We sought to determine the prevalence of phosphodiesterase type 5 inhibitor (PDE-5) mediated drug-drug interactions (DDIs) in males with HIV infection receiving antiretroviral therapy (ART) and ...identify factors associated with PDE-5-mediated DDIs.
Male US Military HIV Natural History Study participants diagnosed with erectile dysfunction (ED) and having a PDE-5 inhibitor and potentially-interacting ART co-dispensed within 30 days were included. DDIs were defined according to criteria found in published guidelines and drug information resources. The primary outcome of interest was overall PDE-5 inhibitor-mediated DDI prevalence and episode duration. A secondary logistic regression analysis was performed on those with and without DDIs to identify factors associated with initial DDI episode.
A total of 235 male participants with ED met inclusion criteria. The majority were White (50.6%) or African American (40.4%). Median age at medication co-dispensing (45 years), duration of HIV infection (14 years), and duration of ED (1 year) did not differ between the two groups (p>0.05 for all). PDE-5 inhibitors included sildenafil (n = 124), vardenafil (n = 99), and tadalafil (n = 14). ART regimens included RTV-boosted protease inhibitors (PIs) atazanavir (n = 83) or darunavir (n = 34), and COBI-boosted elvitegravir (n = 43). Potential DDIs occurred in 181 (77.0%) participants, of whom 122 (67.4%) had multiple DDI episodes. The median DDI duration was 8 (IQR 1-12) months. In multivariate analyses, non-statistically significant higher odds of DDIs were observed with RTV-boosted PIs or PI-based ART (OR 2.13, 95% CI 0.85-5.37) and in those with a diagnosis of major depressive disorder (OR 1.74, 95% CI 0.83-3.64).
PDE-5-mediated DDIs were observed in the majority of males with HIV infection on RTV- or COBI-boosted ART in our cohort. This study highlights the importance of assessing for DDIs among individuals on ART, especially those on boosted regimens.
Abstract Purpose Despite advances in the care of patients with severe burn injury, infection-related morbidity and mortality remain high and can potentially be reduced with antimicrobial dosing ...optimized for the infecting pathogen. However, anti-infective dose selection is difficult because of the highly abnormal physiologic features of burn patients, which can greatly affect the pharmacokinetic (PK) disposition of these agents. We review published PK data from burn patients and offer evidence-based dosing recommendations for antimicrobial agents in burn-injured patients. Methods Because most infections occur at least 48 hours after initial burn injury and anti-infective therapy often lasts ≥10 days, we reviewed published data informing PK-pharmacodynamic (PD) dosing of anti-infectives administered during the second, hypermetabolic stage of burn injury, in those with >20% total body surface area burns, and in those with normal or augmented renal clearance (estimated creatinine clearance ≥130 mL/min). Analyses were performed using 10,000-patient Monte Carlo simulations, which uses PK variability observed in burn patients and MIC data to determine the probability of reaching predefined PK-PD targets. The probability of target attainment, defined as the likelihood that an anti-infective dosing regimen would achieve a specific PK-PD target at the single highest susceptible MIC, and the cumulative fraction of response, defined as the population probability of target attainment given a specific dose and a distribution of MICs, were calculated for each recommended anti-infective dosing regimen. Findings Evidence-based doses were derived for burn-injured patients for 15 antibiotics and 2 antifungal agents. Published data were unavailable or insufficient for several agents important to the care of burn patients, including newer antifungal and antipseudomonal agents. Furthermore, available data suggest that antimicrobial PK properties in burned patients is highly variable. We recommend that, where possible, therapeutic drug monitoring be performed to optimize PK-PD parameter achievement in individual patients. Implications Given the high variability in PK disposition observed in burn patients, doses recommended in the package insert may not achieve PK-PD parameters associated with optimal infectious outcomes. Our study is limited by the necessity for fixed assumptions in depicting this highly variable patient population. New rapid-turnaround analytical technology is needed to expand the menu of antimicrobial agents for which therapeutic drug monitoring is available to guide dose modification within a clinically actionable time frame.
Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. A major contributor in patients with unimpaired renal function may be Augmented Renal ...Clearance (ARC), wherein urinary creatinine clearance exceeds that predicted by serum creatinine concentration. We used pharmacokinetic data to evaluate the diagnostic accuracy of a recently proposed ARC score.
Pharmacokinetic data from trauma/surgical intensive care unit patients receiving piperacillin/tazobactam were evaluated. We combined intermediate scores (4-6 points) into a single low score (≤6) group and compared pharmacokinetic parameters against the high (≥7) ARC score group. Diagnostic performance was evaluated using median clearance and volume of distribution, area under the antibiotic time-concentration curve (AUC), and achievement of free concentrations greater than a minimum inhibitory concentration (MIC) of 16 μg/mL for at least 50% of the dose interval (fT > MIC ≥ 50%). Alternative dosing strategies were explored in silico.
The ARC score was 100% sensitive and 71.4% specific for detecting increased clearance, increased volume of distribution, decreased AUC, and fT > MIC < 50% at an MIC of 16 μg/mL. The area under the receiver operating characteristic curve was 0.86 for each, reflecting a high degree of diagnostic accuracy for the ARC score. Serum creatinine less than 0.6 mg/dL had comparable specificity (71.4%) but was less sensitive (66.7%) and accurate (area under the receiver operating characteristic curve, 0.69) for detecting higher clearance rates. Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic drug levels with extended infusion dosing at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens.
Given its ability to predict antimicrobial clearance above population medians, which could compromise therapy, the ARC score should be considered as a means to identify patients at risk for subtherapeutic antibiotic levels. Adequately powered studies should prospectively confirm the utility of the ARC score and the role of antimicrobial therapeutic drug monitoring in such patients.
Diagnostic tests, level III.
Objective:
To review the efficacy of cefepime for use in infections caused by extended-spectrum beta-lactamase (ESBL)-producing organisms.
Data Sources:
A PubMed literature search (May 2000 to June ...2017) was performed using the keyword cefepime and the MeSH terms beta-lactamases, cephalosporinases, and Enterobacteriaceae infections.
Study Selection and Data Extraction:
All human, English language studies evaluating cefepime use for the treatment of ESBL-producing Escherichia coli and Klebsiella pneumoniae infections were included.
Data Synthesis:
Studies assessing the use of cefepime for ESBL infections are few, and clinical studies are limited by design and sample size. The largest pharmacokinetic/pharmacodynamic study, a Monte Carlo simulation using data from the U.S. SENTRY antimicrobial surveillance program, evaluating cefepime use for infections due to ESBL-producing organisms found a 95% to 100% probability of target attainment with traditional cefepime dosing regimens. Most clinical studies found that patients treated with cefepime empirically and definitively had higher rates of mortality than those treated with carbapenems. However, in concordance with other studies reporting minimum inhibitory concentration (MIC) data, lower MICs were associated with lower mortality.
Conclusions:
Cefepime should be avoided for empiric treatment of suspected ESBL infections and should only be considered for definitive treatment if the MIC ≤1 µg/mL. However, the site and severity of infection, local resistance patterns, and patient-specific risk factors should also help guide antimicrobial selection.
Amikacin clearance can be increased in burn injury, which is often complicated by renal insufficiency. Little is known about the impact of renal replacement therapies, such as continuous venovenous ...hemofiltration (CVVH), on amikacin pharmacokinetics. We retrospectively examined the clinical pharmacokinetics, bacteriology, and clinical outcomes of 60 burn patients given 15 mg/kg of body weight of amikacin in single daily doses. Twelve were treated with concurrent CVVH therapy, and 48 were not. The pharmacodynamic target of ≥10 for the maximum concentration of drug in serum divided by the MIC (Cmax/MIC) was achieved in only 8.5% of patients, with a small reduction of Cmax in patients receiving CVVH and no difference in amikacin clearance. Mortality and burn size were greater in patients who received CVVH. Overall, 172 Gram-negative isolates were recovered from the blood cultures of 39 patients, with amikacin MIC data available for 82 isolates from 24 patients. A 10,000-patient Monte Carlo simulation was conducted incorporating pharmacokinetic and MIC data from these patients. The cumulative fraction of response (CFR) was similar in CVVH and non-CVVH patients. The CFR rates were not significantly improved by a theoretical 20 mg/kg amikacin dose. Overall, CVVH did not appear to have a major impact on amikacin serum concentrations. The low pharmacodynamic target attainment appears to be primarily due to higher amikacin MICs rather than more rapid clearance of amikacin related to CVVH therapy.
While colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of ...drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonal Acinetobacter baumannii and receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of ≥ 60 at an MIC of ≥ 1 μg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 μg/ml, with free colistin levels ranging from 0.4 to 2.2 μg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy.
Purpose of Review
Clinicians should be encouraged to use pharmacokinetic-pharmacodynamic (PK-PD) studies to optimize antifungal drug dosing in the absence of robust comparative effectiveness data or ...in cases where evidence of causality has not yet been firmly established. The purpose of this article is to review how new triazole and echinocandin PK-PD studies have contributed to our current understanding of antifungal selection and dose optimization against invasive fungal infections. Emerging infections such as
C. auris
and novel antifungal drugs such as rezafungin will also be highlighted. Future research endeavors are suggested where currently robust clinical outcomes data associated with PK-PD target attainment are lacking.
Recent Findings
Recent results from clinical fluconazole PK-PD studies may indicate that unique AUC
24
/MIC thresholds exist for specific
Candida
species. The inability of recent studies to confirm previous fluconazole AUC
24
/MIC clinical PK-PD targets of 11 to 400 may also be due to previously unrecognized PK variability in special patient populations such as those with augmented renal clearance. A free AUC
24
/MIC threshold of 25 appears to be conserved across the azole antifungal class in animal models of invasive candidiasis. Current therapeutic drug monitoring guidance with voriconazole, posaconazole, and itraconazole has been used to indirectly confirm pre-clinical AUC
24
/MIC PK-PD targets in invasive candidiasis and aspergillosis. Elucidation of the PK-PD targets in pre-clinical models has led to successful isavuconazole dose optimization in human studies and has contributed to dosing recommendations for the novel echinocandin rezafungin. PK-PD research will also be important in guiding antifungal selection against infections caused by emerging pathogens, such as
Candida auris
, and those caused by fungi for which reduced susceptibility is a growing concern, including
Coccidioides
species and azole-resistant
Aspergillus fumigatus
.
Summary
PK-PD research may be used to inform treatment decisions for rare fungal infections, infections with rapidly changing epidemiology, in patient populations expected to have altered pharmacokinetics, for novel antifungal drugs or those with new formulations, and in cases where evidence of causality cannot be established from large randomized comparative studies. A number of animal models have been developed and more clinical PK-PD studies are being conducted. In the absence of clinical PK-PD outcome data in human studies, researchers have expanded the use of currently available therapeutic drug monitoring to gain insight into possible PK-PD targets.
We evaluated vancomycin levels as recent guidelines for therapeutic monitoring of vancomycin (not available at the time these data were collected) recommend trough levels of 15 to 20 μg/mL; however, ...this may be more difficult to achieve in patients with accelerated vancomycin clearance, such as burn patients or recipients of continuous venovenous hemofiltration (CVVH) therapy. We retrospectively studied 2110 serum vancomycin levels of 171 patients admitted to the burn intensive care unit for more than 4 years and who received vancomycin by continuous infusion (CI) or intermittent infusion (II), with or without simultaneous CVVH. In-hospital mortality, 14- and 28-day mortality following vancomycin therapy were not different between dosing methods, although increased mortality was observed in the subgroup of patients receiving CI vancomycin empirically for clinical sepsis with negative blood cultures. More vancomycin was delivered to patients daily by CI than II, and therapeutic drug monitoring costs were similar. After controlling for differences in vancomycin dose by case matching with propensity scores, mean vancomycin levels were 20.0 ± 3.8 μg/mL for CI, vs 14.8 ± 4.4 μg/mL for II (P < .001). CI dosing resulted in similar levels with or without CVVH, whereas in II dosing, CVVH appeared to significantly decrease vancomycin levels. Although CI dosing was associated with higher vancomycin levels in general and fewer levels of <10 μg/mL, significant nephrotoxicity or neutropenia was not observed. Fifty-seven patients (33.3%) developed bacteremia, and 106 Gram-positive bacteria were recovered, including 63 Staphylococcus aureus. Recurrent bacteremia while receiving vancomycin was infrequent. The 90th percentile minimum inhibitory concentration (MIC₉₀) for vancomycin of 36 available S. aureus isolates tested by broth microdilution was 1.5 μg/mL. CI produced more frequent therapeutic vancomycin levels and less frequent subtherapeutic levels compared to II. However, therapeutic vancomycin levels were achieved infrequently by either method of dosing. Given equivalent therapeutic drug monitoring costs and the lack of a clear clinical benefit, the role of CI dosing remains to be defined in spite of practical and theoretical advantages, particularly when administered in the setting of CVVH.
Adjusting the dose of antifungal agents for renal and hepatic impairment can be challenging given that clinicians must rely on limited pharmacokinetic data to derive specific regimens. These ...pharmacokinetic studies are typically performed in a small number of patients without invasive fungal infection, and results are not often reported in concert with accepted pharmacodynamic indices. This article aims to review pertinent pharmacokinetic studies of antifungal drugs in patients with renal or hepatic dysfunction. The impact of novel continuous renal replacement therapy techniques on the pharmacokinetic disposition of antifungal agents will also be described where data are available. Subsequently, this review provides recommendations for antifungal drug dosing in patients with kidney or liver dysfunction after accounting for established or emerging pharmacokinetic-pharmacodynamic relationships as they relate to antifungal drug efficacy in vivo.
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