Chlorhexidine treatment for ventilation-associated pneumonia, is timing everything?

Ventilator-associated pneumonia (VAP) is linked to high morbidity and mortality rates especially in hospital intensive care units (ICU’s). VAP is associated with significantly longer hospital stays, increased costs, and as already mentioned, death. Oral chlorhexidine treatment prophylaxis has been known to decrease the occurrence of VAP, but as far as establishing time frames for initiating and durations of therapy, there are not really any publicized. For the purpose of this study, Schlichting and colleagues wanted to see if early administration of oral chlorhexidine is associated with lower incidences of early ventilator-associated pneumonia, established as occurring within five days of ICU admission.

The researchers performed a single-center retrospective cohrt study of intubated adults from July 2011-April 2013. Early administration of the drug was defined as being administered within 6 hours of arrival at the ICU. The study included 134 patients. Among them, 49%  were treated with chlorhexidine before 6 hours, 84% were treated before 12 hours, and 11% were treated for early pneumonia. Early chlorhexidine (before 6 hours) was not associated (P = .21) with early pneumonia. Furthermore, median times to chlorhexidine did not differ significantly (P = .23) between patients in whom pneumonia developed (5.2 hours) and patients with no pneumonia (6.1 hours).

Analyzing the data,this research team was able to show that there was no significant difference between early administration of oral chlorhexidine in intubated patients and reduction in the occurrence of ventilator-associated pneumonia.

Am J Crit Care. 2016;25(2):173-77.


Effect of Discontinuation of Prednisolone Therapy on Risk of Cardiac Mortality Associated With Worsening Left Ventricular Dysfunction in Cardiac Sarcoidosis

Prednisolone (PSL) therapy is currently the gold standard of care treatment for patients with cardiac sarcoidosis (CS), a rare disease in which clusters of white blood cells form in the heart tissue. However, the debate is whether physicians are to continue or discontinue prednisolone therapy in long-term treatment.

In this retrospective study, 111 patients were  group, however only 61 were included in the analysis. All of the 61 patients had newly suspected CS based on clinical indications, were without coronary artery disease, and were admitted to a particular institution between 1979-2009.

Of the 61 that were included in the study, 49 patients had continuation of PSL and 12 had PSL discontinuation. After discontinuation of PSL, 5 patients suffered from cardiac mortality. Discontinuation of PSL was associated with significantly higher cardiac fatality than compared to the continuation group (p=0.035). Discontinuation of PSL also contributed to greater percent decrease in left ventricular ejection fraction (LVEF) compared with continued therapy (p=0.037).

From this seemingly small study, the investigators were able to shed some insight into the importance of long-term prednisolone treatment maintenance even with observed cardiac improvement.

Am J Cardiol. 2016;117:966-71.



Assessment of Clinical Criteria for Sepsis

Sepsis, as it is most difficulty defined, is the “life-threatening organ dysfunction due to a dysregulated host response to infection.” This retrospective cohort study was performed among adults (greater than 18) with suspected infection. The primary cohort was from 12 hospitals within the UPMC system. Four external data sets were obtained and analyzed as well. The purpose of this restrospective study was to evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis.

To accomplish this, 1.3 million electronic health records were analyzed from January 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania. Confirmatory analyses were performed at 165 US and non-US hospitals examining 706,399 patient’s records.  In order to determine clinical criteria for sepsis, existing measures were implored and indicators were used and compared to the systemic inflammatory response syndrome (SIRS) criteria; the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score; and the Logistic Organ Dysfunction System (LODS) score, a weighted organ dysfunction score. A modified version of the LODS score was used, as urine output, prothrombin levels, nor urea levels were accurately detailed. Pairwise analysis was used to compare the methods and the results were expressed as the fold change in risk of death over baseline, as well as the area under the receiver operating characteristic curve (AUROC).

At 177 hospitals over the span of 5 years, 4,885,558 encounters were analyzed. In the primary cohort, 148,907 of the encounters had suspected infections. Within the ICU encounters for the validation cohort, the predictive validity for mortality was lower for SIRS (AUROC = 0.64) and qSOFA (AUROC = 0.66) vs SOFA (AUROC = 0.74) or LODS (AUROC = 0.75), all with a 95% confidence interval. With regards to non-ICU encounters within the validation cohort, Among non-ICU encounters in the validation cohort (n = 66 522 with suspected infection), qSOFA had predictive validity (AUROC = 0.81) that was greater than SOFA (AUROC = 0.79) and SIRS (AUROC = 0.76).

So what does all of this alphabet soup of abbreviations mean? Well, the restrospective analysis showed that the predictive ability of SOFA for ICU encounters was not significantly different from LODS, but was statistically more significant than SIRS and qSOFA, indicating its potential for use in a clinical setting. However, in a non-ICU setting, the predictive validity for suspected infections of qSOFA was statistically more significant that SOFA and SIRS, supporting its use as an indicator for potential sepsis.

JAMA. 2016;315(8):762-74.




Comparison of telavancin and vancomycin lock solutions in eradication of biofilm-producing staphylococci and enterococci from central venous catheters

Staphylococcal and enterococcal infections are very prominent in hospital settings, especially prevalent in patients with inserted devices such as catheters. The bacteria that cause these infections are hard to get rid of and can lead to more serious infections.

In this study, a central venous catheter model was utilized to evaluate lock solutions and their efficacy against bacterial in-line growth. The experiment was done in vitro. Lock solutions containing vancomycin (5 mg/mL) or telavancin (5 mg/mL), with and without preservative containing heparin sodium (2,500 units/mL), heparin, and normal saline solution. The solutions were put into the catheters after the bacteria was given a 24-hour growth period. After 72 hours of exposure to the lock solutions, the catheters were flushed, segmented, and analyzed for bacterial colony growth. In order to establish a baseline, catheters were processed after 24 hours of incubation with any lock solution.

The examined catheter and lock solutions revealed that vancomycin and telavancin (with or without heparin) had similar activity against S. epidermidis and that vancomycin alone was more effective that telavancin against E. faecalis.  Against S. aureus, vancomycin plus heparin had activity similar to that of vancomycin alone; both lock agents had greater activity than telavancin. However, addition of heparin to vancomycin decreased efficacy against E. faecalis and S. epidermidis.


Am J Health-Syst Pharm. 2016;73(5):315-21.



Visual and absorbance analyses of admixtures containing vancomycin and piperacillin–tazobactam at commonly used concentrations

Piperacillin-tazobactam and vancomycin are two of the most commonly used antibiotics in a hospital setting. They are often the go-to first line therapies for numerous indications, including hospital-acquired and ventilation-associated pneumonias, severe hospital-acquired intraabdominal infections, and severe skin and soft issue infections such as necrotizing fasciitis. Extended infusion (EI) dosing schemes have been developed for piperacillin-tazobactam in order to improve patient outcomes. EI dosing of piperacillin-tazobactam is commonly administered as 3.375 g (piperacillin 3 g and tazobactam 0.375 g) every 8 hours as a 4-hour infusion, while there is limited data to support compatibility of coinfusion.


O’Donnell et al. conducted a compatibility study to test the compatibility of vancomycin and piperacillin-tazobactam in concentrations typically used in extended-infusion dosing schemes. In order to test this, various concentrations of piperacillin-tazobactam specifically 33.75, 45, 50, 60, 67.5, 80, and 90 mg/mL were reconstituted and diluted. Vancomycin was diluted to concentrations of 4–8, 10, and 12 mg/mL. Frozen formulations of each medication and brand name Zosynâ were also studied. The mixtures were visually observed from hours 1-4 and after 24 hours for abnormalities or precipitates. Each concentration combination of each product was tested for precipitation as well as microscopic analyses were performed to discern less perceptible incompatibilities that did not result in clear visual precipitation.


Visual analyses resulted in observed compatibility for all concentrations of piperacillin-tazobactam when combined with vancomycin 4-7mg/mL. Also, at higher doses when piperacillin-tazobactam 80 or 90 mg/mL was added to vancomycin 8 mg/mL, a transient and reversible precipitate had formed lasting less than 30 seconds. Most notably of the results observed was the formation of an irreversible precipitate between vancomycin 10 mg/mL and all concentrations of piperacillin-tazobactam. Absorbance and microscopic analyses resulted in findings that did not differ significantly between the controls (0.9% sodium chloride) and the solutions that exhibited reversible visual precipitation. From these results, O’Donnell et al. was able to show through visual, microscopic, and absorbance analyses that no evidence of incompatibility was observed when piperacillin-tazobactam 33.75-90 mg/mL was combined with vancomycin ≤7 mg/mL. Reversible and irreversible precipitates formed when piperacillin–tazobactam was combined with vancomycin ≥8 mg/mL.


Am J Health-Syst Pharm. 2016; 73:241-46.


Stability of tacrolimus solutions in polyolefin containers

Tacrolimus is an immunosuppressant used for organ rejection prophylaxis in patients receiving liver, kidney, or heart transplantation. Tacrolimus is also indicated for prevention and treatment of graft-versus-host disease after hematopoietic stem cell transplantation. It is preferred via oral route of administration; however, an injectable solution can be administered via continuous infusion. The manufacturer recommends an expiration of 24 hours after preparation, so the combination of giving a drug by continuous infusion and a 24-hour expiration time may create challenges for some pharmacies.

Lee et al. conducted a study to determine the stability of tacrolimus solutions stored in polyolefin containers under various conditions. Triplicate solutions of tacrolimus (0.001, 0.01, and 0.1 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection were prepared in polyolefin containers. Some samples were stored at room temperature (20–25 °C); others were refrigerated (2–8 °C) for 20 hours and then stored at room temperature for up to 28 hours. The solutions stabilities were analyzed through high-performance liquid chromatography (HPLC) assay at various time points spanning 48 hours. The primary end point of this analysis was stability, defined as retaining greater than 90% of the initial tacrolimus concentration.

The results indicated that all samples, with the exception of the 0.001mg/mL sample solution prepared in 0.9% sodium chloride, had maintained greater than 90% of the initial concentration at all of the time points tested. The results suggest little to no loss of viable product to degradation or adsorption.  Lee et al. were able to show the stability of tacrolimus stored in polyolefin containers for at least 48 hours with the exception of the 0.001mg/mL sample solution prepared in 0.9% sodium chloride.

Am J Health-Syst Pharm. 2016;73(3):137-42.

Fresh versus frozen fecal microbiota transplantation in patients with recurrent Clostridium difficile infection

               Clostridium difficile infection (CDI), both in community and in  inpatient hospital settings, has gained notoriety for its clinical and economic concerns. Conventional treatment methods such as antibiotics like metronidazole or vancomycin have been proven less effective for recurrent episodes of CDI, however restoring colonic microbiota through fecal microbiota transplantation (FMT) has yielded positive results. Administered rectally by enema, high cure rates have been achieved, however this approach can be limited by difficulties in preparing fresh matter. Previous studies have been performed to show that frozen-and-thawed (frozen) FMT is effective in treating CDI but none have compared fresh to frozen material.

In this study, Lee and colleagues conducted a randomized, double-blind, noninferiority trial to determine whether frozen-and-thawed (frozen) FMT is noninferior to fresh (standard treatment) FMT with regards to clinical efficacy among patients with recurrent or refractory CDI and the safety of both types.  The primary end points observed were clinical resolution of diarrhea without relapse at 13 weeks post FMT and adverse events. It was noted that the noninferiorty margin was set at 15%. A total of 232 patients were randomly assigned to receive frozen (n=114) or fresh (n=118) FMT via enema administration, however, these patients were further stratified into either the per-protocol group or the modified intention-to-treat (mITT) populations. The per-protocol population was comprised of patients who received up to 2 same-modality FMTs, did not require antibiotic for CDI between the first 2 FMTs, and did not receive systemic antibiotic for intercurrent infection during the study period. The mITT population was comprised of all randomized patients who received at least 1 FMT but required antibiotic for CDI between the FMTs, who received a type of FMT different from the first FMT, who were lost to follow-up, or who required systemic antibiotic therapy for other infections. The study showed that clinical resolution of diarrhea in the per-protocol population was 76 of 91 (83.5%) in the frozen FMT group and 74 of 87 (85.1%) in the fresh FMT group for a difference of -1.6%. In the mITT population, the corresponding proportions were 81 of 108 (75.0%) in the frozen FMT group and 78 of 111 (70.3%) in the fresh FMT group, after up to 2 FMTs for a difference of 4.7%. It should also be noted that there were no differences in the proportions of adverse events between the treatment groups. Based on the data observed, Lee and colleagues were able to conclude that the use of frozen-and-thawed (frozen) compared with fresh FMT did not result in decreased clinical resolution of diarrhea (efficacy).

This result is favorable because it could potentially make for a treatment option that is favorable for many reasons compared to standard fresh material. It should be noted that the study only monitored these patients for 13 weeks after FMT and long term safety and effects of FMT were not observed.


JAMA. 2016;315(2):142-49.


Acetazolamide to decrease invasive mechanical ventilation in critically ill patients with Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) can lead to intensive care unit (ICU) admission with some patients requiring the need for invasive mechanical ventilation. Acetazolamide has been used as a respiratory stimulant in patients with COPD and metabolic alkalosis. Faisy and colleagues conducted the DIABLO study to determine whether acetazolamide reduces mechanical ventilation duration in critically ill patients with COPD and metabolic alkalosis. The DIABLO study was a randomized, double-blind, multicenter, parallel-group trial conducted from October 2011 to July 2014 in 15 ICU’s in France. Patients were randomized to receive either 500 mg or 1000 mg (if loop diuretics were co-prescribed) of acetazolamide twice daily or placebo (10mL of saline). The primary end point of the study was duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy with secondary end points including alterations in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality. Of the 380 patients that completed the study, 187 were randomzed to the acetazolamide treatment group and 193 to the placebo treatment group. The study resulted in a total duration of invasive ventilation median of 136.5 hours in the acetazolamide group versus 163.0 hours in the placebo group, for a between group difference of -16.0 hours, which did not differ significantly (statistically). Secondary end point analysis between the groups showed no respiratory stimulant effect on respiratory rate, tidal volume, or median minute ventilation change. However, daily changes in serum bicarbonate (between group difference, −0.8 mEq/L; 95% CI, −1.2 to −0.5 mEq/L; P < .001) and number of days with metabolic alkalosis (between-group difference, −1; 95% CI, −2 to −1 days; P < .001) decreased significantly more in the acetazolamide group. The study concluded that patients with COPD receiving invasive mechanical ventilation that were treated with acetazolamide, compared with placebo, showed no statistically significant reduction in duration of invasive mechanical ventilation.

It was noted in the study that although the data suggested that no statistically significant change was observed, there was a reduction in the drug treatment group by 16 hours indicating a clinically significant result. The sooner that critically ill patients can be weaned off artificial respiration, the sooner they are to be discharged.
JAMA. 2016;315(5):480-88.