Page 818 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 61: Principles of Antimicrobial Therapy and the Clinical Pharmacology of Antimicrobial Drugs 549

of 8 to 10 mg/kg per day. For patients with renal dysfunction, dap- agents is suspect in the current era of resistance, the pneumococcal
tomycin administration should be reduced to every 48 hours as the activity of levofloxacin and moxifloxacin is sufficient to successfully
clearance is largely dependent on renal function. Daptomycin exhibits treat this organism as monotherapy.
concentration-dependent killing and therefore the AUC : MIC ratio
is the best predictor of efficacy. In patients with neutropenic fever,
55
daptomycin at 6mg/kg per day is effective and achieves appropri- RENAL REPLACEMENT THERAPY
ate AUC : MIC ratios. Daptomycin is usually well tolerated, however Acute kidney injury often occurs as a result of sepsis in critically ill
there is a low risk of rhabdomyolysis, which can be increased in patients. Patients with acute kidney injury due to sepsis typically have
the setting of renal dysfunction. Therefore, serum creatinine phos- more severe organ dysfunction and higher mortality compared with
phokinase (CPK) levels should be checked periodically while on nonseptic patients. Continuous renal replacement therapy (CRRT) is
daptomycin therapy. In addition, while the compound has been used often used to treat acute kidney injury in these patients as it has been
in a safe and effective manner for the management of infections in shown to improve survival. Although CRRT can benefit the patient
63
obese patients, it should be recognized that calculating creatinine by preventing unfavorable outcomes, the extracorporeal clearance
clearance using conventional equations in this population may can significantly alter the pharmacokinetics of drugs, including anti-
not accurately estimate renal function. Thus care should be taken microbials. These pharmacokinetic changes can lead to suboptimal
to adjust for renal function when using doses calculated on total exposures, which can lead to treatment failures and the emergence
body weight. 56 of resistance.
■ FLUOROQUINOLONES blood, but using different mechanisms. With continuous venovenous
Hemodialysis and hemofiltration both remove solutes from the

Fluoroquinolones, often used to treat urinary tract infections and hemodialysis (CVVHD) drug removal occurs by diffusion across a
pneumonia, have a wide spectrum of antimicrobial activity including semipermeable membrane and the process is driven by a gradient,
Enterobacteriaceae, gram-negative bacilli such as P aeruginosa, and while with continuous venovenous hemodiafiltration (CVVHDF) drug
gram-positive cocci such as Streptococcus spp. 57,58 Currently the most removal occurs via convection with a pump drive pressure gradient.
commonly used fluoroquinolones include moxifloxacin, ciprofloxacin, Typically, the efficiency of drug removal is greater with CVVHDF
and levofloxacin, all of which are available in oral and intravenous compared with CVVHD.
formulations. Ciprofloxacin has slightly better activity against P aeru- As one would expect, antimicrobials that are predominantly cleared
ginosa, than levofloxacin, but overall gram-negative coverage of cip- via the kidneys are the drugs most affected by CRRT pharmacokineti-
rofloxacin and levofloxacin is similar between the two agents. Neither cally. Hydrophilic antimicrobials such as β-lactams and aminoglyco-
gemifloxacin nor moxifloxacin have activity against P aeruginosa. sides are typically excreted via the kidneys and therefore are greatly
Levofloxacin, moxifloxacin, and gemifloxacin have the most activity affected by CRRT. Some exceptions include drugs such as ceftriaxone,
against respiratory pathogens such as S pneumoniae. Moxifloxacin also which is cleared via biliary elimination and therefore is not signifi-
has activity against anaerobes such as B fragilis. Standard doses used cantly affected by CRRT. Drugs with a large volume of distribution are
for serious infections include 400 mg every 12 hours (ciprofloxacin), less affected by CRRT as these agents tend to distribute into further
750 mg every 24 hours (levofloxacin), and 400 mg every 24 hours compartments as opposed to remaining in the extracellular space.
(moxifloxacin). Since fluoroquinolones concentrate so well into urine, Lastly, only unbound drug will be removed by CRRT and therefore
lower doses can often be used for urinary tract infections caused by drugs with high protein binding will have lower clearance via CRRT.
susceptible pathogens. Levofloxacin and ciprofloxacin require dose Critically ill patients often have hypoalbuminemia and therefore
adjustments based on renal function, however moxifloxacin does not will have higher concentrations of free or unbound drug that can be
need to be renally dose adjusted. 2 removed.
The most significant adverse effects associated with fluoroquinolones It is important to understand the pharmacodynamic targets of the
are QT interval prolongation and cognitive effects such as dizziness. antimicrobials administered so that dosing is appropriate to maintain
The risk of QT interval prolongation is higher in patients who are older adequate exposures in patients receiving CRRT. The pharmacokinetics
and receiving concomitant medications that can increase QT interval or of meropenem and imipenem/cilastatin have been studied in criti-
cause arrhythmias. These drug toxicities are not a contraindication to cally ill patients receiving CVVH and CVVHDF. Since carbapenems
64
therapy, especially for patients admitted to the hospital as they would be have relatively low protein binding and volume of distribution, both
adequately monitored. agents are readily removed by CRRT. A significant amount of vari-
Since fluoroquinolones exhibit concentration-dependent killing, a ability in meropenem pharmacokinetics within this population exists
C max : AUC or AUC : MIC are the pharmacodynamic parameters best where doses of 0.5 g every 12 hours to 2 g every 8 hours have been
correlated with efficacy. The exposure required depends on the type of studied. While it was anticipated that meropenem would be removed
5
64
pathogen being treated. Typically, for gram-negative pathogens a total by CVVH and CVVHDF, it was also noted that the amount of drug
drug AUC : MIC ratio of greater than 100 is required and an fAUC : MIC clearance depended on the patient’s residual renal function. The
ratio of 30 to 50 is required for gram-positive pathogens. 59-61 Previous amount of meropenem cleared by CRRT was less in patients with pre-
pharmacodynamic Monte Carlo simulation studies suggest that the served renal function versus those in total renal failure (3.6% vs 22%).
maximum probability of achieving target AUC : MIC to treat P aerugi- Likewise, in patients with preserved renal function drug half-life was
nosa infections is only around 70% with a ciprofloxacin dose of 400 mg shorter than in those with total renal failure (1.51 vs 3.72 hours).
every 8 hours. Adequate exposure is essential in an effort to eradicate Importantly, it was noted that subtherapeutic C concentrations were
min
bacteria before they can develop resistance. Pharmacokinetically, observed (<1 µg/mL) in patients with preserved renal function even
62
the volume of distribution of fluoroquinolones does not seem to be with aggressive doses of 2 g every 8 hours. To treat serious infections,
affected greatly in critically ill patients; studies have shown a decreased a C of 4 to 8 µg/mL should be achieved and while some recommend
min
half-life, which can further reduce the overall AUC exposure. Given starting with 0.5 g every 6 to 8 hours, this can also be increased to
2
the potential of suboptimal exposures and the rise in MICs of gram- 1 g every 4 to 6 hours for very severe infections or if the MIC of the
negative pathogens, particularly P aeruginosa, fluoroquinolones should infecting pathogen is likely to be increased. Likewise, similar observa-
not be used as empiric monotherapy when treating serious infection. tions have been made with imipenem including subtherapeutic C
min
Once the gram-negative pathogen and susceptibility profile have been concentrations with doses of 0.5 g every 8 to 12 hours and therefore it
established, the fluoroquinolone may be effectively utilized as step- is recommended that doses of 0.5 g every 6 hours be administered in
down or IV-PO therapy. While the gram-negative activity of these patients receiving CRRT. 65,66

section05_c61-73.indd 549 1/23/2015 12:47:13 PM