Risk factors for vancomycin nephrotoxicity

Vancomycin Nephrotoxicity Risk Factors

Onset / Magnitude

The onset of vancomycin nephrotoxicity typically ranges from three to eight days from the start of therapy. The degree of vancomycin-induced renal dysfunction is usually modest, with a typical decrease of 35-45% in creatinine clearance from baseline. However, severe renal toxicity has been associated with vancomcyin.

The histology of most cases of vancomycin-induced nephrotoxicity is unknown, but it is has traditionally been associated with interstitial nephritis.20, 21, 22 However, there are published case reports of biopsy-proven acute tubular necrosis associated with vancomycin.17, 18, 19

Concomitant nephrotoxins

The use of concomitant nephrotoxins is a significant risk factor for development of nephrotoxicity with vancomycin. Common drugs include:

Mechanism of nephrotoxicity:

  1. Acute interstitial nephritis
  2. Glomerulonephritis
  3. Tubular cell toxicity
  4. Altered intraglomerular hemodynamics
  5. Loop diuretics may also cause dehydration, which further increases the risk of developing nephrotoxicity. One study showed that a loop diuretic was present in 63% of adult patients who had nephrotoxicity during vancomycin therapy as compared with 44% with no renal toxicity.

Piperacillin-tazobactam

Piperacillin-tazobactam is increasingly being recognized as a contributor to vancomycin nephrotoxicity. In a single center retrospective study of 735 patients nephrotoxicity was reported in 4.9% of vancomycin alone and 11.1% of pip-taz alone, compared with 18.6% in combination of vancomycin and pip-taz.28 A second single center study observed a cumulative incidence of nephrotoxicity of 40.5% with combination vancomycin and pip-taz compared with 9.0% in the vancomycin alone group among 140 surgical intensive care patients.29 In a single center, retrospective, cohort study of 68 patients, nephrotoxicity occurred in 19.4% of patients in the vancomycin and pip-taz combination group compared with 6.3% in the control group.30

Obesity

Obesity was seen to be a significant predictor for occurrence and time of development of nephrotoxicity. It is postulated that the volume of distribution in the central compartment does not increase proportionally with weight and thus accounts for the higher trough values observed among obese patients.

High dose

Nephrotoxicity occurred in 9-40% of patients on high-dose therapy compared with 2% in patients on standard-dose therapy in the absence of concomitant risk factors for nephrotoxicity. Doses greater than 4 g/day are associated with both an increased incidence and a more rapid onset of nephrotoxicity.5

Duration of therapy

A recent two-phase retrospective analysis identified vancomycin serum trough concentrations >= 14 mcg/ml, duration of vancomycin therapy >= 7 days, and baseline SCR levels >= 1.7 mg/dl as independent predictors of nephrotoxicity.10

Prabaker et al. observed that the rate of nephrotoxicity increased from 12 to 22% beyond ten days of therapy. Jeffres et al. observed an odds ratio of 2.55 for nephrotoxicity after >= 14 days of treatment. 7 In another study, Hidayat et al. found that the risk appeared to increase incrementally as the treatment was prolonged in patients who achieved high trough levels (15 to 20 mcg/ml): 6% for >=7 days, 21% for 8 to 14 days and 30% for >14 days.3
Vancomycin Nephrotoxicity Risk Factors

ICU patients

A high APACHE II score, ICU stay, and receipt of vasopressor agents appear to be significant risk factors for the development of nephrotoxicity.

Lodise et al. observed that ICU patients have a higher baseline risk for development of nephrotoxicity than non-ICU patients at a lower trough concentration threshold: >20% probability of nephrotoxicity at a trough >10 mcg/ml in ICU patients versus trough >20 mcg/ml in non-ICU patients.14

Long term outcome

Acute vancomycin nephrotoxicity may rarely lead to chronic kidney damage. Biopsy proven tubular necrosis has been reported.

Conclusion

The 2009 Vancomycin therapeutic guidelines advocating much higher vancomycin doses carry a substantial risk for nephrotoxicity. The risk is incremental with higher trough levels and longer duration of therapy. Patients with multiple risk factors are particularly at risk for vancomycin induced nephrotoxicity.

References

  1. Goetz MB, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination. J Antimicrob Chemother. 1993 Aug;32(2):325-34.
  2. Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy. 1995;15:85-91.
  3. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166:2138-44.
  4. Nguyen M, Wong J, Lee C, et al. Nephrotoxicity associated with high dose vs. standard dose vancomycin therapy. In: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: ASM Press; 2007. Abstract K-1096.
  5. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52:1330-6.
  6. Haque NZ, Kiyan PO, Reyers K, et al. Nephrotoxicity in Intensive Care Unit patients with Hospital-Acquired Pneumonia : the IMPACT-HAP Project. In: 47th Annual Meeting of Infectious Diseases Society of America. Arlington, VA: IDSA; 2009. Abstract 388.
  7. Prabaker K, Tran T, Pratummas T, Goetz M, Graber C. Association of vancomycin trough levels with nephrotoxicity. In: 47th Annual Meeting of Infectious Diseases Society of America. Arlington, VA: IDSA; 2009. Abstract 192.
  8. Mora A, Dzintars K, Lat A, Frei CR, Echevarria K. Incidence of vancomycin nephrotoxicity in the absence of concomitant nephrotoxins or confounders. In: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: ASM Press; 2009. Abstract A1-1294a.
  9. Ingram PR, Lye DC, Fisher DA, Goh WP, Tam VH. Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy. Int J Antimicrob Agents. 2009;34:570-4.
  10. Pritchard L, Baker C, Leggett J, Sehdev P, Brown A, Bayley KB. Increasing vancomycin serum trough concentrations and incidence of nephrotoxicity. Am J Med. 2010;123:1143-9.
  11. McKamy S, Hernandez E, Jahng M, Moriwaki T, Deveikis A, Le J. Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children. J Pediatr. 2011;158:422-6.
  12. Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. Int J Antimicrob Agents. 2011 Feb;37(2):95-101.
  13. Gupta A, Biyani M, Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med. 2011 Sep;69(9):379-83.
  14. Lodise TP, et al. Relationship between initial vancomycin concentration and nephrotoxicity. Clin Infect Dis 2009;49:507-14.
  15. Elyasi S, et al. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol (2012) 68:1243-1255.
  16. Ladino M, et al. Acute and reversible Vancomycin Nephrotoxicity: case reports. JNRT 1(1) 2008: 4-10.
  17. Htike N, et al. Biopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis. Clin Exp Nephrol 2012 Apr;16(2):320-4.
  18. Belen C, et al. Biopsy-proven acute tubular necrosis associated with vancomycin in an adult patient. Ren Fail. 2012;34(4):502-5.
  19. Shah-Khan F, et al. Biopsy-proven acute tubular necrosis due to vancomycin toxicity. Int Journal Nephrology 2011. Article ID 436856.
  20. Gelfand MS1, Cleveland KO, Mazumder SA. Vancomycin-induced interstitial nephritis superimposed on coexisting renal disease: the importance of renal biopsy. Am J Med Sci. 2014 Apr;347(4):338-40.
  21. Wai AO, Lo AM, et al. Vancomycin-induced acute interstitial nephritis. Ann Pharmacother 1998 Nov;32(11);160-4.
  22. Hong S, Valderrama E, et al. Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci 2007 Oct;334(40:296-300.
  23. Plakogiannis R, Nogid A. Acute Interstitial nephritis associated with coadministration of Vancomycin and Ceftriaxone. Pharmacother 2007;27(20):1456-1461.
  24. Bosso JA, Nappi J, et al. Relationship between Vancomycin Trough Concentrations and Nephrotoxicity: a Prospective Multicenter Trial Antimicrobial Agents And Chemotherapy, Dec. 2011, Vol. 55, No. 12, p. 5475–5479
  25. van Hal SJ, Paterson DL, and Lodise TP. Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 Milligrams per Liter Antimicrob. Agents Chemother. 2013, 57(2):734. DOI:
  26. Horey A, Mergenhagen KA, Mattappallil A. The Relationship of nephrotoxicity to vancomycin trough serum concentrations in a veteran's population: a retrospective analysis. Ann Pharmacother. 2012 Nov;46(11):1477-83.
  27. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC, Craig WA, Billeter M, Dalovisio JR, Levine DP. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009 Aug 1;49(3):325-7
  28. Hellwig T, Hammerquist R, Loecker B, Shields J. Retrospective Evaluation of the Incidence of Vancomycin and/or Piperacillin-Tazobactam Induced Acute Renal Failure (Abstract). Crit Care Med 2011;12:79.
  29. Min E, Box K, Lane J, et al. Acute Kidney Injury in Patients Recieving Concomitant Vancomycin and Piperacillin/Tazobactam (Abstract). Crit Care Med 2011;12:200.
  30. Zeiler M, Mayhall G, Lee E. Incidence of nephrotoxicity with concomitant vancomycin and piperacillin-tazobactam versus vancomycin alone or in combination with a carbapenem, aztreonam, or levofloxacin in adult patients (Abstract). Crit Care Med 2009;12:A415.

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