Use of the DMAIC Lean Six Sigma quality improvement framework to improve beta-lactam antibiotic adequacy in the critically ill.

BACKGROUND: Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the DMAIC Lean Six Sigma quality improvement framework. METHODS: A multidisciplinary steering committee was formed and completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention which included bundled education with the use of therapeutic drug monitoring (TDM; i.e., drug level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. RESULTS: The education and TDM intervention were deployed through a Plan, Do, Study, Act (PDSA) cycle. In the three months after 'go-live,' 54 episodes of beta-lactam TDM occurred in 41 unique ICU patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. 94% of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; p=0.73). CONCLUSIONS: Application of the DMAIC Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

Metabolic remodeling by RNA polymerase gene mutations is associated with reduced ß-lactam susceptibility in oxacillin-susceptible MRSA.

The emergence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) has imposed further challenges to the clinical management of MRSA infections. When exposed to ß-lactam antibiotics, these strains can easily acquire reduced ß-lactam susceptibility through chromosomal mutations, including those in RNA polymerase (RNAP) genes such as rpoBC, which may then lead to treatment failure. Despite the increasing prevalence of such strains and the apparent challenges they pose for diagnosis and treatment, there is limited information available on the actual mechanisms underlying such chromosomal mutation-related transitions to reduced ß-lactam susceptibility, as it does not directly associate with the expression of mecA. This study investigated the cellular physiology and metabolism of six missense mutants with reduced oxacillin susceptibility, each carrying respective mutations on RpoBH929P, RpoBQ645H, RpoCG950R, RpoCG498D, RpiAA64E, and FruBA211E, using capillary electrophoresis-mass spectrometry-based metabolomics analysis. Our results showed that rpoBC mutations caused RNAP transcription dysfunction, leading to an intracellular accumulation of ribonucleotides. These mutations also led to the accumulation of UDP-Glc/Gal and UDP-GlcNAc, which are precursors of UTP-associated peptidoglycan and wall teichoic acid. Excessive amounts of building blocks then contributed to the cell wall thickening of mutant strains, as observed in transmission electron microscopy, and ultimately resulted in decreased susceptibility to ß-lactam in OS-MRSA. IMPORTANCE: The emergence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) strains has created new challenges for treating MRSA infections. These strains can become resistant to ß-lactam antibiotics through chromosomal mutations, including those in the RNA polymerase (RNAP) genes such as rpoBC, leading to treatment failure. This study investigated the mechanisms underlying reduced ß-lactam susceptibility in four rpoBC mutants of OS-MRSA. The results showed that rpoBC mutations caused RNAP transcription dysfunction, leading to an intracellular accumulation of ribonucleotides and precursors of peptidoglycan as well as wall teichoic acid. This, in turn, caused thickening of the cell wall and ultimately resulted in decreased susceptibility to ß-lactam in OS-MRSA. These findings provide insights into the mechanisms of antibiotic resistance in OS-MRSA and highlight the importance of continued research in developing effective treatments to combat antibiotic resistance.

Clinically important pharmacokinetic drug-drug interactions with antibacterial agents.

Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.

Emergence of lineage III of Shigella sonnei ST152 belonging to a high-risk clone harboring the blaCTX-M-15 gene in Peru.

Multidrug-resistant Shigella sonnei ST152, global lineage III, is a high-risk clone, whose dissemination has limited therapeutic options for shigellosis. This study aimed to characterize two isolates of S. sonnei, which were recovered in Lima, Peru, during November 2019, exhibiting resistance to extended-spectrum cephalosporins and quinolones, and concurrently harboring blaCTX-M-15 and qnrS1 genes, in addition to mutations in gyrA-S83L. These isolates were resistant to ceftriaxone, ciprofloxacin and trimethoprim/sulfamethoxazole. The molecular analysis showed that both isolates belonged to lineage III, sublineages IIIa and IIIb. The blaCTX-M-15 gene was located in the same genetic platform as qnrS1, flanked upstream by ISKpn19, on a conjugative plasmid belonging to the IncI-γ group. To the best of our knowledge, this would be the first report on S. sonnei isolates carrying the blaCTX-M-15 gene in Peru. The global dissemination of S. sonnei ST152, co-resistant to ß-lactams and quinolones, could lead to a worrisome scenario in the event of potential acquisition of genetic resistance mechanisms to azithromycin.

A validated LC-MS/MS method for simultaneous quantitation of piperacillin, cefazolin, and cefoxitin in rat plasma and twelve tissues.

BACKGROUND: The investigation of drug disposition in tissues is critical to improving dosing strategy and maximizing treatment effectiveness, yet developing a multi-tissue bioanalytical method could be challenging due to the differences among various matrices. Herein, we developed an LC-MS/MS method tailored for the quantitation of piperacillin (PIP), cefazolin (CFZ), and cefoxitin (CFX) in rat plasma and 12 tissues, accompanied by validation data for each matrix according to the FDA and EMA guidelines. RESULTS: The method required only a small sample volume (5 µL plasma or 50-100 µL tissue homogenates) and a relatively simple protocol for simultaneous quantitation of PIP, CFZ, and CFX within different biological matrices. Mobile phase A was composed of 5 mM ammonium formate and 0.1 % formic acid in water, while mobile phase B contained 0.1 % formic acid in acetonitrile. The mobile phase was pumped through a Synergi Fusion-RP column equipped with a guard column with a gradient elution program at a 0.3 mL/min flow rate. The mass spectrometer was operated in positive ionization mode (ESI+) using multiple reaction monitoring. SIGNIFICANCE: The validated method has been successfully applied to quantify PIP, CFZ, and CFX from the plasma and tissue samples collected in a pilot rat study and will further be used in a large pharmacokinetic study. To our knowledge, this is also the first report presenting long-term, freeze-thaw, and autosampler stability data for PIP, CFZ, and CFX in rat plasma and multiple tissues.

Determinants of beta-lactam PK/PD target attainment in critically ill patients: A single center retrospective study.

PURPOSE: We aimed to identify factors associated with achieving target BL plasma concentrations and describe real world data for therapeutic drug monitoring (TDM). METHODS: A retrospective single center study was conducted. We collected data from patients admitted to ICU with at least one BL TDM. We assessed the proportion of patients attaining the recommended plasma concentrations (i.e 100%fT > 4 to 8 MIC). Univariate and multivariate analyses was performed to identify the determinants of BL target attainment. RESULTS: 156 patients were included. At the first dosing, 34% achieved target BL plasma concentrations, 50% were overdosed, and 16% were underdosed. Median time for 1st TDM were 4 (SD = 2.9) days. Multivariate analysis revealed that CKD-EPI estimated glomerular filtration rate (OR = 1.02; CI [1.01; 1.03]; p < 0.0001) and total body weight (OR = 1.03; CI [1.01; 1.04]; p = 0.0048) were the main determinant of BL target attainment. Conversely, Continuous Renal Replacement Therapy (OR = 0.28; CI [0.09; 0.89]; p = 0.0318) and meropenem use (OR = 0.31; CI [0.14; 0.69]; p = 0.0041) were identified as risk factors for overdosing. No factor was associated with underdosing. CONCLUSION: Achieving target BL plasma concentrations remains challenging in ICUs. Identifying predictive factors of BL target attainment would favor implementing rapid dosing optimization strategies in both under and overdosing high risk patients.

The Spx stress regulator confers high-level ß-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin-resistant Staphylococcus aureus.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation ß-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased ß-lactam MICs up to 16-fold and transformed MRSA cells with low levels of resistance to being homogenously highly resistant to ß-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPR interference (CRISPRi) to knock down spx transcription, we unambiguously linked hyper-resistance to the accumulation of Spx. Spx was previously proposed to be essential; however, our data suggest that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in ß-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane, including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox-sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum ß-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.

Catalytic physiological amyloids.

Amyloid fibrils have been identified in many protein systems, mostly linked to progression and cytotoxicity in neurodegenerative diseases and other pathologies, but have also been observed in normal physiological systems. A growing body of work has shown that amyloid fibrils can catalyze chemical reactions. Most studies have focused on catalysis by de-novo synthetic amyloid-like peptides; however, recent studies reveal that physiological, native amyloids are catalytic as well. Here, we discuss methodologies and major experimental aspects pertaining to physiological catalytic amyloids. We highlight analyzes of kinetic parameters related to the catalytic activities of amyloid fibrils, structure-function considerations, characterization of the catalytic active sites, and deciphering of catalytic mechanisms.

High-resolution genomics identifies pneumococcal diversity and persistence of vaccine types in children with community-acquired pneumonia in the UK and Ireland.

BACKGROUND: Streptococcus pneumoniae is a global cause of community-acquired pneumonia (CAP) and invasive disease in children. The CAP-IT trial (grant No. 13/88/11; https://www.capitstudy.org.uk/ ) collected nasopharyngeal swabs from children discharged from hospitals with clinically diagnosed CAP, and found no differences in pneumococci susceptibility between higher and lower antibiotic doses and shorter and longer durations of oral amoxicillin treatment. Here, we studied in-depth the genomic epidemiology of pneumococcal (vaccine) serotypes and their antibiotic resistance profiles. METHODS: Three-hundred and ninety pneumococci cultured from 1132 nasopharyngeal swabs from 718 children were whole-genome sequenced (Illumina) and tested for susceptibility to penicillin and amoxicillin. Genome heterogeneity analysis was performed using long-read sequenced isolates (PacBio, n = 10) and publicly available sequences. RESULTS: Among 390 unique pneumococcal isolates, serotypes 15B/C, 11 A, 15 A and 23B1 were most prevalent (n = 145, 37.2%). PCV13 serotypes 3, 19A, and 19F were also identified (n = 25, 6.4%). STs associated with 19A and 19F demonstrated high genome variability, in contrast to serotype 3 (n = 13, 3.3%) that remained highly stable over a 20-year period. Non-susceptibility to penicillin (n = 61, 15.6%) and amoxicillin (n = 10, 2.6%) was low among the pneumococci analysed here and was independent of treatment dosage and duration. However, all 23B1 isolates (n = 27, 6.9%) were penicillin non-susceptible. This serotype was also identified in ST177, which is historically associated with the PCV13 serotype 19F and penicillin susceptibility, indicating a potential capsule-switch event. CONCLUSIONS: Our data suggest that amoxicillin use does not drive pneumococcal serotype prevalence among children in the UK, and prompts consideration of PCVs with additional serotype coverage that are likely to further decrease CAP in this target population. Genotype 23B1 represents the convergence of a non-vaccine genotype with penicillin non-susceptibility and might provide a persistence strategy for ST types historically associated with vaccine serotypes. This highlights the need for continued genomic surveillance.

Impact of attaining aggressive vs. conservative PK/PD target on the clinical efficacy of beta-lactams for the treatment of Gram-negative infections in the critically ill patients: a systematic review and meta-analysis.

BACKGROUND: To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. RESULTS: A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15-2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01-0.29). Male gender, body mass index > 30 kg/m2, augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. CONCLUSIONS: Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

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.

Antimicrobial-associated encephalopathy due to ampicillin.

Because the ß-lactam ring has a molecular structure similar to that of gamma-aminobutyric acid (GABA) neurotransmitters, it binds to GABA A receptors and inhibits GABAergic transmission, causing AAE. The possibility of antimicrobial-associated encephalopathy should be considered in cases of neurological or psychiatric symptoms after initiating an antimicrobial regimen.

Comparative Efficacy of Continuous Ceftazidime Infusion vs. Intermittent Bolus against In Vitro Ceftazidime-Susceptible and -Resistant Pseudomonas aeruginosa Biofilm.

Background: As the anti-biofilm pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics are not well-defined, we have evaluated the PK/PD indices for different regimens of ceftazidime (CAZ; with/without colistin) against Pseudomonas aeruginosa biofilm. Methods: We have used the Center for Disease Control and Prevention Biofilm Reactor with two susceptible (PAO1 and HUB-PAS) and one resistant (HUB-XDR) strains of P. aeruginosa. The regimens were CAZ monotherapies (mimicking a human dose of 2 g/8 h, CAZ-IB; 6 g/daily as continuous infusion at 50 mg/L, CAZ-CI50; and 9 g/daily at 70 mg/L, CAZ-CI70) and CAZ-colistin combinations. Efficacy was correlated with the CAZ PK/PD parameters. Results: CAZ-CI70 was the most effective monotherapy against CAZ-susceptible strains (Δlog CFU/mL 54-0 h = -4.15 ± 0.59 and -3.05 ± 0.5 for HUB-PAS and PAO1, respectively; p ≤ 0.007 vs. other monotherapies), and adding colistin improved the efficacy over CAZ monotherapy. CAZ monotherapies were ineffective against the HUB-XDR strain, and CAZ-CI50 plus colistin achieved higher efficacy than CAZ-IB with colistin. The PK/PD index that correlated best with anti-biofilm efficacy was fAUC0-24h/MIC (r2 = 0.78). Conclusions: CAZ exhibited dose-dependent anti-biofilm killing against P. aeruginosa, which was better explained by the fAUC0-24h/MIC index. CAZ-CI provided benefits compared to CAZ-IB, particularly when using higher doses and together with colistin. CAZ monotherapies were ineffective against the CAZ-resistant strain, independently of the optimized strategy and only CAZ-CI plus colistin appeared useful for clinical practice.

Phenotypic and molecular characterization of ß-lactamase-producing Klebsiella species among children discharged from hospital in Western Kenya.

BACKGROUND: The emergence and spread of ß-lactamase-producing Klebsiella spp. has been associated with a substantial healthcare burden resulting in therapeutic failures. We sought to describe the proportion of phenotypic resistance to commonly used antibiotics, characterize ß-lactamase genes among isolates with antimicrobial resistance (AMR), and assess the correlates of phenotypic AMR in Klebsiella spp. isolated from stool or rectal swab samples collected from children being discharged from hospital. METHODS: We conducted a cross-sectional study involving 245 children aged 1-59 months who were being discharged from hospitals in western Kenya between June 2016 and November 2019. Whole stool or rectal swab samples were collected and Klebsiella spp. isolated by standard microbiological culture. ß-lactamase genes were detected by PCR whilst phenotypic antimicrobial susceptibility was determined using the disc diffusion technique following standard microbiology protocols. Descriptive analyses were used to characterize phenotypic AMR and carriage of ß-lactamase-producing genes. The modified Poisson regression models were used to assess correlates of phenotypic beta-lactam resistance. RESULTS: The prevalence of ß-lactamase carriage among Klebsiella spp. isolates at hospital discharge was 62.9% (154/245). Antibiotic use during hospitalization (adjusted prevalence ratio [aPR] = 4.51; 95%CI: 1.79-11.4, p < 0.001), longer duration of hospitalization (aPR = 1.42; 95%CI: 1.14-1.77, p < 0.002), and access to treated water (aPR = 1.38; 95%CI: 1.12-1.71, p < 0.003), were significant predictors of phenotypically determined ß-lactamase. All the 154 ß-lactamase-producing Klebsiella spp. isolates had at least one genetic marker of ß-lactam/third-generation cephalosporin resistance. The most prevalent genes were blaCTX-M 142/154 (92.2%,) and blaSHV 142/154 (92.2%,) followed by blaTEM 88/154 (57.1%,) and blaOXA 48/154 (31.2%,) respectively. CONCLUSION: Carriage of ß-lactamase producing Klebsiella spp. in stool is common among children discharged from hospital in western Kenya and is associated with longer duration of hospitalization, antibiotic use, and access to treated water. The findings emphasize the need for continued monitoring of antimicrobial susceptibility patterns to inform the development and implementation of appropriate treatment guidelines. In addition, we recommend measures beyond antimicrobial stewardship and infection control within hospitals, improved sanitation, and access to safe drinking water to mitigate the spread of ß-lactamase-producing Klebsiella pathogens in these and similar settings.

Case Report: Mast cell anergy: absence of symptoms after accidental re-exposure to amoxicillin/clavulanic acid 3 days after anaphylaxis.

Empty mast cell syndrome, also named post anaphylaxis mast cell anergy (PAMA), is a temporary state of loss of mast cell responsiveness after a severe immediate hypersensitivity reaction. In this study, we describe a case of PAMA after accidental re-exposure to amoxicillin in a patient who developed severe anaphylaxis to this drug three days earlier in the operating room. To our knowledge, this report is the second to document this phenomenon.

Antibiotic dosing recommendations in critically ill patients receiving new innovative kidney replacement therapy.

BACKGROUND: The Tablo Hemodialysis System is a new innovative kidney replacement therapy (KRT) providing a range of options for critically ill patients with acute kidney injury. The use of various effluent rate and treatment durations/frequencies may clear antibiotics differently than traditional KRT. This Monte Carlo Simulation (MCS) study was to develop antibiotic doses likely to attain therapeutic targets for various KRT combinations. METHODS: Published body weights and pharmacokinetic parameter estimates were used to predict drug exposure for cefepime, ceftazidime, imipenem, meropenem and piperacillin/tazobactam in virtual critically ill patients receiving five KRT regimens. Standard free ß-lactam plasma concentration time above minimum inhibitory concentration targets (40-60%fT> MIC and 40-60%fT> MICx4) were used as efficacy targets. MCS assessed the probability of target attainment (PTA) and likelihood of toxicity for various antibiotic dosing strategies. The smallest doses attaining PTA ≥ 90% during 1-week of therapy were considered optimal. RESULTS: MCS determined ß-lactam doses achieving ∼90% PTA in all KRT options. KRT characteristics influenced antibiotic dosing. Cefepime and piperacillin/tazobactam regimens designed for rigorous efficacy targets were likely to exceed toxicity thresholds. CONCLUSION: The flexibility offered by new KRT systems can influence ß-lactam antibiotic dosing, but doses can be devised to meet therapeutic targets. Further clinical validations are warranted.

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review-To Do Small Things in a Great Way.

The subcutaneous (s.c.) route is a commonly used method for delivering various drugs, although its application in the administration of antibiotics is relatively uncommon. In this case, we report a successful treatment of nosocomial pneumonia using piperacillin/tazobactam via continuous subcutaneous administration. Furthermore, this article provides an overview of the current literature regarding the s.c. administration of beta-lactam antibiotics. Based on our analysis, we identified only 15 studies that described the s.c. use of beta-lactam antibiotics in human subjects. Among these studies, cephalosporins were the most extensively investigated antibiotic class, with 10 available studies. According to the study findings, all three antibiotic classes (cephalosporins, penicillins, and carbapenems) demonstrated a similar pharmacokinetic profile when administered via the subcutaneous route. The subcutaneous route appears to be associated with a lower peak serum concentration (Cmax) but a comparable minimum blood concentration (Cmin) and an extended half-life (t1/2) when compared to conventional routes of antibiotic administration. Further research is necessary to determine whether subcutaneously administered beta-lactam antibiotics in human subjects achieve pharmacodynamic targets and demonstrate clinical efficacy.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

El farmacéutico clínico en el abordaje del paciente con sospecha de alergia a beta-lactámicos: una revisión sistemática / The role of clinical pharmacists in patients with suspected allergy to B-lactams: A systematic review

Objetivo analizar el papel desempeñado por el farmacéutico clínico y su impacto en el ámbito de los programas de optimización de antimicrobianos ante la sospecha de alergia a antibióticos beta-lactámicos.Método se realizaron 2 búsquedas bibliográficas independientes. Se encontraron un total de 35 artículos incluyéndose 12. Se analizaron los artículos incluidos y se recogieron variables de eficacia, seguridad y aplicabilidad de herramientas de evaluación a pacientes con sospecha de alergia a beta-lactámicos. Además, se analizó la variación en el consumo y en el perfil de prescripción de antibióticos alternativos. Resultados los estudios seleccionados analizaron cuestionarios, desetiquetado, test intradérmicos y pruebas de provocación oral realizados por farmacéuticos. Se hallaron diferencias significativas en la variable principal de eficacia en 4 estudios incluidos a favor de la intervención farmacéutica. En un estudio cuasi experimental, la utilización de cefazolina aumentó tras la intervención farmacéutica (65 vs. 28%; p < 0,01). En otro estudio cuasi experimental, la dosis diaria definida media de aztreonam y la media de días de terapéutica por 1.000 pacientes/día disminuyeron (21,23 vs. 9,05; p < 0,01) y (8,79–4,24; p = 0,016), pre y postintervención, respectivamente, aumentando las desescaladas antibióticas (p ≤ 0,01). En otro estudio, disminuyó la prescripción de antibióticos de uso restringido (42,5 vs. 17,9%; p < 0,01) y en otro, la utilización de antibióticos profilácticos prequirúrgicos alternativos a cefazolina (81,9 vs. 55,9%; p < 0,01). En otro estudio, el tiempo medio por entrevista fue de 5,2 minutos por paciente. No se reportaron eventos adversos en ningún estudio. Conclusiones la intervención del farmacéutico en la evaluación del paciente con sospecha de alergia a beta-lactámicos resulta eficaz, segura y aplicable a la práctica clínica (AU)

Objective To analyze the role played by the clinical pharmacist and its impact in antibiotic stewardship facing suspected allergy to beta-lactam antibiotics. Method We performed two different independent bibliographic searches. A total of 35 articles were found, and the final number included in the study was 12. We analysed the articles and collected variables of efficacy, safety and applicability of evaluation tools applied to patients with suspected allergy to beta-lactams. Also, the variation in the consumption and prescription profile of alternative antibiotics was analyzed. Results The selected studies analysed questionnaires, allergy delabeling, intradermal tests and oral challenge tests performed by pharmacists. Significant differences in the efficacy endpoint were found in 4 studies in favour of pharmaceutical intervention. In the study of Kwiatkowski et al, cefazolin use increased in surgical patients after pharmacist intervention (65 vs. 28%; p < 0.01). In a quasi-experimental study, the mean defined daily dose of aztreonam and the mean days of therapy per 1000 patients/day decreased (21.23 vs 9.05, p <0.01) and (8.79–4.24, p = 0.016), pre and post-intervention, respectively, increasing antibiotic de-escalations (p ≤ 0.01). In another quasi-experimental study, the prescription of restricted-use antibiotics decreased (42.5% vs. 17.9%, p < 0.01) and the use of pre-surgical prophylactic antibiotics alternative to cefazolin (81.9% vs 55.9%, p<0.01) in another study. Other study showed that the mean time per interview was 5.2 minutes per patient. No adverse events were reported in any study. Conclusion The pharmacist intervention in the evaluation of the patient with suspected allergy to beta-lactams is effective, safe and feasible to implement on daily clinical practice (AU)

mSphere of Influence: Targeting bacterial signaling and metabolism to overcome antimicrobial resistance.

Dr Merve Suzan Zeden works in the field of molecular bacteriology and antibiotic resistance. In this mSphere of Influence article, she reflects on how three papers, entitled "c-di-AMP modulates Listeria monocytogenes central metabolism to regulate growth, antibiotic resistance and osmoregulation," "Amino acid catabolism in Staphylococcus aureus and the function of carbon catabolite repression," and "Evolving MRSA: high-level ß-lactam resistance in Staphylococcus aureus is associated with RNA polymerase alterations and fine tuning of gene expression," made an impact on her work on bacterial metabolism and antimicrobial resistance and how it shaped her research in understanding the link in between.