The study was conducted from January to June 2026 at the Gastroenterology and Hepatology Teaching Hospital/Medical City in Baghdad. The hospital treats patients from across Iraq, but the study did not recruit a population-based sample from every governorate. Eligible participants were adults with documented Crohn’s disease who attended the center during the study period and provided informed consent. The researchers used convenience sampling and excluded patients with several other immune conditions, recent steroid use, cancer, specified Crohn’s disease complications, or insufficient monitoring data.

All participants received intravenous induction ustekinumab at week 0, using a weight-based dose of 260 mg for patients below 55 kg, 390 mg for those weighing 55–85 kg, and 520 mg for those above 85 kg. Maintenance treatment consisted of 90 mg administered subcutaneously every eight weeks, beginning eight weeks after induction. Participants had completed at least 24 weeks of continuous treatment before enrollment, allowing assessment during maintenance therapy at what the investigators described as pharmacokinetic steady state.

Each patient was sampled once, immediately before a scheduled maintenance dose and at the end of the eight-week dosing interval. The same visit provided a concurrent measurement of disease activity using the Crohn’s Disease Activity Index. Remission was defined as a score below 150, while a score of 150 or higher indicated active disease. Blood samples were used to quantify the ustekinumab trough level, assess anti-drug antibodies, and measure laboratory and inflammatory markers.

The study grouped patients according to whether they met a 1 μg/mL trough threshold derived from earlier literature. Among the 55 patients who reached the threshold, the median ustekinumab concentration was 1.50 μg/mL, with an interquartile range of 1.25–1.73 μg/mL. Among the 21 who did not reach it, the median was 0.70 μg/mL, with an interquartile range of 0.56–0.87 μg/mL; the difference was significant at p<0.001. Only one patient was positive for anti-ustekinumab antibodies, and the difference in antibody positivity between the concentration groups was not statistically significant.

Unadjusted binary logistic regression estimated that each additional 1 μg/mL of trough concentration was associated with 9.35 times the odds of clinical remission, with a 95% confidence interval of 2.61–33.33 and p=0.001. After adjustment for concomitant azathioprine use and ustekinumab treatment duration, the reported adjusted odds ratio was 14.30, with a 95% confidence interval of 3.35–58.80 and p<0.001. These estimates came from the same observational dataset, and the study did not report a statistical comparison between the unadjusted and adjusted coefficients. The results therefore describe an association rather than establishing that increasing ustekinumab exposure would cause remission.

Patients at or above the target concentration also had lower inflammatory markers and higher serum albumin. Median C-reactive protein was 1.90 mg/L in the target-level group and 22.00 mg/L in the lower-concentration group. Median erythrocyte sedimentation rates were 24 and 64 mm/hr, respectively, while median serum albumin was 41.60 and 35.00 g/L. All three comparisons were significant at p<0.001. The analysis did not determine whether lower inflammation contributed to higher drug concentrations, higher concentrations were associated with lower inflammation, or other factors influenced both measures.

The investigators classified the patients’ treatment-response patterns using concentration, antibody status, and disease activity. Among 55 patients at the target level, 43 were in remission and 12 had active disease; the latter pattern was categorized as mechanistic treatment failure. Among the 21 patients below the target, six were in remission, 14 had active disease with negative anti-drug antibodies, and one had active disease with positive antibodies. The authors classified the antibody-negative cases as non-immune pharmacokinetic failure and the antibody-positive case as immune pharmacokinetic failure. These classifications were the basis of the study’s proposed management options, rather than outcomes tested in an intervention trial.

The findings add an Iraqi clinical cohort to earlier evidence that the investigators described as inconsistent. They cited a Spanish real-world cohort in which trough levels were associated with clinical response, while studies from the Netherlands and Italy reported no association. The authors cited differences in remission definitions, laboratory assays, treatment phase, and dosing intervals as possible explanations. This study used a uniform eight-week maintenance schedule and measured drug exposure and disease activity concurrently, but it was not designed to resolve those differences comparatively.

Important limitations include the modest single-center sample, convenience sampling, and restriction to patients who attended the Baghdad center during the six-month enrollment period. These features may limit statistical power, introduce selection bias, and restrict external validity. Samples were also stored for up to five months before laboratory analysis, which delayed the availability of treatment advice. The authors stated that larger multicenter research is needed to confirm the results and clarify the role of therapeutic drug monitoring in patients with Crohn’s disease receiving ustekinumab.

Subject of Research: Association between maintenance ustekinumab trough concentrations and clinical remission in adults with Crohn’s disease

Article Title: Therapeutic drug monitoring of ustekinumab in Crohn’s disease patients: a real-world study

Article References: Jebur, N. J., Jabbar Kadhim, D., & Al Issa, I. H. (2026). Therapeutic drug monitoring of ustekinumab in Crohn’s disease patients: a real-world study. Pharmacia, 73, Article e211586. https://doi.org/10.3897/pharmacia.73.e211586

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e211586

Keywords: Crohn’s disease, ustekinumab, therapeutic drug monitoring, trough concentration, clinical remission, anti-drug antibodies, inflammatory markers, cross-sectional study, real-world evidence, Therapeutic, drug, monitoring

The research team, led by corresponding author Bo Guo of the hospital’s Department of Pharmacy, analyzed six years of clinical data from neonates treated with vancomycin in the hospital’s Neonatal Intensive Care Unit. All of these infants had undergone trough concentration monitoring, meaning clinicians measured the lowest concentration of the drug in the blood just before the next dose was administered. This measurement is a cornerstone of therapeutic drug monitoring, the practice of adjusting drug doses based on measured blood concentrations rather than relying solely on weight-based formulas. The study was approved by the hospital’s Medical Ethics Committee, which waived the requirement for written informed consent because the research used only fully de-identified retrospective clinical data and involved no direct interventions on enrolled neonates.

What makes the new findings particularly striking is the shape of the relationship the researchers uncovered. Rather than a simple linear association between gestational age and initial vancomycin trough concentration, the data revealed a non-linear pattern with a clear inflection point at approximately 34.6 weeks of gestation, or roughly 242 days. Using a two-piecewise linear regression model, the team found that the log-likelihood ratio test yielded a P-value of 0.007, indicating that the piecewise model fit the data significantly better than a single straight line would have. This statistical approach essentially allows the data to reveal where the underlying biology changes direction, rather than forcing researchers to guess in advance.

Below that 34.6-week threshold, the study found a positive correlation between gestational age and the initial vancomycin trough concentration, with a beta coefficient of 0.08 and a 95 percent confidence interval of 0.01 to 0.14, and a P-value of 0.021. In practical terms, this means that as preterm infants approach the mid-30s weeks of gestation, their trough concentrations tend to rise, suggesting that the drug is being cleared more slowly or distributed differently in their bodies. Above the threshold, however, the trend reversed, showing a negative direction of borderline significance, with a beta coefficient of -0.10, a 95 percent confidence interval of -0.20 to 0.00, and a P-value of 0.059. This reversal suggests that once infants pass roughly 34.6 weeks of gestation, the pharmacokinetic landscape shifts in a way that current gestational-age-based dosing protocols may not adequately capture.

The pharmacokinetic explanation for this inflection point likely lies in the dramatic developmental changes that occur in neonatal renal function. Vancomycin is almost entirely eliminated by the kidneys through glomerular filtration, and glomerular filtration rate in neonates is strongly dependent on both gestational age and postnatal age. Extremely preterm infants have immature nephrons and reduced glomerular filtration, meaning vancomycin lingers longer in their circulation and trough concentrations can accumulate to potentially toxic levels if dosing is not carefully adjusted. As infants mature, nephrogenesis completes and filtration capacity increases, which would normally be expected to lower trough concentrations for a given dose. The reversal observed above 34.6 weeks may reflect this transition, where increasing renal clearance begins to outpace the effects of maturing body composition.

Body water compartments also play a significant role in vancomycin distribution in newborns. The drug has a relatively large volume of distribution in neonates because of their high total body water content, which is especially pronounced in preterm infants. As gestational age increases, body fat proportion rises and total body water declines, reducing the volume of distribution and concentrating the drug in a smaller plasma space. These competing developmental forces, changing renal clearance on one hand and changing distribution on the other, likely interact in complex ways that produce the non-linear relationship observed in the study data rather than a simple monotonic trend.

The clinical implications of these findings are substantial. Current vancomycin dosing guidelines for neonates, including those informed by the Infectious Diseases Society of America, typically stratify doses by gestational age and postnatal age. The new study suggests that these existing protocols may inadequately account for the pharmacokinetic transitions occurring around 34.6 weeks of gestation. In other words, a neonate at 33 weeks and a neonate at 36 weeks may sit on opposite sides of a critical biological threshold, yet both could receive doses calculated from the same broad gestational-age category. This could explain why initial trough concentrations frequently fall below therapeutic levels in neonates administered vancomycin, a problem the study authors explicitly noted in their background.

Subtherapeutic vancomycin levels are not merely a theoretical concern. When trough concentrations fall below the therapeutic range, the drug may fail to achieve the pharmacodynamic target of a 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio, known as AUC24/MIC, that is needed to effectively kill resistant bacteria. This raises the specter of treatment failure and, more worryingly, the potential for resistance to develop. On the other end of the spectrum, excessively high trough concentrations increase the risk of vancomycin-associated nephrotoxicity, a particularly dangerous complication in neonates whose kidneys are still developing. The narrow therapeutic window of this drug makes precise dosing not just desirable but essential.

The study’s retrospective, single-center design carries important limitations that the authors themselves acknowledged. Because the data came from one hospital over a defined six-year period, the findings may not generalize to neonatal populations with different demographic characteristics, different vancomycin formulations, or different clinical practices. The borderline significance of the negative trend above the inflection point, with a P-value of 0.059, also means that this reversal should be interpreted with caution until confirmed in larger or more diverse cohorts. The authors emphasized that prospective studies are needed to validate therapeutic drug monitoring protocols stratified by gestational age, rather than relying on the retrospective associations uncovered here.

Nevertheless, the identification of a specific inflection point at approximately 34.6 weeks of gestation offers a concrete target for future research and clinical refinement. Rather than treating gestational age as a smooth continuum for dosing purposes, neonatal pharmacologists may need to recognize distinct pharmacokinetic phases separated by this threshold. The study, funded by the Xi’an Science and Technology Research Program and the Shaanxi Provincial Science and Technology Research Project, adds to a growing body of evidence that individualized vancomycin dosing in neonates requires more nuanced attention to developmental stage than current protocols provide. As therapeutic drug monitoring becomes increasingly routine in neonatal intensive care units worldwide, findings like these could help clinicians fine-tune doses to the specific developmental biology of each infant, potentially improving outcomes for the most vulnerable patients in medicine.

Subject of Research: Association between vancomycin trough concentration monitoring and gestational age in neonates

Article Title: Association between vancomycin trough concentration monitoring and gestational age in neonates: a single-center, retrospective observational study

Article References: Chen, H., Liu, X., Ju, K., Song, X., Zhao, K., Wei, Z., & Guo, B. (2026). Association between vancomycin trough concentration monitoring and gestational age in neonates: a single-center, retrospective observational study. BMC Pediatrics, 26(1), Article 1015. https://doi.org/10.1186/s12887-026-07630-8

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07630-8

Keywords: vancomycin, neonates, gestational age, therapeutic drug monitoring, trough concentration, pharmacokinetics, neonatal intensive care, BMC Pediatrics, individualized dosing, inflection point, Association, between

Fibrinogen sits at the heart of hemostasis. When blood vessels are injured, the enzyme thrombin cleaves fibrinogen into fibrin strands, which weave together into the meshwork of a stable clot. When fibrinogen levels fall below roughly 2.0 grams per liter, the threshold the researchers used to define hypofibrinogenemia in this study, that meshwork becomes fragile or fails to form at all, leaving patients exposed to bleeding risks at a time when many are already fighting severe, multidrug-resistant infections. The problem for clinicians has long been that hypofibrinogenemia in intensive care patients has many potential causes, including sepsis itself, disseminated intravascular coagulation, liver dysfunction, and massive transfusion, making it difficult to know when the antibiotic rather than the underlying illness is to blame.

The research team, led by Xiong Guo, Yao Zhang, Tao Yin, and corresponding author Ping Wang, addressed this ambiguity by focusing on the tigecycline trough concentration, the lowest level of the drug in plasma, measured just before the next dose is administered. Trough concentrations are a cornerstone of therapeutic drug monitoring because they capture the baseline exposure a patient carries between doses. Patients treated between January 2018 and May 2026 were enrolled, and every case of hypofibrinogenemia was adjudicated using WHO-UMC causality criteria, a standardized pharmacovigilance framework that helps separate drug-induced adverse events from those attributable to disease processes. Patients were then divided into a hypofibrinogenemia group and a normal group based on their fibrinogen measurements.

Using multivariable logistic regression, a statistical technique that isolates the independent contribution of each factor while controlling for the others, the team identified three independent risk factors for developing the complication: baseline fibrinogen level, duration of tigecycline treatment, and, critically, the trough concentration of the drug itself. Baseline fibrinogen carried a p-value of 0.022, treatment duration a p-value of 0.007, and trough concentration a p-value of 0.026, all of which reached conventional thresholds of statistical significance. Receiver operating characteristic analysis, which evaluates how well a continuous variable discriminates between patients who do and do not experience an outcome, then translated these risk factors into practical clinical cutoffs. Patients with a trough concentration of 0.27 micrograms per milliliter or higher, a treatment duration of 6.50 days or longer, or a baseline fibrinogen below 4.55 grams per liter faced markedly elevated risk.

Perhaps the most striking finding emerged when the investigators sorted patients into quartiles according to their trough concentrations. The incidence of hypofibrinogenemia rose in a clean, stepwise gradient across the quartiles, climbing from 36.11 percent in the lowest quartile to 82.05 percent in the highest, with a p-value for trend below 0.001. This dose-response relationship is exactly the kind of biological signal that lends credibility to a causal association: as exposure to the drug increases, so does the probability of harm, in a predictable and monotonic fashion. For intensive care physicians, the implication is that a simple blood measurement, available through routine therapeutic drug monitoring, could flag patients heading toward a coagulation crisis before fibrinogen levels collapse.

Beyond establishing who is at risk, the study mapped the natural history of the complication in unusual detail. The median time from the start of therapy to the onset of hypofibrinogenemia was 7 days, meaning clinicians should not assume that early uneventful treatment rules the risk out. Once established, the median duration of hypofibrinogenemia was 6 days. Most reassuring, however, was the recovery phase: after tigecycline was discontinued, fibrinogen levels returned to normal within a median of just 2.5 days. This rapid rebound suggests that the drug’s effect on fibrinogen is, at least in most patients, reversible rather than a sign of lasting injury to the synthetic machinery of the liver, which produces the vast majority of circulating fibrinogen.

The correlation analysis revealed an intriguing internal logic to the recovery process. Fibrinogen recovery time after discontinuation of tigecycline was positively correlated with both the time to hypofibrinogenemia onset and the duration of the hypofibrinogenemia episode, with both correlations reaching a p-value of 0.004. In other words, patients whose fibrinogen fell early, and those whose levels remained suppressed for longer, also took longer to bounce back once the drug was withdrawn. This pattern hints at a cumulative exposure phenomenon: the deeper and more prolonged the disruption, the more time the body’s fibrinogen production requires to restore equilibrium. It also reinforces the practical value of early detection, since patients identified and managed before prolonged suppression sets in may recover faster.

Importantly, the researchers also examined whether hypofibrinogenemia translated into worse short-term survival. Using Cox regression, they assessed 30-day mortality and found no significant association between the complication and death within a month, with a p-value of 0.289. That null finding should not be read as license for complacency, the study’s structure suggests, because the enrolled patients were already among the sickest in the hospital, with severe infections caused by multidrug-resistant pathogens, and competing risks in such a population can obscure the specific contribution of any single complication. Nevertheless, the result provides useful context: tigecycline-induced hypofibrinogenemia appears to be a common and monitorable adverse effect whose clinical management can focus on surveillance and timely drug withdrawal rather than panic.

The mechanistic story behind these observations remains an open question, and the authors are careful not to overclaim. Tigecycline is extensively metabolized and cleared through the liver and biliary system, and previous reports have linked the drug to elevations in liver enzymes, bilirubin, and coagulation parameters including prothrombin time and the international normalized ratio. One plausible explanation is that high cumulative exposure interferes directly or indirectly with hepatic fibrinogen synthesis, or with the clotting cascade more broadly, though the precise molecular pathway has not been pinned down. What the new study adds is a quantitative framework: a specific trough concentration threshold, a specific treatment duration, and a specific baseline fibrinogen level that together allow clinicians to stratify risk before the complication develops.

For the growing field of therapeutic drug monitoring in critical care, the findings carry a broader message. Antibiotics are often dosed by standard weight-based formulas that ignore the enormous pharmacokinetic variability among critically ill patients, whose organ function, fluid status, and protein binding can swing dramatically from day to day. Tigecycline, despite its approval and widespread use against serious Gram-positive and Gram-negative infections, has no well-established therapeutic range for safety, and this study suggests that establishing one could prevent a substantial burden of harm. The work was supported by the Hunan Natural Science Foundation, and the team notes that the risk gradient across concentration quartiles was prominent and progressive. If future prospective studies confirm the cutoffs identified here, routine trough measurement could become as standard a part of tigecycline therapy as the drug’s acclaimed antimicrobial coverage, turning an invisible pharmacokinetic variable into an actionable shield for patients who have little physiological reserve left to spare.

One reason trough monitoring may be especially informative for tigecycline lies in the drug’s unusual pharmacokinetic profile. Unlike most antibiotics, tigecycline distributes extensively into tissues, yielding a large volume of distribution and plasma concentrations that are only a small fraction of total body exposure. Critically ill patients are notoriously variable in this regard: shifts in fluid balance, hypoalbuminemia, hepatic congestion, and evolving organ dysfunction can all reshape how the drug behaves in a given individual, so two patients receiving the same weight-based dose may carry very different internal exposures. A trough measurement offers a practical window into that variability at the bedside.

The choice of a 2.0 grams per liter fibrinogen threshold also deserves comment. Fibrinogen is an acute-phase reactant, meaning it typically rises during inflammation, so many patients with severe infections start therapy with elevated levels. This may explain why a baseline value below 4.55 grams per liter emerged as a risk factor: patients whose fibrinogen reserves are already modest have less buffer before drug-related suppression pushes them into the hypofibrinogenemic range. It also complicates interpretation, since a falling fibrinogen in an inflamed patient may still represent a meaningful decline even if the absolute value remains above conventional cutoffs.

As a retrospective, single-center analysis, the study has inherent limitations that temper broad generalization. Concentration measurements were obtained as part of routine care rather than a standardized sampling protocol, and unmeasured confounders such as concurrent transfusions, blood products, or other fibrinogen-lowering drugs cannot be fully excluded. The authors’ use of WHO-UMC adjudication mitigates but does not eliminate this concern. Nevertheless, the open-access dataset, the dose-response gradient, and the internally consistent timing relationships provide a solid foundation for the prospective validation studies that would be needed before the proposed cutoffs enter routine clinical practice.

Subject of Research: The association between tigecycline trough plasma concentration and tigecycline-induced hypofibrinogenemia in critically ill patients.

Article Title: Tigecycline trough concentration and its relationship with hypofibrinogenemia: from onset and duration to recovery

Article References: Guo, X., Zhang, Y., Yin, T., & Wang, P. (2026). Tigecycline trough concentration and its relationship with hypofibrinogenemia: from onset and duration to recovery. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14419-8

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14419-8

Keywords: tigecycline, hypofibrinogenemia, trough concentration, therapeutic drug monitoring, fibrinogen, intensive care unit, antibiotic adverse effects, coagulation, multidrug-resistant infections, pharmacokinetics, drug safety, BMC Infectious Diseases