**1. Introduction**

182 Basic Nephrology and Acute Kidney Injury

Parikh CR & Devarajan P New biomarkers of acute kidney injury. Crit Care Med 2008,

Parikh CR, Mishra J,Thiesse-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P&

after cardiac surgery. Kidney Int 2006,70:199-203

Edelstein CL. Urinary IL-18 is an early predictive biomarker of acute kidney injury

364):S159-S16

Nephrotoxicity associated with vancomycin administration has been a topic of debate for over five decades (Tables 1 & 2). Vancomycin is a glycopeptide antibiotic excreted by the kidney and has been used extensively, especially for methicillin-resistant staphylococcus aureus (MRSA) and for many strains of pathogenic staphylococcus epidermis. The nephrotoxic potential of vancomycin is neither fully appreciated nor well characterized. Previously, most reports of acute kidney injury (AKI) associated with vancomycin had blamed the acute renal failure (ARF) on early, relatively impure formulations of vancomycin (impurities popularly known as Mississippi mud). This conventional belief and the ensuing ambiguity if not controversy in the literature about its nephrotoxic potential have led to common notion that it is rather innocuous. Its popularity as an inexpensive and effective anti-staph medication and its widespread use had contributed to the increased incidence of AKI. But the impurity theory no longer holds because the modern purified preparations are devoid of additives.

The incidence of vancomycin (Van)-induced AKI (Van-AKI) has been on the rise due to (1) the staphylococcal epidemic, (2) the increasing incidence of health-care associated pneumonia (HCAP) and osteomyelitis (due to mounting use of prosthetic hard-wares and more ready diagnosis by routine MRI and CT scans), and (3) wider acceptance and practice of protracted vancomycin administration as outpatient or in nursing homes, where unfortunately physician involvement and toxicity monitoring are inherently less vigorous.

This issue is further compounded by the poor recognition and/or delayed diagnosis due to (1) the outdated notion that vancomycin is relatively benign and safe (Sorrel et al 1985, Kalil et al 2010), (2) the lack of modern guidelines in drug and creatinine monitoring, (3) the recent Infectious Disease (ID) recommendation to target trough levels of 15-20 mg/L in treating MRSA with potentially higher minimal inhibitory concentration (MIC) than the typical sensitivity range of <1 mg/L, (4) the prevailing assumption of renal tolerance based on absolute serum creatinine levels below certain rather arbitrary threshold, instead of using changes in serum creatinine or changes in estimated creatinine clearance from baseline, and

<sup>\*</sup> Both authors contributed equally to the work in this Chapter)

Vancomycin-Induced Nephrotoxicity 185

Farber et al (1983) 12 39 - 65 Use of aminoglycosides, pre-existing

Odio et al (1984) 4 Not given Concurrent aminoglycosides, 3 patients

Sokol et al (2004) 1 Not given Bacteremia, concomitant nephrotoxins

Ladino et al (2008) 5 42 - 86 Sepsis in 1, Bacteremia in 1, and acute

Shah-Khan et al (2011) 1 64.7 Sepsis secondary to Serratia

38 - 110; Mean ± SE ( 70 ± 10)

adverse events in large cohorts usually succeeded in identifying a substantial and statistically significant incidence of renal complications (Bailie et al., (1988); Colomo et al., (2010); Farber et al., (1983); Goetz et al., (1993); Hidayat et al., (2006); Ingram et al., (2008); Lodise et al., (2008); Pritchard et al., (2008); Rybak et al., (1990); Vance-Bryan et al., (1994) ), due to the inherently retrospective and epidemiologic nature, most if not all such largegroup analyses were unable to capture sufficient key details in the affected individual patients to unequivocally establish a cause-and-effect relationship. There are also growing numbers of case reports, albeit is less than two dozen spanning over 50 years, which attributed the AKI to vancomycin (Barraclough et al., (2007); Dangerfield et al., (1960); Dutton & Elmes et al., (1959); Frimat et al., (1995); Ladino et al., (2008); Odio et al., (1984); Psevdos et al., (2009); Shah-Khan et al., (2011); Sokol et al., (2004)). But as will be reviewed in detail below, they often failed to definitely exclude other potential causes of acute renal failure (ARF), including sepsis, allergic interstitial nephritis, urinary tract obstruction, hemodynamic derangements, other concomitant nephrotoxic agents, radio-contrast dyes,

We have three objectives in writing this chapter. One, we shall draw upon the evidence from a thorough review of the published literature and from the detailed analyses of our own experience to argue for the existence of Van-AKI. Two, based on the insights deduced from these two sources, we will describe and characterize the typical picture of Van-AKI,

Frimat et al (1995) 1 50 None

Barraclough et al (2007) 1 66 None

Psevdos et al (2009) 2 38.6 - 60.5 HIV

Table 2. Case reports describing Vancomycin-induced Nephrotoxicity

6

ischemia, volume depletion, and other intrinsic renal insults.

Other Unexcluded Confounding or Contributing Factors to ARF

Pre-existing renal disease in all 4; given 6-13 g over 2-5 days & as boluses in 30 min

renal disease

had pre-existing renal disease

(piperacillin/tazobactam, amikacin)

allergic interstitial nephritis in 1

marcescense

None

Highest serum vancomycin levels (mg/L)

No. of patients

Duton and Elmes (1959) 4 Not given

Authors and publication dates

Bilal, Abu-Romeh, Rousan & Lau

[current study]

**2. Objectives** 

(2011)


Table 1. Literature on Vancomycin-induced Nephrotoxicity: Large Epidemiologic Surveys and Drug Toxicity & Efficacy Monitoring Studies

(4) the failure to appreciate AKI causes accumulation of the renally excreted vancomycin, excess of which in turn inflicts further damage to the kidney, setting up a vicious cycle. Indeed, the literature is replete with observational studies (Table 1) and case reports (Table 2) which in the overall aggregate provide a large body of evidence in support of the contention that vancomycin could be nephrotoxic. Although published studies monitoring

Possibility of additive toxicity between vancomycin and aminoglycosides should be considered

Vanomycin is a safe drug with minimal side effects as long as levels are kept below 10 mg/L

Area under the curve (AUC) is more important in determining the toxicity of vancomycin as compared to magnitude of peak concentration.

Combination of vancomycin and aminoglycosides is more nephrotoxic than individual agents alone

Risk of nephrotoxicity in elderly is greater than young and independent of aminoglycoside administration

Serum steady-state vancomycin levels >28 mg/L markedly increase the risk of nephrotoxicity

Increasing trough vancomycin levels >14 mg/L and length of therapy increase the risk of nephrotoxicity

Vancomycin > 4 g/day are associated with 3 fold increased rates of nephrotoxicity vs. < 4 g/day; both doses associated with higher risks than linezolid

Daptomycin is superior to vancomycin in treating cellulitis and has with minimal side effect profile

Vancomycin and teicoplanin are not associated with more renal dysfunction as compared to linezolid.

Vancomycin should be used with caution in critically ill patients with acute renal failure

Publication years Aim of study Key Results and Conclusions

Retrospective study of toxicity of preparations of Vancomycin from 1974 to 1981

A prospective study of adverse reactions of vancomycin therapy

Literature review of vanomcyin induced nephrotoxicity and ototoxicity.

Prospective study to compare toxicity of vancomycin and aminoglycosdies in combination and alone.

Comparative assessment of vancomycin toxicity in young and elderly hospitalized patients

To identify risk factors of nephrotoxicity with continuous vancomycin infusion in outpatient setting

Relationship between increasing vancomycin trough concentrations and incidence of nephrotoxicity

To determine nephrotoxic potential of vancomycin based on dosage and compare to linezolid

To determine efficacy and safety of daptomycin vs vancomycin against cellulitis

Linezolid vs vancomycin or teicoplanin for nosocomial pneumonia

Impact of administration of vancomycin or linezolid to critically ill patients

and Drug Toxicity & Efficacy Monitoring Studies

Table 1. Literature on Vancomycin-induced Nephrotoxicity: Large Epidemiologic Surveys

(4) the failure to appreciate AKI causes accumulation of the renally excreted vancomycin, excess of which in turn inflicts further damage to the kidney, setting up a vicious cycle. Indeed, the literature is replete with observational studies (Table 1) and case reports (Table 2) which in the overall aggregate provide a large body of evidence in support of the contention that vancomycin could be nephrotoxic. Although published studies monitoring

Authors &

Farber et al 1983

Sorrell et al 1985

Bailie et al 1988

Goetz et al 1993

Vance-Bryan et al 1994

> Ingram et al 2008

Pritchard et al 2008

Lodise et al 2008

Pertel et al 2009

Kalil et al 2010

Colomo et al 2010


Table 2. Case reports describing Vancomycin-induced Nephrotoxicity

adverse events in large cohorts usually succeeded in identifying a substantial and statistically significant incidence of renal complications (Bailie et al., (1988); Colomo et al., (2010); Farber et al., (1983); Goetz et al., (1993); Hidayat et al., (2006); Ingram et al., (2008); Lodise et al., (2008); Pritchard et al., (2008); Rybak et al., (1990); Vance-Bryan et al., (1994) ), due to the inherently retrospective and epidemiologic nature, most if not all such largegroup analyses were unable to capture sufficient key details in the affected individual patients to unequivocally establish a cause-and-effect relationship. There are also growing numbers of case reports, albeit is less than two dozen spanning over 50 years, which attributed the AKI to vancomycin (Barraclough et al., (2007); Dangerfield et al., (1960); Dutton & Elmes et al., (1959); Frimat et al., (1995); Ladino et al., (2008); Odio et al., (1984); Psevdos et al., (2009); Shah-Khan et al., (2011); Sokol et al., (2004)). But as will be reviewed in detail below, they often failed to definitely exclude other potential causes of acute renal failure (ARF), including sepsis, allergic interstitial nephritis, urinary tract obstruction, hemodynamic derangements, other concomitant nephrotoxic agents, radio-contrast dyes, ischemia, volume depletion, and other intrinsic renal insults.
