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The main results of the present study are: 1) our protocol seems to consent to a fast
achievement of a target VSC in patients with normal kidney function and in those with
kidney dysfunction; 2) the presence of an augmented renal clearance was the main determinant
of the difficulties in reaching a target VSC.

Early antibiotic administration should aim to reach adequate target VSC within a few
hours from infusion 10], 17], 19]. However, critically ill patients usually have a large volume of distribution which
likely reflects significant capillary leakage. The latter, coupled with aggressive
fluid loading, can expand the interstitial space 4], 20]. Hence hydrophilic antimicrobials — distributed exclusively in the extracellular
compartment— are expected to be diluted. This shift of fluid may favour movement of
drug into the interstitium and a decreased VSC is expected. Moreover, while critical
illness might alter the volume of distribution, renal dysfunction additionally makes
antibiotic pharmacokinetics even more unpredictable 8]. As a consequence, patients with decreased renal function require vancomycin to be
administered following dose adjustments. Hence our protocol was designed in order
to avoid both a VSC under and over the target range, although we choose to favour
the avoidance of a VSC under the range since its association with an increased in-hospital
mortality. At the same time we felt that patients with kidney dysfunction should have
had a specific protocol because of reduced renal clearance. Finally, target VSC may
be difficult to achieve because of the presence of augmented renal clearance 9], 12], 21]. ARC is characterised by an enhanced renal elimination of circulating solutes observed
in critically ill patients 8], 22]. The presence of ARC might imply subtherapeutic levels of a given drug for substantial
periods of the dosing interval resulting in treatment failure or selection of resistant
organisms 1], 12], 22].

All the above mentioned factors imply great inter-individual variability in pharmacokinetics,
complicating accurate prediction of serum concentrations in ICU patients, making evident
the need of a frequent dosage of VSC in order to make the daily dose of this antibiotics
adequate 5].

A below-range VSC was observed in only 20 % of patients of both groups. However, only
patients with kidney dysfunction progressively and significantly reduced this percentage,
which became about 9 % at the third VSC determination. Interestingly, the group with
normal kidney function had a different behaviour. Between the first and the third
VSC determination, it became progressively evident the relevance of an ARC that did
not allow this group to decrease the percentage of patients with VSC under the range.
This is of clinical relevance since patients who reached a subtherapeutic level at
the first VSC measurement had a significant correlation with in-hospital mortality
(OR 2.1; p 0.003).

As to the VSC in the desired range, only at the first determination group B had higher
percentage of patients with VSC in the normal range and, as a consequence, a lower
percentage with a VSC over the range (Fig. 2). At the second and the third VSC determination the two groups were almost identical.
This was the case also for VSC over the target range, being the percentage of patients
with a VSC higher than 30 mg/L of about 28 %. The increase of VSC over the target
range has been associated with a risk of nephrotoxicity that has a reported incidence
up to 35 % during vancomycin therapy 23], 24]. Hence we investigated the effects of VSC over the target range on renal function.
Interestingly no correlation was found between VSC and renal toxicity, even in patients
with kidney dysfunction. This is relevant from the clinical point of view, since other
and more expensive antibiotics are usually proposed in patients at risk of kidney
dysfunction. Such result can be explained by several factors. First of all, we considered
15–25 mg/L as a target range since a VSC over 25 mg/L can be associated with increase
of nephrotoxicity, as previously described 6]. However, other studies have proposed an upper limit of 30 mg/L 12], suggesting that nephrotoxicity could be enhanced when the VSC reaches values higher
than 30 mg/L, as it was the case of the present study. The VSC??30 mg/L was found
in about 30 % of the patients of both groups (Fig. 2), whilst the % of patients with a VSC higher than 35 mg/dl was extremely low in both
groups (about 1 %, see results section). These results underline that our algorithm
is able to adjust the VSC preventing the progressive accumulation of vancomycin without
incurring the opposite phenomenon, that is a VSC below 15 mg/dl.

Our algorithm is based on a continuous infusion of vancomycin that might have advantages
over intermittent administration 25], 26] since this strategy appears to reduce renal toxicity 25]. Despite previous studies comparing continuous and intermittent administration have
reached conflicting results 27], others demonstrated that continuous infusion of vancomycin is less expensive and
quicker in achieving target concentration, resulting in less variability in serum
concentrations 27], 19].

The presence of patients with a VSC??30 mg/L implies that our algorithm should not
be changed by increasing the daily dose of vancomycin in order to avoid a VSC under
the desired range. This is suggested by the AUC/MIC ratio, which was even at the first
VSC determination much higher than 400 (Table 2). This is of clinical relevance since Holmes et al 28] have previously demonstrated a 12 % lower mortality 30-day mortality in patients
achieving a vancomycin AUC/MIC of 373 within the first 96 h of vancomycin therapy
compared to those who did not. Instead, we believe that our algorithm should take
into account the presence of ARC, therefor increasing the dose only in patients that
really need this adjustment of the therapy.

Limitation of the study

We used a loading dose of about 15 ml/Kg of actual body weight to avoid too high VSC.
However, the LD varies among different studies and other authors suggest a LD of about
25–30 mg/Kg (low level of evidence – III – and grade of recommendation B) 5], with the aim of rapid achievement of the target VSC. Looking at our data, between
40 and 50 % of patients of both groups were over-range, generating a clinical dilemma.
Should we modify our algorithm by increasing the loading dose or should we maintain
the LD used in the present study? Indeed, it can be hypothesized that higher LD would
have determined higher plasmatic concentration. Hence it could be expected an increased
% of patient in over-range or even of patients in over range with VSC much higher
than those obtained in the present study, leading to an increase of nephrotoxicity.
Moreover, the AUC/MIC was much higher than 400 for both groups Table 2), suggesting that the LD might have been sufficient to reach the expected VSC. Further
studies are required to clarify if an increased LD could decrease the % of patients
in under-range without increasing nephrotoxicity.

Finally, calculation of creatinine clearance implies determination of urinary creatinine.
The latter, however is influenced by the volume status of the patient, treatment with
the loops diuretics and vasopressor agents, and release of antidiuretic hormone. Indeed,
correct estimation of glomerular filtration rates implies its determination by using
inulin or iohexol clearance, and radionucleotide. Unfortunately, these methods are
largely unavailable in the clinical setting.