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twice daily dose had a 53.6% probability of temperature

resolution compared with 79.7% for the once daily regimen.

Additionally, nephrotoxicity of the twice daily dose was

predicted to be significantly greater (24.6%) than the once

daily regimen (

1%). The specific dose needed to obtain

efficacy would therefore be dependent on the MIC of

gram-negative bacteria in one’s clinical population and the

patient’s renal function. If MICs are below 1mg/L, doses of

3-5mg/kg once daily would be sufficient to obtain adequate

exposure thresholds. The Hartford Nomogram dose of

7mg/kg was designed to achieve optimal Cmax/MIC ratios

for gentamicin and tobramycin at the MIC of 2mg/L,

which was the MIC90 for

P. aeruginosa

at the institution

at that time. In contrast, MICs of 4mg/L would require

dosages of 10-14mg/kg daily to achieve the requisite

pharmacodynamic targets. For patients with normal kidney

function, these doses could be administered daily; however,

for patients with moderate to severe renal failure, re-dosing

should be delayed until concentrations fall below 1mg/L.

Despite no change to the FDA labels, optimized, high-dose,

extended-interval aminoglycoside dosing is now the most

common dosing regimen employed for this antibiotic class (10).

BETA-LACTAMS

Beta-lactam

antibiotics

display

time-dependent

bactericidal activity, and in general, require fT

MIC for

50% of the dosing interval to achieve maximal effects;

however, exposure can vary by the specific beta-lactam

class. For instance, while the penicillin-based beta-

lactams are reported to require 50% fT

MIC, human and

animal studies with cephalosporins suggest a requirement

between 50% and 70% fT

MIC (11-13). The carbapenems

(i.e., doripenem, ertapenem, imipenem, meropenem) are

generally thought to achieve maximum bactericidal activity

40% fT

MIC (14). As a result, maximizing the time that

concentrations remain above the MIC is the administration

strategy. Various methods have been employed to

maximize T

MIC, including giving higher dosages,

administering the drugs more often, and prolonging the

infusion time (either to 3-4 hours depending on room

temperature stability or continuously over 24 hours). In

general, the most effective way to optimize exposure,

particularly against MDR gram-negative bacteria, to both

increase the administered dose and prolong the infusion,

thereby maintaining a concentration above higher MICs

for the required bactericidal exposure time. This has been

applied to beta-lactams such as cefepime, doripenem,

and meropenem in numerous studies. In patients with

normal renal function, 2 grams every 8 hours (each dose

administered as a 3 or 4 hour prolonged infusions) dosing

regimens achieve a high probability of treating organisms

considered resistant with MICs of 8-16μg/ml and

16-32μg/ml for doripenem/meropenem and cefepime,

respectively, which is significantly greater than if the same

dosage regimen were infused over the standard 30 minutes

(15). Piperacillin/tazobactam dosing regimens can also be

optimized by employing continuous or prolonged infusion

administration. Kim and colleagues found that a 4.5g

every 6 hour dose (with each dose infused over 3 hours)

would achieve a similar pharmacodynamic exposure to

the same daily dose (18.0g) administered as a continuous

infusion, and both would have higher probabilities of

target attainment than the standard 4.5g every 6 hour (30

minute infusion) dose (16). Superior clinical outcomes were

observed by Lodise and colleagues after implementing a

piperacillin/tazobactam dosing regimen at their medical

center where all piperacillin/tazobactam orders for 3.375g

every 6 hours (30 minute infusion) were changed to 3.375g

every 8 hours (4 hour prolonged infusions) (17). In patients

with

P. aeruginosa

infections, the prolonged infusion had

a lower 14-day mortality rate (12.2% vs. 31.6%, p=0.04)

and shorter hospital stay (21 days vs. 38 days, p=0.02)

that reached statistical significance when limited to

critically-ill patients with an APACHE II score of

≥

17. A

number of clinical trials, mostly observational in design,

have been conducted with continuous or prolonged

infusion beta-lactams. A more thorough review of these

studies is outside the scope of this paper, but can be found

here (15,18). However, the most rigorous designed clinical

studies comparing continuous infusion directly to the

same beta-lactam administered as a standard 30 minute

infusion include the BLING (Beta-Lactam INfusion Group) I

and II studies, which were both multicenter, prospective,

double-blind, randomized controlled trials (19,20).

BLING I (19) enrolled 60 patients with severe sepsis who

were randomized to continuous infusions of piperacillin/

tazobactam, meropenem or ticarcillin/clavulanate or the

same drugs administered as an intermittent schedule.

Clinical cure in the continuous infusion arm was 70%

compared with only 43% (p=0.037) in the intermittent

infusion treated patients. T

MIC was also significantly

greater in the continuous arm. BLING II (20) enrolled 432

patients from 25 intensive care units across Australia,

Asia and Europe. The larger study, however, did not find

a difference in the primary endpoint, which was alive

intensive care unit free days at day 28, a different and

more challenging endpoint from the earlier trial. BLING

II had notable limitations including a high prevalence

of susceptible bacteria. In summary, most studies with

continuous and prolonged infusion beta-lactams have

demonstrated their greatest value in treating patients who

are more critically ill and infected with higher MIC pathogens

(i.e., less susceptible).

[REV. MED. CLIN. CONDES - 2016; 27(5) 615-624]