**Objective 2: To describe and characterize the clinical and renal function profile for a typical Van-AKI, using lessons and insights from the reviewed literature and our own experience**

To this end, we examined and tested the validity of the various independent risk factors proposed from the literature, namely serum vancomycin levels, total dose administered, and the duration of administration in our group of 6 patients. We attempted to generate insights from our own experience and that of the literature by doing the following statistical analyses. We first grouped their demographic data and clinical characteristics including hematologic data. We abstracted and tabulated the various parameters and indices of vancomycin therapy and longitudinal renal function, for each patient and also the entire group, using 100/serum creatinine as the estimate of creatinine clearance (CrCl) (Table 6). We analyzed their serial serum creatinine (and the associated CrCl) by calculating group means (and variance as standard errors), throughout the entire course of their AKI (Figure 7), starting from their initial baseline, to the days just before serum vancomycin reached its peak, through the days of peak vancomycin levels, then the days of peak serum creatinine,

Vancomycin-Induced Nephrotoxicity 189

surveys and drug toxicity monitoring studies performed in sizable patient cohorts taking vancomycin, which suggested an association between the drug and acute elevation of serum creatinine (Farber et al. (1983), Sorrell et al. (1985), Bailie et al. (1988), Rybak et al. (1990), Goetz et al. (1993), Vance-Bryan et al. (1994), Hidayat et al. (2006), Lodise et al, (2008), Pritchard et al. (2008), Ingram et al. (2008), Pertel et al. (2009), Kalil et al. (2010), Rodriguez Colomo et al. (2010). The second body of evidence (2) (Table 2) is based on the growing number of case reports describing the association between acute nephrotoxicity and vancomycin (Dutton & Elmes et al.(1959), Dangerfield et al. (1960), Odio et al. (1984), Frimat et al. (1995), Sokol et al.

These studies have collectively provided four lines of evidence implicating vancomycin in the pathophysiology of AKI: (a) Correlation between acute rise in serum creatinine and high serum vancomycin levels (Rybak et al 1990, Hidayat et al 2006, Ingram et al 2008, Lodise et al 2008, Pritchard et al 2008); (b) Increased incidence of acute renal failure (or potentiation of nephrotoxicity) when vancomycin was also administered concurrent with aminoglycosides (Farber et al 1983, Rybak et al 1990, Goetz et al 1993); (c) Increased incidence of AKI with prolonged duration of vancomycin therapy (Hidayat et al, 2006, Pitchard et al 2008); (d) Increased incidence of AKI with vancomycin compared to linezolid in comparable cohorts with similar patient characteristics (Lodise et al 2008, Colomo et al, 2010). The studies

a. ARF was more often associated with a higher steady-state or trough serum vancomycin

Rybak et al reported in 1990 that higher serum trough vancomycin levels were associated with the development of elevated serum creatinine (Rybak et al., 1990). In the ensuing two decades, this observation was not only confirmed but also extended by the studies of

Since the new millennium, the widespread use of vancomycin has led to the expected emergence of strains of methicillin resistant staphylococcus aureus (MRSA) that have only intermediate sensitivity to vancomycin, based on higher than the classical minimum inhibitory concentration (MIC) of 1 mg/L. Accordingly, the Infectious Disease (ID) guidelines have recommended higher trough concentrations like between 15-20 mg/L (Rybak et al., 2009) in order to maximize the chances of eradicating such infections. One unintended consequence was the apparent rise in the incidence of AKI by following such

Thus, in a prospective study on the efficacy and toxicity of vancomycin during treatment of these relatively resistant MRSA strains by targeting and achieving the higher trough level of 15-20 mg/L, Hidayat et al. (2006) not only noted a higher mortality rate and a poorer end-oftreatment response**,** but also the development of nephrotoxicity in the subset of patients

In 2008, Ingram et al. performed a retrospective cohort study of 102 adults to identify risk factors for nephrotoxicity during continuous outpatient vancomycin administration between 2004 and 2007. The incidence of nephrotoxicity, defined as ≥ 50% increase in baseline serum creatinine, was about 15.7%. Based on their analyses, a steady-state serum vancomycin concentration of ≥ 28 mg/L was thought to be an independent risk factor for

Since the published new ID guidelines to keep trough level between 15-20 mg/L for resistant strains of MRSA, a good number of clinicians have increased the dose to >4 g/day

(2004), Barraclough et al. (2007), Ladino et al. (2008), Psevdos et al. (2009)).

providing these four lines of evidence will be presented in the same order.

guidelines too rigidly but without closer vigilance of the level of renal function.

Hidayat et al (2006), Ingram et al (2008), and Lodise et al (2008).

**(A) (1): Epidemiologic and drug toxicity monitoring studies** 

levels and linked to higher daily doses.

with demonstrably higher trough levels.

developing nephrotoxicity.


Table 5. For Intra-renal insults (N = 78 or 77% of the 101 cases of Acute Kidney Injury)

the days of nadir vancomycin levels, and finally to the days of nadir serum creatinine at maximal recovery 60 days after the initiation of vancomycin. We also plotted serial vancomycin levels against the renal functional profile to evaluate and define the temporal relationships between drug levels and kidney function during the evolution of and recovery from AKI (Fig 7).
