**6. Conclusions and recommendations**

In conclusion, the era of vancomycin administration has spanned over half a century. Due to the widespread use of antibiotics whether indicated or not, there has been a growing emergence of microorganisms increasingly resistant to the existing antibiotics. MRSA has dictated the greater reliance on vancomycin. This in turn breeds the development of strains relatively insensitive to vancomycin, forces physicians to target higher drug levels and

Vancomycin-Induced Nephrotoxicity 223

9. Since it is unproven that achieving trough levels of 15-20 mg/L is necessarily and unequivocally associated with superior clinical response than 10-15 mg/L (Hermsen, Hanson et al. 2010, Chan, Pham et al. 2011), a balance must be struck for a given patient between the efficacy in combating infection and the avoidance of Van-AkI in

10. For patients with ARF, rapidly rising serum creatinine, and/or sustained vancomycin levels in the toxic range (>45 mg/L), renal consultation should be considered to assist with dosage adjustment and perhaps removal by hemodialysis, possibly to ameliorate

consequently increasing the incidence of Van-AKI. The growing incidence of diagnosed diabetic foot ulcers and osteomyelitis and the mounting incidence of HCAP have further escalated the prescriptions of vancomycin, contributing to the increasing appearance of Van-AKI. Though unproven, it appears from personal and anecdotal experience of the senior author over the last 4 decades that the incidence of vancomycin-induced nephrotoxicity has

Although vancomycin levels are typically monitored (albeit without any systematic or rational pattern) the primary goal is to ensure a relative drug excess and therefore adequacy of bacterial killing, not to prevent nephrotoxicity. Generally, renal safety almost appears to be an afterthought, only considered when serum creatinine is found to be very high or vancomycin level is in the blatantly toxic range. This is because to date Van-AKI as a real clinical entity of major concern has remained a debatable issue and eluded the attention of the most physicians except the ID experts and nephrologists. We believe and hope this chapter has firmly and fully established this as a serious and significant predictable adverse consequence of vancomycin administration, especially during dosage escalation, during prolonged therapy, used at rather high doses, and/or given without any following tight and

There have been few if any published specific and pragmatic guidelines aimed at preventing and/or ameliorating AKI. Until large and prospective studies have been conducted to generate better alternatives, we would recommend the following interim and tentative

Bailie, G. R. and D. Neal (1988). "Vancomycin ototoxicity and nephrotoxicity. A review."

Baker, R. J. and C. D. Pusey (2004). "The changing profile of acute tubulointerstitial

Barraclough, K., M. Harris, et al. (2007). "An unusual case of acute kidney injury due to

Cavalcanti, A. B., A. R. Goncalves, et al. (2010). "Teicoplanin versus vancomycin for proven

Chan, J. D., T. N. Pham, et al. (2011). "Clinical Outcomes of Linezolid vs Vancomycin in

or suspected infection." *Cochrane Database Syst Rev*(6): CD007022.

vancomycin lessons learnt from reliance on eGFR." *Nephrol Dial Transplant* 22(8):

Methicillin-Resistant Staphylococcus aures Ventilator-Associated Pneumonia:

Table 7. Recommendations for the Prevention of Vancomycin-induced Nephrotoxicity

the actual dosing to achieve certain recommended target ranges.

nephrotoxicity and accelerate recovery.

close safety precautions.

2391-2394.

guidelines.

**7. References** 

been under-recognized, under-diagnosed, and under-reported.

*Med Toxicol Adverse Drug Exp* 3(5): 376-386.

nephritis." *Nephrol Dial Transplant* 19(1): 8-11.

Retrospective Analysis." *J Intensive Care Med*.


1. Vancomycin is nephrotoxic and should be used only if truly indicated and in the

2. Close surveillance for Van-AKI must be performed throughout treatment by measuring drug levels and serial serum creatinine, once daily the first week, thrice weekly the second week, and no fewer than twice weekly thereafter. These preventive measures should be mandatory and in some cases done daily for the following cohorts at increased risks for AKI. (a) Those treated in the outpatient setting, nursing homes, or long-term care facilities; (b) Critically ill and complicated patients; (c) Patients needing high trough levels of ~15-20 mg/L and/or rapid dose escalation; (d) Protracted duration > 2 weeks; (e) Pre-existing CKD; (f) ARF or unstable/fluctuating

3. Scheduled vancomycin dosing should be abandoned, and if absolutely necessary, written for less than 2 - 3 days at a time (like titrating Coumadin dosage in anticoagulation). To take advantage of the latest creatinine and vancomycin levels, daily orders should be written for (a) pre-existing elevated serum creatinine or changing levels, (b) the first week of initiating therapy due to the inherent non-steady

4. Vancomycin should be stopped or drastically cut if any of the following thresholds emerges: (a) Doubling of normal baseline serum creatinine, (b) A serum creatinine ≥ 1.5 mg/dl for adults, (c) 10- to 12-h trough levels > 20-25 mg/L. Vancomycin must be stopped immediately if (a) or (b) plus (c) are present. A better safeguard will be a standard protocol by which the ordering MD &/or the RN executing the order is required to review, register, and document the latest trough level and the latest serum creatinine *before* administering the vancomycin (similar to blood sugar documentation

5. Since serum creatinine is an insensitive and inaccurate index of GFR, its reciprocal x 100 (100/serum creatinine) should be used to better estimate CrCl (and GFR). For a given patient, the decrement in CrCl will yield a more accurate measure of relative GFR losses and if this exceeds 20-30 %, nephrotoxicity should be considered and

6. Ordering "random" serum vancomycin levels should be discouraged because they are un-interpretable (without published data to extrapolate to or correlate with the AUC). Reconstruction of the timing of a "random" level relative to the last dose is tedious, time-consuming and prohibitive. Since they tend to confuse and mislead in clinical decisions on proper dosage adjustments, only true 10-12 h trough levels (or in some

7. For safety reasons, the default mode should be to *"give* the *next dose only if the trough level falls below the therapeutic target*", as opposed to *"keep giving to sustain the trough level*

8. After an initial loading dose (identical regardless of renal function), the daily maintenance dose must be reduced in CKD and/or ARF, using the published nomogram (15 x CrCl in ml/min) (in mg per day). If serum creatinine is stable, CrCl (in ml/min) can be estimated by the Cockcroft-Gault formula [(140 – age in years) x (lean body mass in kg) / (serum creatinine in mg/dl x 72). A smaller dose than calculated must be given in: (a) elderly, (b) emaciated, (c) edematous, (d) obese, and (e) paralysis

or amputees because the formula will over-estimate CrCl in these conditions.

absence of other safer suitable alternatives.

serum creatinine.

state, and (c) rapid dose escalation.

before giving the next dose of insulin).

vancomycin stopped or reduced.

*above the target range*".

special necessary cases 24- or 48-h) should be obtained.


Table 7. Recommendations for the Prevention of Vancomycin-induced Nephrotoxicity

consequently increasing the incidence of Van-AKI. The growing incidence of diagnosed diabetic foot ulcers and osteomyelitis and the mounting incidence of HCAP have further escalated the prescriptions of vancomycin, contributing to the increasing appearance of Van-AKI. Though unproven, it appears from personal and anecdotal experience of the senior author over the last 4 decades that the incidence of vancomycin-induced nephrotoxicity has been under-recognized, under-diagnosed, and under-reported.

Although vancomycin levels are typically monitored (albeit without any systematic or rational pattern) the primary goal is to ensure a relative drug excess and therefore adequacy of bacterial killing, not to prevent nephrotoxicity. Generally, renal safety almost appears to be an afterthought, only considered when serum creatinine is found to be very high or vancomycin level is in the blatantly toxic range. This is because to date Van-AKI as a real clinical entity of major concern has remained a debatable issue and eluded the attention of the most physicians except the ID experts and nephrologists. We believe and hope this chapter has firmly and fully established this as a serious and significant predictable adverse consequence of vancomycin administration, especially during dosage escalation, during prolonged therapy, used at rather high doses, and/or given without any following tight and close safety precautions.

There have been few if any published specific and pragmatic guidelines aimed at preventing and/or ameliorating AKI. Until large and prospective studies have been conducted to generate better alternatives, we would recommend the following interim and tentative guidelines.
