Changes of PK/PD of Meropenem in patients with abdominal septic shock and exploration of clinical rational administration plan: a prospective exploratory study.

This study aimed to explore the changes of pharmacokinetic parameters after meropenem in patients with abdominal septic shock after gastrointestinal perforation, and to simulate the probability of different dosing regimens achieving different pharmacodynamic goals. The study included 12 patients, and utilized high performance liquid chromatography-tandem mass spectrometry to monitor the plasma concentration of meropenem. The probability of target attainment (PTA) for different minimum inhibitory concentration (MIC) values and %fT > 4MIC was compared among simulated dosing regimens. The results showed that in 96 blood samples from 12 patients, the clearance (CL) of meropenem in the normal and abnormal creatinine clearance subgroups were 7.7 ± 1.8 and 4.4 ± 1.1 L/h, respectively, and the apparent volume of distribution (Vd) was 22.6 ± 5.1 and 17.2 ± 5.8 L, respectively. 2. Regardless of the subgroup, 0.5 g/q6h infusion over 6 h regimen achieved a PTA > 90% when MIC ≤ 0.5 mg/L. 1.0 g/q6h infusion regimen compared with other regimen, in most cases, the probability of making PTA > 90% is higher. For patients at low MIC, 0.5 g/q6h infusion over 6 h may be preferable. For patients at high MIC, a dose regimen of 1.0 g/q6 h infusion over 6 h may be preferable. Further research is needed to confirm this exploratory result.

[A case of acute purulent otitis media complicated by atypical mastoiditis on the background of an unverified HIV infection]. / Sluchai ostrogo gnoinogo srednego otita, oslozhnennogo atipichnym mastoiditom, na fone neverifitsirovannoi VICh-infektsii.

According to the literature, acute otitis media is complicated by mastoiditis in 0.15-1% of cases. In turn, mastoiditis can be complicated by meningitis, encephalitis, abscess of temporal lobe of brain and cerebellum, epidural and subdural abscesses, facial nerve paresis, labyrinthitis, phlegmon of soft tissues of neck, as well as subperiosteal abscess, which makes 7% in the structure of mastoiditis complications. Nowadays, when doctors have a wide range of antibacterial preparations at their disposal, a complicated course of acute otitis media and further mastoiditis is caused both by an aggressive atypical infectious agent and immunocompromised status of a patient. The article deals with a clinical case of a prolonged course of acute otitis media complicated by mastoiditis and subperiosteal abscess against the background of outpatient courses of antibacterial therapy. The examination revealed an atypical pathogen of otitis media Pseudomonas aeruginosa and HIV-positive status of the patient, previously unknown. Timely surgical intervention and the right combination of antibacterial drugs, meropenem and ciprofloxacin, prevented the development of intracranial and septic complications, despite the presence of multiple foci of bone destruction of the mastoid process and temporal bone pyramid, bordering the middle fossa and sigmoid sinus, according to multispiral head computed tomography. As a part of additional examination in the Center for AIDS and Infectious Diseases Prevention and Control, the patient was diagnosed with HIV infection, clinical stage 4C, progressing phase on the background of absence of antiretroviral therapy, and the necessary amount of treatment was prescribed.

A case report on rapid development of simultaneous liver and musculature calcifications in severe sepsis.

A 76-year-old Malay female presented with 2 days history of fever and vomiting. She was found to have Escherichia coli and Klebsiella pneumoniae bacteraemia with no clear intra-abdominal cause on the initial computed tomography of the abdomen and pelvis (CTAP). She clinically improved with 2 weeks duration of intravenous meropenem. She subsequently developed septic shock and a repeated CTAP demonstrated increased hepatic parenchymal density with extensive parenchymal calcifications. Curvilinear calcifications were seen in the paraspinal and pelvic musculature.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

OBJECTIVE: This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. METHODS: We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. RESULTS: The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 µg/mL) compared with that before co-administration (88.8 ± 13.6 µg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 µg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). CONCLUSIONS: In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.

OBJECTIVES: The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase: producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics. METHODS: To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC. RESULTS: The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations. CONCLUSIONS: Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.

Increase of healthcare-onset Clostridioides difficile infection in adult population since SARS-CoV-2 pandemic: A retrospective cohort study in a tertiary care hospital from 2019 to 2022.

OBJECTIVES: The aim was to assess the impact of the SARS-CoV-2 pandemic on the prevalence, relative incidence (RI), incidence density (ID), ratio of rate incidence (RRI), rate of incidence density (RID), and relative risks (RR) of healthcare-onset Clostridioides difficile infection (HO-CDI) as well as its correlation with the antibiotic consumption. METHODS: Demographic and analytical data of adult patients exhibiting diarrhoea and testing positive for C. difficile were systematically collected from a tertiary care hospital in Madrid (Spain). The periods analysed included: prepandemic (P0), first pandemic-year (P1), and second pandemic-year (P2). We compared global prevalence, RI of HO-CDI per 1,000-admissions, ID of HO-CDI per 10,000-patients-days, RRI, RID, and RR. Antibiotic consumption was obtained by number of defined daily dose per 100 patient-days. RESULTS: In P0, the prevalence of HO-CDI was 7.4% (IC95%: 6.2-8.7); in P1, it increased to 8.7% (IC95%: 7.4-10.1) (p = 0.2), and in P2, it continued to increase to 9.2% (IC95%: 8-10.6) (p < 0.05). During P1, the RRI was 1.5 and RID was 1.4. However, during P2 there was an increase in RRI to 1.6 and RID to 1.6. The RR also reflected the increase in HO-CDI: at P1, the probability of developing HO-CDI was 1.5 times (IC95%: 1.2-1.9) higher than P0, while at P2, this probability increased to 1.6 times (IC95%: 1.3-2.1). There was an increase in prevalence, RI, ID, RR, RRI, and RID during the two postpandemic periods respect to the prepandemic period. During P2, this increase was greater than the P1. Meropenem showed a statistically significant difference increased consumption (p < 0.05) during the pandemic period. Oral vancomycin HO-CDI treatment showed an increase during the period of study (p > 0.05). CONCLUSIONS: Implementation of infection control measures during the SARS-CoV-2 pandemic did not appear to alleviate the burden of HO-CDI. The escalation in HO-CDI cases did not exhibit a correlation with overall antibiotic consumption, except for meropenem.

Meropenem versus piperacillin-tazobactam for the treatment of pancreatic necrosis.

PURPOSE: To date, there are three published guidelines discussing management of infected pancreatic necrosis (IPN) with conflicting recommendations. Specifically, The World Society of Emergency Surgery lists piperacillin-tazobactam as a treatment option in addition to meropenem and ciprofloxacin plus metronidazole. Piperacillin-tazobactam may serve as an effective carbapenem-sparing alternative. Although previous studies shed light on antimicrobial penetration data, there is a lack of clinical data comparing piperacillin-tazobactam to meropenem. The purpose of this study is to compare the efficacy of meropenem and piperacillin-tazobactam for the treatment of IPN. METHODS: This was a multicenter, retrospective cohort study conducted across three institutions. Patients with IPN who received either meropenem or piperacillin-tazobactam from January 2015 to December 2020 were included. The primary composite outcome was the incidence of 90-day clinical failure, which encompassed 90-day all-cause mortality and 90-day intra-abdominal infection recurrence. Secondary outcomes included length of hospital stay, antimicrobial duration of therapy, and the need for surgical intervention. RESULTS: We identified 229 patients with IPN that received either meropenem or piperacillin-tazobactam during hospital admission. After screening, 63 patients were included in the study. Incidence of 90-day clinical failure was observed in 33 % of the meropenem group and 50 % in the piperacillin-tazobactam group (OR, 1.98; 95 % CI 0.57 to 7.01, p = 0.259). The meropenem group had a lower incidence of 90-day infection recurrence in the piperacillin-tazobactam group (56 % vs 29 %, p = 0.047). CONCLUSIONS: Piperacillin-tazobactam may be an efficacious carbapenem-sparing treatment alternative for infected pancreatic necrosis.

Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Comparison of three doses of amikacin on alternate days with a daily dose of meropenem during the same period for the treatment of urinary tract infection with E. coli: a double-blind clinical trial.

OBJECTIVES: Urinary tract infections (UTIs) are very common infections in humans, and Escherichia coli (E. coli) is the commonest pathogen leading to UTIs. The generation of beta-lactamase enzymes in this bacterium results in its resistance against many antibiotics. This study compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli in a double-blind clinical trial. METHODS: The current double-blind clinical trial compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli. The patients were assigned to two groups: Intervention (receiving a single dose of amikacin once a day at 48-h intervals for a week, three doses) and control (receiving meropenem for 1/TDS for a week). RESULTS: The E. coli infection frequency was 61 (21 cases of non-ESBL and 40 cases of ESBL-positive infections) and the frequency of the other infections was 52 (46%). In the patients with ESBL E. coli infection, ciprofloxacin (21; 70%) showed the highest antibiotic resistance, and nitrofurantoin (33; 91.7%) showed the highest sensitivity. The baseline variables between the control and intervention groups indicated no significant difference (p > 0.05). The frequency of signs and symptoms showed no significant difference between the amikacin and meropenem groups in the first 24 h and the first week. In the second week of follow-up, no clinical signs or symptoms were observed in the two groups. CONCLUSION: The results of this study showed that treatment with amikacin, 1 g q48h, for one week (three doses) has the same result as meropenem, 1 g q8h, for one week (21 doses). The results are the same for the treatment of UTIs with ESBL positive and ESBL negative. Amikacin can be used once every 48 h to treat UTIs, is less expensive and can be administered on an outpatient basis. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20170417033483N2 on the date 2018-02-13.

Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Bloodstream Infections in Children With Cancer: Pathogen Distribution and Antimicrobial Susceptibility Patterns Over a 10-Year Period.

Bloodstream infections (BSIs) adversely affect clinical outcome in children with cancer. Over 1 decade, this retrospective cohort study describes pathogen distribution in BSIs and antimicrobial susceptibility against empirical antibiotics frequently prescribed in children with cancer. The antibiotic efficacy was evaluated through the determination of minimal inhibitory concentrations for piperacillin-tazobactam and meropenem and by disk diffusion for remaining antibiotics. From 2004 to 2013, 398 BSIs occurred in 196 children with cancer (median age: 5.4 y), resulting in 457 bacteria. Overall, 266 (58.2%) were Gram-positive, and 191 (41.8%) were Gram-negative with a significant Gram-positive increase over time (P=0.032). Coagulase-negative staphylococci (74, 16.2%), viridans group streptococci (67, 14.7%), Escherichia coli (52, 11.4%), and Staphylococcus aureus (39, 8.5%) were the most common pathogens. Susceptibility to piperacillin-tazobactam (95.9%, P=0.419) and meropenem (98.9%, P=0.752) was stable over time, and resistance was observed among viridans group streptococci against piperacillin-tazobactam (18%) and meropenem (7%) and among Enterobacterales against piperacillin-tazobactam (3%). Vancomycin showed 98% Gram-positive activity, gentamicin 82% Gram-negative activity and ampicillin, cefotaxime, and cefuroxime were active in 50%, 72%, and 69% of pathogens, respectively, and BSI-related mortality was 0%. In conclusion, over 1 decade, we report an increase in Gram-positive BSIs, and stable, low-resistance rates against currently recommended empirical antibiotics, piperacillin-tazobactam and meropenem.

Conceptual model of adding antibiotics to dialysate fluid during renal replacement therapy.

Studies have shown significant variability in antibiotic trough concentrations in critically ill patients receiving renal replacement therapy (RRT). The purpose of this study was to assess whether adding beta-lactam antibiotics to dialysate solution can maintain stable antibiotic concentrations during RRT in experimental conditions. A single compartment model reflecting the patient was constructed and connected to the RRT machine. Dialysate fluid was prepared in three different concentrations of meropenem (0 mg/L; 16 mg/L; 64 mg/L). For each dialysate concentration various combinations of dialysate and blood flow rates were tested by taking different samples. Meropenem concentration in all samples was calculated using spectrophotometry method. Constructed experimental model results suggest that decrease in blood meropenem concentration can be up to 35.6%. Moreover, experimental data showed that antibiotic loss during RRT can be minimized and stable plasma antibiotic concentration can be achieved with the use of a 16 mg/L Meropenem dialysate solution. Furthermore, increasing meropenem concentration up to 64 mg/L is associated with an increase antibiotic concentration up to 18.7-78.8%. Administration of antibiotics to dialysate solutions may be an effective method of ensuring a constant concentration of antibiotics in the blood of critically ill patients receiving RRT.

Impact of an electronic alert on prescription patterns of meropenem, voriconazole and caspofungin.

BACKGROUND: Antimicrobial stewardship programs promote the appropriate use of antimicrobial substances through the implementation of evidence-based, active and passive interventions. We analyzed the effect of a computer-assisted intervention on antimicrobial use in a tertiary care hospital. METHODS: Between 2011 and 2016 we introduced an electronic alert for patients being prescribed meropenem, voriconazole and caspofungin. At prescription and at day 3 of treatment, physicians were informed about the risk related to these antimicrobial substances by an electronic alert in the medical records. Physicians were invited to revoke or confirm the prescription and to contact the infectious disease (ID) team. Using interrupted time series regression, the days of therapy (DOTs) and the number of prescriptions before and after the intervention were compared. RESULTS: We counted 64,281 DOTs for 5549 prescriptions during 4100 hospital stays. Overall, the DOTs decreased continuously over time. An additional benefit of the alert could not be observed. Similarly, the number of prescriptions decreased over time, without significant effect of the intervention. When considering the three drugs separately, the alert impacted the duration (change in slope of DOTs/1000 bed days; P = 0.0017) as well as the number of prescriptions (change in slope of prescriptions/1000 bed days; P < 0.001) of voriconazole only. CONCLUSIONS: The introduction of the alert lowered prescriptions of voriconazole only. Thus, self-stewardship alone seems to have a limited impact on electronic prescriptions of anti-infective substances. Additional measures such as face-to-face prompting with ID physicians or audit and feedback are indispensable to optimize antimicrobial use.

Elution and Biomechanical Properties of Meropenem-Loaded Bone Cement.

OBJECTIVE: To investigate the biomechanical and elution properties of meropenem-loaded bone cement. METHODS: Bone cement (Palacos LV) with 5% (2 g/4 0g), 10% (4 g/40 g), and 15% (6 g/40 g) meropenem; 5% (2 g/40 g) and 10% (4 g/40 g) vancomycin; and blank bone cement were prepared in a total of six groups named A2, A4, A6, B2, B4, and A0 (antibiotic-free). 36 cylinder specimens (6-mm diameter and 12-mm height) of all six groups were molded for a compression test. After the compression test, because of mechanical properties below the ISO standard requirements, groups B2, B4 were not subjected to a bending test. So a total of 24 rectangular strip specimens (10-mm width, 75-mm length, and 3.3-mm thickness) for groups A2, A4, A6 and A0 were molded for the bending test. Between-group differences of compressive strength, bending strength and bending modulus were analyzed. The meropenem standard was prepared as a series of standard solutions to calculate the standard curve. At a constant temperature of 37 °C, separately, meropenem-loaded bone cement cylinder specimens (12 mm in diameter and 17 mm in length) of A2, A4 and A6 were serially immersed in saline solution without stirring. The eluent drug concentration at 24, 48, 72 h and 6, 12, 24 days was measured and the drug concentration-time curve of meropenem was constructed. RESULTS: With the exception of groups B2 and B4, all cements compressive strength values were well above the minimum requirement of the ISO 5833 standard (70 MPa). The compressive strength and bending strength values of group A4 were higher than those of group A0 (P < 0.05), but no difference was found between the A0, A2 and A6 groups (P > 0.05). There were no intergroup differences of bending modulus between the A0, A2, A4 and A6 groups (P > 0.05). A standard curve of meropenem was obtained and a regression equation was constructed: Y = 15.0265 X + 13.5218, r = 1.00. At 37 °C, the release of meropenem was rapid during the first 48 h for all A2, A4, A6 samples, and subsequent release continued to decrease. CONCLUSION: When adding up to 15% (6 g/40 g) meropenem to the bone cement, the biomechanical properties were not reduced, and bone cement with 10% (4 g/40 g) meropenem had the best performance. At a constant temperature of 37°C, meropenem can be released from bone cement for up to 24 days.

Factors associated with the appropriate use of ultra-broad spectrum antibiotics, meropenem, for suspected healthcare-associated pneumonia.

ABSTRACT: Pneumonia is a common disease-causing hospitalization. When a healthcare-associated infection is suspected, antibiotics that provide coverage for multi-drug resistant (MDR) or extended-spectrum beta-lactamase (ESBL) bacteria are frequently prescribed. Limited data is available for guidance on using meropenem as a first-line empiric antimicrobial in hospitalized patients with risk factors for MDR/ESBL bacterial infections.This was a single-center, retrospective study designed and conducted to identify factors associated with positive cultures for MDR/ESBL pathogens in hospitalized patients with suspected healthcare-associated pneumonia.Of the 246 patients, 103 patients (41%) received meropenem. Among patients prescribed meropenem, MDR/ESBL pathogens were detected in only 20 patients (13%). Patients admitted from a skilled nursing facility/long-term acute care (SNF/LTAC) or with a history of a positive culture for MDR/ESBL pathogens were significantly associated with positive cultures of MDR/ESBL pathogens during the hospitalization (odds ratio [95% confidence intervals], 31.40 [5.20-189.6] in SNF/LTAC and 18.50 [2.98-115.1] in history of culture-positive MDR/ESBL pathogen). There was no significant difference in mortality between the 3 antibiotic groups.Admission from a SNF/LTAC or having a history of cultures positive for MDR/ESBL pathogens were significantly associated with a positive culture for MDR/ESBL pathogens during the subsequent admission. We did not detect significant association between meropenem use as a first-line drug and morbidity and mortality for patients admitted to the hospital with suspected healthcare-associated pneumonia, and further prospective studies with larger sample size are needed to confirm our findings.

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Patients: How to Achieve Best Dosage Regimen According to the Clinical Situation.

BACKGROUND AND OBJECTIVES: Meropenem is frequently used for the treatment of severe bacterial infections in critically ill patients. Because critically ill patients are more prone to pharmacokinetic variability than other patients, ensuring an effective blood concentration can be complex. Therefore, describing this variability to ensure a proper use of this antibiotic drug limits the rise and dissemination of antimicrobial resistance, and helps preserve the current antibiotic arsenal. The aims of this study were to describe the pharmacokinetics of meropenem in critically ill patients, to identify and quantify the patients' characteristics responsible for the observed pharmacokinetic variability, and to perform different dosing simulations in order to determine optimal individually adapted dosing regimens. METHODS: A total of 58 patients hospitalized in the medical intensive care unit and receiving meropenem were enrolled, including 26 patients with renal replacement therapy. A population pharmacokinetic model was developed (using NONMEM software) and Monte Carlo simulations were performed with different dosing scenarios (bolus-like, extended, and continuous infusion) exploring the impact of clinical categories of residual diuresis (anuria, oliguria, and preserved diuresis) on the probability of target attainment (MIC: 1-45 mg/L). RESULTS: The population pharmacokinetic model included five covariates with a significant impact on clearance: glomerular filtration rate, dialysis (continuous and semi-continuous), renal function status, and volume of residual diuresis. The clearance for a typical patient in our population is 4.20 L/h and volume of distribution approximately 44 L. Performed dosing regimen simulations suggested that, for equivalent doses, the continuous infusion mode (with loading dose) allowed the obtaining of the pharmacokinetic/pharmacodynamic target for a larger number of patients (100% for MIC ≤ 20 mg/L). Nevertheless, for the treatment of susceptible bacteria (MIC ≤ 2 mg/L), differences in the probability of target attainment between bolus-like, extended, and continuous infusions were negligible. CONCLUSIONS: Identified covariates in the model are easily accessible information in patient health records. The model highlighted the importance of considering the patient's overall condition (renal function and dialysis) and the pathogen's characteristics (MIC target) during the establishment of a patient's dosing regimen.

Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study.

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5-6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15-2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration-time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.