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Purpose There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. Methods This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100 % f T >4MIC [percentage of time during a dosing interval that the free ( f ) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100 % f T >4MIC and 100 % f T >MIC at 72 h. Results Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100 % f T >4MIC was achieved in 21 % of the PTZ patients and in none of the MEM patients; 100 % f T >MIC was achieved in 71 % of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100 % f T >4MIC and 100 % f T >MIC were higher in the intervention group: 58 vs. 16 %, p  = 0.007 and 95 vs. 68 %, p  = 0.045, respectively. Conclusions Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Background and Objective Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). Methods Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cl eff ) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. Results HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem ( β = − 8.90 (95% CI − 12.9 to − 4.87), p < 0.001) and tazobactam ( β = − 8.29 (95% CI − 13.5 to − 3.08), p = 0.002) and Cl eff for each antibiotic (meropenem β = − 10,206 (95% CI − 14,787 to − 5787), p = 0.001); tazobactam ( β = − 4551 (95% CI − 7781 to − 1322), p = 0.012); piperacillin ( β = − 3913 (95% CI − 6388 to − 1437), p = 0.002), even if the carryover effect influenced the Cl eff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin ( β = − 38.1 (95% CI − 47.9 to − 28.3), p < 0.001) and tazobactam ( β = − 4.45 (95% CI − 6.17 to − 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. Conclusion MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

The primary aim of the present study was to compare the reduction in periodontal probing depth after the use of either local or systemic adjuvant antibiotics during non-surgical periodontal therapy at baseline and the six-month follow-up. Secondary aims were to compare other clinical outcomes, total bacterial count, and relative expression levels of certain pro-inflammatory mediators following the use of locally and systemically delivered adjuvant antibiotics during the initial non-surgical periodontal therapy (NSPT). A total of 38 periodontitis stage III grade B or C patients were randomly and equally assigned to receive either local (LA) (tazobactam + piperacillin preparation) or systemic antibiotics (SA) (amoxicillin and metronidazole combination) during NSPT. Clinical periodontal parameters (periodontal probing depth, clinical attachment level, bleeding on probing, and plaque index), and microbiological and immunological parameters: total bacterial count, and relative expression levels of IL-17 and TNF-α were evaluated at baseline and six months after NSPT. Both LA and SA significantly improved all clinical parameters after six months (p<0.001 for all comparisons). While a significant decrease of total bacterial count was observed after LA (p=0.001) and SA treatment (p=0.013), the insignificant differences between the two groups were observed after the sixth-month follow-up (p>0.05). Conversely, relative gene expression levels of IL-17 and TNF-α did not differ significantly between LA and SA six months after the NSPT. The insignificant differences between these cytokines' relative levels were observed in both SA and LA between baseline and follow-up measurements. The adjuvant use of piperacillin + tazobactam led to the comparable improvement of clinical, microbiological and immunological parameters to the conventional use of amoxicillin and metronidazol combination six months following the initial therapy of periodontitis. Therefore, these locally delivered antibiotics might be a promising alternative to the standard use of systemic amoxicillin and metronidazol combination during initial therapy of stage III periodontitis.

The purpose of this study was to assess the pharmacokinetic (PK) characteristics, clinical efficiency, and pharmacoeconomic parameters of piperacillin/tazobactam administered by extended infusion (EI) or intermittent infusion (II) in the treatment of hospital-acquired pneumonia (HAP) in critically ill patients with low illness severity in China. Fifty patients completed the study, with 25 patients receiving 4/0.5 g piperacillin/tazobactam over 30 min as the II group and 25 patients receiving 4/0.5 g piperacillin/tazobactam over 3 h every 6 h as the EI group. Drug assay was performed using high-performance liquid chromatography (HPLC). The percentage of the dosing interval for which the free piperacillin concentration (% f T) exceeds the minimum inhibitory concentration (MIC) was calculated. The patients’ therapy cost, clinical efficiency, and adverse effects were also recorded. % f T>MIC was about 100, 98.73, and 93.04 % in the EI arm versus 81.48, 53.29, and 42.15 % in the II arm, respectively, when the microorganism responsible for HAP had an MIC of 4, 8, and 16 mg/L. The therapy cost in the EI group was lower than that of the II group ($1351.72 ± 120.39 vs. $1782.04 ± 164.51, p  = 0.001). However, the clinical success rate, clinical failure rate, and drug-related adverse events did not significantly differ between groups. EI treatment with piperacillin/tazobactam was a cost-effective approach to the management of HAP, being equally clinically effective to conventional II.

Objectives To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population. Methods A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration–time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients. Results For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants. Conclusions Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.

Background There is lack of information on the efficacy and safety of piperacillin–tazobactam administered by continuous infusion. Objective The aim of this study was to investigate whether continuous infusion of piperacillin–tazobactam is superior in terms of efficacy to a 30 % higher dose administered by intermittent infusion to treat suspected or confirmed infection due to Pseudomonas aeruginosa . Setting Multicenter clinical trial with 11 third level Spanish hospitals. Method Randomized, double-blind parallel-group clinical trial, controlled by conventional administration of the drug. Patients randomly assigned in a 1:1 ratio to receive piperacillin–tazobactam as continuous infusion (CI) or intermittent (II). Main outcome measure Primary efficacy endpoint was percentage of patients having a satisfactory clinical response at completion of treatment, defined as clinical cure or clinical improvement. Adverse events were reported. Results 78 patients were included, 40 in the CI group and 38 in the II group. Mean (standard deviation) duration of treatment was 7 (±4.44) days. 58 patients (74.4 %) experienced cure or improvement at the end of the treatment. There were no statistical differences in cure rates between the two treatment arms and no adverse events were reported. Conclusion Continuous infusion of piperacillin–tazobactam is an alternative administration drug method at least similar in efficacy and safety to conventional intermittent infusion. Multivariate analysis is needed to determine whether continuous administration might be more beneficial than intermittent in certain patient subgroups.

Tazobactam/piperacillin is a first-line treatment option for hospital-acquired pneumonia; however, drug-induced liver injury (DILI) is relatively frequently observed with tazobactam/piperacillin in clinical practice. This study aimed to verify the usefulness of available patient data for predicting DILI prior to tazobactam/piperacillin administration. Tazobactam/piperacillin-treated patients were retrospectively selected and divided into patients with and without DILI. Comparative analysis was performed regarding age, gender, dose, duration of treatment, clinical laboratory values prior to treatment initiation, and the types of organ-specific infections in both groups. Multiple logistic regression analyses indicated that elevated C-reactive protein (odds ratio (OR), 1.284; 95% confidence interval (CI), 1.172 - 1.406; p < 0.001) and high hemoglobin (OR, 1.697; 95% CI, 1.259 - 2.286; p < 0.001) levels prior to the administration of tazobactam/piperacillin were risk factors for DILI in males who received a 4.5-g dose. A predictive model for DILI risk was constructed by combining these test values and analyzed using receiver operating characteristic curves, obtaining 0.910 for the model construction set and 0.845 for the validation set. The development of DILI was predicted with good accuracy in males who received a 4.5-g dose with elevated C-reactive protein and hemoglobin.

Objective The aim was to compare the efficacy and safety of two antibiotic regimens in patients with diabetic foot infections (DFIs). Methods Data of a subset of patients enrolled in the RELIEF trial with DFIs requiring surgery and antibiotics were evaluated retrospectively. DFI was diagnosed on the basis of the modified Wagner, University of Texas, and PEDIS classification systems. Patients were randomized to receive either intravenous/oral moxifloxacin (MXF, N  = 110) 400 mg q.d. or intravenous piperacillin/tazobactam 4.0/0.5 g t.d.s. followed by oral amoxicillin/clavulanate 875/125 mg b.d. (PIP/TAZ–AMC, N  = 96), for 7–21 days until the end of treatment (EOT). The primary endpoint was clinical cure rates in the per-protocol (PP) population at the test-of-cure visit (TOC, 14–28 days after EOT). Results There were no significant differences between the demographic characteristics of PP patients in either treatment group. At TOC, MXF and PIP/TAZ–AMC had similar efficacy in both the PP and intent-to-treat (ITT) populations: MXF: 76.4 % versus PIP/TAZ–AMC: 78.1 %; 95 % confidence interval (CI) −14.5 %, 9.0 % in the PP population; MXF: 69.9 % versus PIP/TAZ–AMC: 69.1 %; 95 % CI −12.4 %, 12.1 % in the ITT population. The overall bacteriological success rates were similar in both treatment groups (MXF: 71.7 % versus PIP/TAZ–AMC: 71.8 %; 95 % CI −16.9 %, 10.7 %). A similar proportion of patients (ITT population) experienced any adverse events in both treatment groups (MXF: 30.9 % versus PIP/TAZ–AMC: 31.8 %, respectively). Death occurred in three MXF-treated patients and one PIP/TAZ–AMC-treated patient; these were unrelated to the study drugs. Conclusion Moxifloxacin has shown favorable safety and efficacy profiles in DFI patients and could be an alternative antibiotic therapy in the management of DFI. Clinical trial: NCT00402727.

The objective of the study was to evaluate the effect of administering prophylactic antibiotics on the development of neonatal sepsis in term neonates born through meconium-stained amniotic fluid (MSAF). Two hundred and fifty eligible neonates were randomized to study group (Antibiotic group—receiving first-line antibiotics for 3 days) and control group (No Antibiotic group). Both groups were evaluated clinically and by laboratory parameters (sepsis screen and blood cultures) for development of sepsis. All neonates were monitored for respiratory, neurological, and other systemic complications and received supportive treatment according to standard management protocol of the unit. One hundred and twenty one neonates were randomized to ‘Antibiotic’ group and 129 to ‘No Antibiotic’ group. The overall incidence of suspect sepsis was 9.6 % in the study population with no significant difference between ‘No Antibiotic’ and ‘Antibiotic’ groups (10.8 vs. 8.2 %, p  = 0.48, odds ratio (OR) 0.74, 95 % confidence interval (CI) 0.32–1.73). Incidence of culture-proven sepsis was also not significantly different between the two groups (5.42 vs. 4.13 %, p  = 0.63, OR 0.75, 95 % CI 0.23–2.43). The incidence of mortality, meconium aspiration syndrome, and other complications was comparable amongst the two groups. Conclusion : Routine antibiotic prophylaxis in neonates born through MSAF did not reduce the incidence of sepsis in this study population. (Clinicaltrials.gov no. - NCT01290003)

Abstract Background ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. Results Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. Conclusions ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. Clinical Trial Registration NCT02753946 ZEUS, a Phase 2/3 trial, studied ZTI-01 (fosfomycin for injection) in the treatment of hospitalized adults with complicated urinary tract infection and acute pyelonephritis versus piperacillin-tazobactam. ZTI-01 was non-inferior to piperacillin-tazobactam and was well tolerated.