Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland.

BACKGROUND: The prevalence of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin. METHODS: A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents. RESULTS: Sixty-nine percent of patients (N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively. CONCLUSIONS: This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.

The changing pattern of antimicrobial resistance within 42,033 Escherichia coli isolates from nosocomial, community and urology patient-specific urinary tract infections, Dublin, 1999-2009.

OBJECTIVE: To investigate the changing pattern of antimicrobial resistance in Escherichia coli urinary tract infection over an eleven year period, and to determine whether E. coli antibiotic resistance rates vary depending on whether the UTI represents a nosocomial, community acquired or urology patient specific infection. PATIENT AND METHODS: A retrospective analysis of the 42,033 E. coli urine isolates from the 11-year period 1999-2009 in a single Dublin teaching hospital was performed. WHONET(TM) software was used to analyse the changing pattern of sensitivity and resistance of E. coli to commonly used antibiotics over the study period. The origins of the urine samples were stratified into three groups: inpatients with nosocomial UTIs; urine originating from the emergency department and general practice (community UTIs); and UTIs in urology patients. RESULTS: Urinary tract infections in the urology patient population demonstrate higher antibiotic resistance rates than nosocomial or community UTIs. There were significant trends of increasing resistance over the 11-year period for ampicillin, trimethoprim, gentamicin and ciprofloxacin, and significant differences in co-amoxyclav, gentamicin, nitrofurantion and ciprofloxacin resistance rates depending on the sample origin. Ampicillin and trimethoprim were the least active agents against E. coli, with total 11-year resistance rates of 58.3 and 33.8%, respectively. The overall gentamicin resistance rate was 3.4% and is climbing at a rate of 0.7% per year (P < 0.001). Within the urology patient population the resistance rate was 6.4%. Ciprofloxacin resistance approaches 20% in the nosocomial UTI population and approaches 30% in the urology population; however, it remains a reasonable empirical antibiotic choice in this community, with an 11-year resistance rate of 10.6%. CONCLUSIONS: E. coli remains the commonest infecting uropathogen in the community and hospital setting with its incidence climbing from 50 to 60% of UTIs over the 11-year period. Neither penicillins nor trimethoprim represent suitable empirical antimicrobials for UTI and ciprofloxacin resistance in this Dublin-based study renders it unsuitable empirical therapy for nosocomial UTIs and UTIs in the urology population. The dramatic 11-year rate increase in gentamicin resistance is of paramount concern.

Prospective study of antibiotic prophylaxis for prostate biopsy involving >1100 men.

We aimed to compare infection rates for two 3-day antibiotic prophylaxis regimens for transrectal ultrasound-guided prostate biopsy (TRUSgbp) and demonstrate local microbiological trends. In 2008, 558 men and, in 2009, 625 men had TRUSgpb. Regimen 1 (2008) comprised 400 mg Ofloxacin immediately before biopsy and 200 mg 12-hourly for 3 days. Regimen 2 (2009) comprised Ofloxacin 200 mg 12-hourly for 3 days commencing 24 hours before biopsy. 20/558 (3.6%) men had febrile episodes with regimen 1 and 10/625 (1.6%) men with regimen 2 (P = 0.03). E. coli was the most frequently isolated organism. Overall, 7/13 (54%) of positive urine cultures were quinolone resistant and (5/13) 40% were multidrug resistant. Overall, 5/9 (56%) patients with septicaemia were quinolone resistant. All patients were sensitive to Meropenem. There was 1 (0.2%) death with regimen 1. Commencing Ofloxacin 24 hours before TRUSgpb reduced the incidence of febrile episodes significantly. We observed the emergence of quinolone and multidrug-resistant E. coli. Meropenem should be considered for unresolving sepsis.

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.

Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

BACKGROUND: Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. METHODS: A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. RESULTS: The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg/kg to 4.78 mg/kg/day. CONCLUSIONS: Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.