-4863.
  3. Lee C-C, Lee C-H, Hong M-Y, Tang H-J, Ko W-C. Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia. Crit Care. 2017;21(1):119.
  4. Crass RL, Rodvold KA, Mueller BA, Pai MP. Renal dosing of antibiotics: are we jumping the gun? [published online September 13, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy790
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