Factors linked to tigecycline-associated acute pancreatitis in a multicenter retrospective nested case-control study in patients

Summary

Tigecycline is associated with acute pancreatitis (TAAP), yet clinical factors linked to this adverse event require further identification. We conducted a multicenter, retrospective nested case-control study of 6942 patients receiving tigecycline. Cases were defined as patients who developed TAAP, while controls were matched in a 1:4 ratio by the same center and age. Among the cohort, 52 patients developed TAAP with an incidence of 0.75%. The median duration of tigecycline treatment was 7.5 days (IQR: 4–12.25 days), and the median time from the initiation of tigecycline to the onset of acute pancreatitis was 4 days (IQR: 1–8 days) in the case group. Multivariate analysis identified several factors associated with TAAP, including organ transplantation, elevated serum phosphorus, serum urea, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, serum gamma-glutamyl transferase (GGT), and concomitant use of esomeprazole; however, protopathic bias cannot be excluded. Our findings identified higher-risk individuals and support more cautious use during tigecycline therapy.

Graphical abstract

Highlights

• •TAAP incidence was 0.75% in this multicenter study, with a median onset at 4 days
• •Organ transplantation and elevated serum phosphorus were key factors linked to TAAP
• •Elevated liver enzymes (AST/ALT ratio) and urea were also associated with TAAP
• •Esomeprazole use was linked to TAAP, though protopathic bias may confound this finding

Health sciences

Introduction

Tigecycline is a broad-spectrum glycylcycline antibiotic that exhibits potent activity against pathogens by overcoming common resistance mechanisms such as β-lactamase production and macrolide efflux.¹ Its bacteriostatic effect acts through high-affinity binding to the 30S ribosomal subunit, which inhibits the incorporation of aminoacyl-tRNA into the acceptor site and thereby disrupts bacterial protein synthesis. Clinically, tigecycline is recommended for the treatment of complicated intra-abdominal infections, skin and soft tissue infections, and community-acquired bacterial pneumonia caused by resistant organisms, including methicillin-resistant Staphylococcus aureus and carbapenem-resistant Enterobacterales.^2,3 However, as its clinical use expands, previously underrecognized safety concerns have emerged.

Previous studies have indicated that gastrointestinal disturbances are the most frequently reported adverse effects linked to tigecycline. An initial case reported in 2008 suggested a potential association between tigecycline use and the occurrence of acute pancreatitis.⁴ Subsequent pharmacovigilance analyses and case series have substantiated this association, thereby raising clinical awareness of tigecycline-associated acute pancreatitis (TAAP).⁵

Acute pancreatitis is a rapidly progressing inflammatory condition with a variety of etiologies. Its primary characteristics include elevated levels of amylase and/or lipase, accompanied by abdominal pain. The severity of the condition can be further assessed through imaging examinations.⁶ It can lead to significant adverse outcomes, including pancreatic tissue necrosis and systemic infection, which may necessitate intensive care unit admission or even result in mortality if diagnosis and management are delayed.⁷ Common triggers include gallstones, alcohol consumption, hypertriglyceridemia, and iatrogenic injury following endoscopic retrograde cholangiopancreatography (ERCP).^8,9,10 Although drug-induced pancreatitis was once considered rare, enhanced monitoring of adverse reactions in recent years has identified multiple drug classes, such as immunomodulatory, anticancer, and antibacterial agents, as potential triggers.^11,12,13 Proposed mechanisms for drug-induced pancreatic injury range from direct cytotoxic effects and metabolic dysregulation to idiosyncratic hypersensitivity responses¹⁴; however, the underlying pathophysiology remains unclear. Consequently, early symptoms are frequently overlooked in clinical practice due to a lack of awareness regarding this adverse effect.

Retrospective studies and phase 3–4 clinical trials have demonstrated that the overall incidence of TAAP remains below 1%,^15,16 most of whom experience symptom resolution within one week of treatment following the occurrence of this adverse reaction; however, a small subset of patients may succumb to concurrent shock or severe infections.^17,18 Currently, some studies have conducted to review published case reports or retrospective cohorts to identify the characteristics and comorbidities associated with acute pancreatitis following tigecycline administration. Findings have indicated that renal dysfunction and kidney transplantation are associated factors for TAAP.^16,19 Nevertheless, due to limitations related to sample size and the single-center design of previous studies, further in-depth analyses of population characteristics, laboratory indicators, and concomitant medications are warranted.

The present multicenter study aims to examine factors associated with TAAP and describe its clinical features to facilitate earlier detection and improve management in high-risk patients receiving tigecycline.

Results

A total of 6942 patients who received tigecycline across seven centers between 2015 and 2022 were initially screened. After applying exclusion criteria (age <18 years, history of acute or chronic pancreatitis, other causes of pancreatitis, pregnancy, insufficient data), all eligible patients constituted the base cohort. From this cohort, cases were defined as patients who developed acute pancreatitis following tigecycline administration (n = 52). Controls (n = 208) were selected from the remaining patients who did not develop pancreatitis, using a 1:4 incidence density sampling approach matched on study center and age. The complete selection process and group allocation are detailed in Figure 1.

Figure 1.

Flowchart of the patient selection process

By retrospectively reviewing electronic medical records across seven hospitals from 2015 to 2022, we initially collected 7269 patients who had received tigecycline. We excluded individuals aged <18 years (n = 36), those with other causes of acute pancreatitis (n = 24), and those with missing data (n = 267), resulting in a study cohort of 6942 patients. From this cohort, cases were identified if they met at least two of the following criteria following tigecycline treatment: (1) acute abdominal pain with tenderness in the upper abdomen; (2) serum amylase and/or lipase levels exceeding three times the upper limit of normal (ULN); (3) abnormal findings indicative of acute pancreatitis on imaging studies such as abdominal CT or abdominal ultrasound. A total of 52 patients were identified as the case group. For each case, four controls were selected from tigecycline-treated patients without acute pancreatitis, who were matched based on the same center and age, resulting in 208 controls (1:4 ratio).

Incidence and characteristics of tigecycline is associated with acute pancreatitis

In this study, we included 6942 patients treated with tigecycline, among whom 52 developed acute pancreatitis, resulting in an incidence of 0.75% (95% CI: 0.55–0.95). Sex-specific analyses showed no significant association with TAAP. The cumulative incidence was 0.67% (95% CI: 0.44–0.90) in males and 0.93% (95% CI: 0.53–1.34) in females (p = 0.297). The center-specific rates ranged from 0 to 7.14%. Of the 52 patients who developed acute pancreatitis following tigecycline administration, 41 presented with upper abdominal pain as a clinical symptom. Imaging studies, including abdominal CT or ultrasound, revealed findings consistent with acute pancreatitis in 15 cases. Amylase levels exceeding three times the upper limit of normal (3×ULN) were observed in 35 patients, whereas 31 patients exhibited lipase levels greater than 3×ULN. Based on the diagnostic criteria for acute pancreatitis, most patients were classified as mild or moderate cases (59.62%, 31/52), although 40.38% (21/52) progressed to severe or critical cases. Additionally, the Naranjo scale was employed to assess the association between tigecycline and the onset of acute pancreatitis (Table S1). The 52 cases were categorized as “possible” or “probable” (Table 1).

Table 1.

Incidence and characteristics of TAAP cases

Characteristics	Value	95%CI
Incidence, % (n/N)	0.75 (52/6942)	0.55–0.95
Male	0.67 (32/4801)	0.44–0.90
Female	0.93 (20/2141)	0.53–1.34
Zhongnan Hospital of Wuhan University	0.75 (33/4392)	0.55–0.95
The Central Hospital of Wuhan	0.78 (11/1404)	0.58–0.99
Taihe Hospital	0.35 (2/573)	0.04–1.26
Xiangyang Central Hospital	0.97 (4/412)	0.26–2.46
General Hospital of the Yangtze River Shipping	1.09 (1/92)	0.03–5.91
Xiantao First People’s Hospital	0.00 (0/55)	0.00–6.49
Taikang Tongji (Wuhan) Hospital	7.14 (1/14)	0.18–33.87
Criteria (n,%)
Upper abdominal pain	41 (78.85)	65.30–88.94
Amylase exceeding 3 × ULN	35 (67.31)	52.89–79.67
Lipase exceeding 3 × ULN	31 (59.62)	45.10–72.99
Imaging showing acute pancreatitis	15 (28.85)	17.13–43.08
Grade (n,%)
Mild cases	28 (53.85)	39.47–67.77
Moderate cases	3 (5.77)	1.21–15.95
Severe cases	8 (15.38)	6.58–28.08
Critical cases	13 (25.00)	14.03–38.95
Relevance score (n,%)
Possible	39 (75.00)	61.05–85.97
Probable	13 (25.00)	14.03–38.95
Definite	0 (0.00)	0.00–6.85

Incidence rates are presented as percentage (n/N) with 95% confidence intervals (CIs), based on the total cohort of 6942 patients. Clinical criteria, disease severity grades, and relevance scores are presented as n (%) with 95% CIs among the 52 TAAP cases. ULN, upper limit of normal. Disease severity was categorized as mild, moderate, severe, or critical based on clinical presentation. The association between tigecycline and acute pancreatitis was evaluated using the Naranjo adverse drug reaction probability scale, where scores of 1–4 indicate a “possible” association, scores of 5–8 indicate a “probable” association, and scores of 9 or higher are considered “definite.”

Demographic and clinical characteristics of patients with tigecycline is associated with acute pancreatitis

Table 2 presents the comorbidities, baseline laboratory results, and clinical outcomes for the 52 patients with TAAP and their matched controls. The proportion of male patients did not differ significantly between cases and controls (p = 0.335). Organ transplantation was significantly more prevalent in the case group. Upon admission, the case group exhibited significantly higher levels of procalcitonin, as well as elevated liver function indicators, including AST, the AST/ALT ratio, alkaline phosphatase, and direct bilirubin. Renal function parameters also demonstrated notable differences, with the case group showing increased serum levels of urea, uric acid, and creatinine, alongside a reduced estimated glomerular filtration rate. The median duration of tigecycline therapy was similar between the groups, with 7.5 (4–12.25) days for cases and 7 (4–12) days for controls. No significant differences were observed in infection sites, and tigecycline was predominantly employed for treatment rather than prophylaxis (Table 2).

Table 2.

Comparison of main baseline variables between patients with TAAP (cases) and those without (controls)

Variables	N = 260	Cases (n = 52)	Controls (n = 208)	p-value
Male gender (n,%)	177 (68.08)	32 (61.54)	145 (69.71)	0.335
Age (years)	60 (50–71)	60 (50–71)	60 (50.5–70.5)	1.000
Comorbidity
Hypertension (n,%)	93 (35.77)	24 (46.15)	69 (33.17)	0.113
Diabetes (n,%)	52 (20.00)	11 (21.15)	41 (19.71)	0.969
COPD (n,%)	15 (5.77)	1(1.92)	14 (6.73)	0.317
Chronic kidney disease (n,%)	24 (9.23)	7 (13.46)	17 (8.17)	0.282
Cancer (n,%)	60 (23.08)	6 (11.54)	54 (25.96)	0.043
Organ transplantation (n,%)	10 (3.85)	6 (11.54)	4 (1.92)	0.005
Complete blood count
White blood cells (×109/L)	7.93 (5.11–12.62)	7.59 (5.00–15.29)	8.04 (5.15–12.03)	0.600
Neutrophils (%)	79.8 (64.4–87.68)	79.8 (71.4–86.3)	79.8 (61.55–87.65)	0.134
Red blood cells (×1012/L)	3.23 (2.62–4.03)	3.24 (2.73–3.87)	3.23 (2.56–4.05)	0.848
Platelet (×109/L)	160 (89.25–239)	157 (92–295.5)	162 (89.5–233.5)	0.606
Coagulation indicators
D-dimer (ng/mL)	1020 (379.5–2495)	1230 (334.25–3701.75)	984 (401.5–2324.75)	0.390
APTT (s)	31.5 (27.95–36.55)	32.65 (29–38.62)	31.4 (27.6–36)	0.108
Fibrinogen (mg/dL)	381 (276.5–448)	358 (231.2–410)	385.5 (289–459.5)	0.06
Inflammation indicators
CRP (mg/L)	36.6 (8.25–95.3)	33.3 (7.91–89.3)	39.9 (8.33–95.73)	0.932
IL-6 (pg/mL)	81.78 (26.84–313.85)	145.05 (36.83–922)	73.64 (26.34–247.62)	0.088
PCT (ng/mL)	0.32 (0.09–2.27)	0.75 (0.28–6.42)	0.22 (0.08–1.68)	0.007
Blood lipid
Cholesterol (mmol/L)	3.10 (2.04–3.94)	2.65 (2.04–3.72)	3.18 (2.06–3.97)	0.38
LDL (mmol/L)	1.66 (1.03–2.46)	1.41 (0.9–1.98)	1.79 (1.12–2.48)	0.085
Triglyceride (mmol/L)	1.26 (0.78–1.96)	1.21 (0.87–2.31)	1.26 (0.74–1.93)	0.43
HDL (mmol/L)	0.72 (0.5–1)	0.57 (0.26–0.86)	0.76 (0.5–1.04)	0.041
Hepatic function
AST (U/L)	24 (16–41.77)	32 (19–95)	23 (16–36)	0.037
ALT (U/L)	20 (12–37)	19 (12–55)	20.5 (11.55–34.75)	0.603
AST/ALT ratio	1.31 (1–1.88)	1.71 (1.23–2.33)	1.27 (0.96–1.65)	0.003
Alkaline phosphatase (U/L)	85 (67–123)	94 (78.75–151)	83 (66–115.75)	0.022
Direct Bilirubin (μmol/L)	4.2 (2.3–7.9)	6.25 (3.45–14.26)	3.9 (2.2–6.8)	0.003
GGT (U/L)	32 (21–72)	32 (21.5–79)	32 (20.25–70.5)	0.72
Renal function
Urea (mmol/L)	6.88 (4.69–13.07)	13.75 (6.4–20.14)	6.06 (4.39–9.82)	<0.001
Uric Acid (μmol/L)	285.45 (204.85–407)	350.95 (238.35–501.35)	270.6 (201.95–386.45)	0.005
Creatinine (μmol/L)	72.6 (55.5–131.93)	136.7 (78.22–211.6)	67.15 (53.83–104.08)	<0.001
eGFR (mL/min)	95.19 (44.43–106.5)	45.32 (27.96–97.55)	97.63 (77.32–106.96)	0.032
Electrolyte
Sodium (mmol/L)	139 (135.7–141.85)	139.05 (136–142.82)	138.95 (135.67–141.62)	0.592
Potassium (mmol/L)	3.93 (3.53–4.38)	4.08 (3.62–4.5)	3.91 (3.5–4.34)	0.242
Calcium (mmol/L)	2.09 (1.96–2.22)	2.06 (1.95–2.2)	2.09 (1.96–2.22)	0.553
Phosphorus (mmol/L)	1.06 (0.86–1.27)	1.15 (0.88–1.38)	1.03 (0.83–1.25)	0.068
Tigecycline use
Duration of tigecycline therapy (days)	7 (4–12)	7.5 (4–12.25)	7 (4–12)	0.723
Time from tigecycline use to diagnosis of acute pancreatitis (days)	–	4 (1–8)	–	–
Infection prophylaxis (n,%)	22 (8.46)	4 (7.69)	18 (8.65)	1.000
Infection site				0.054
Central nervous system (n,%)	4 (1.54)	0 (0)	4 (1.92)	–
Pulmonary (n,%)	145 (55.77)	21 (40.38)	124 (59.62)	–
Blood (n,%)	39 (15)	11 (21.15)	28 (13.46)	–
Urinary tract (n,%)	3 (1.15)	1 (1.92)	2 (0.96)	–
Intra-abdominal (n,%)	41 (15.77)	14 (26.92)	27 (12.98)	–
Skin and soft tissue (n,%)	2 (0.77)	0 (0)	2 (0.96)	–
Bone and joint (n,%)	4 (1.54)	1 (1.92)	3 (1.44)	–
Signs during hospitalization
Hospital Stay (days)	25 (14–38)	23.5 (11.75–42.25)	25 (15–38)	0.293
Death (n,%)	45 (17.31)	13 (25.00)	32 (15.38)	0.152

Data are presented as median (interquartile range, IQR) or number (percentage). The complete blood count was performed on whole blood, coagulation tests on plasma, and other laboratory tests on serum.

COPD, Chronic Obstructive Pulmonary Disease; APTT, Activated Partial Thromboplastin Time; CRP, C-reactive protein; IL-6, interleukin-6; PCT, procalcitonin; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; GGT, Gamma-Glutamyl Transferase; eGFR, Estimated Glomerular Filtration Rate. p-values < 0.05 are indicated in bold.

Drugs used in patients with tigecycline is associated with acute pancreatitis during hospitalization

Analysis of concomitant drugs revealed significant differences between cases and controls (Table 3). Patients with TAAP were significantly more likely to receive caspofungin (28.85% vs. 14.90%, p = 0.025), magnesium isoglycyrrhizinate (40.38% vs. 14.42%, p < 0.001) and esomeprazole (34.62% vs. 10.10%, p < 0.001). Conversely, the control group had a significantly higher proportion of patients prescribed atorvastatin (3.85% vs. 15.87%, p = 0.022) and dexamethasone (1.92% vs. 12.02%, p = 0.036).

Table 3.

Comparison of concomitant drugs between patients with TAAP (Cases) and those without (Controls)

Concomitant drugs	N = 260	Cases (n = 52)	Controls (n = 208)	p-value
Cefoperazone sulbactam (n,%)	104 (40)	16 (30.77)	88 (42.31)	0.155
Imipenem/Cilastatin (n,%)	74 (28.46)	20 (38.46)	54 (25.96)	0.086
Meropenem (n,%)	69 (26.54)	19 (36.54)	50 (24.04)	0.08
Linezolid (n,%)	36 (13.85)	11 (21.15)	25 (12.02)	0.114
Caspofungin (n,%)	46 (17.69)	15 (28.85)	31 (14.90)	0.025
Fluconazole (n,%)	41 (15.77)	10 (19.23)	31 (14.90)	0.523
Esomeprazole (n,%)	39 (15.00)	18 (34.62)	21 (10.10)	<0.001
Magnesium isoglycyrrhizinate (n,%)	51 (19.62)	21 (40.38)	30 (14.42)	<0.001
Atorvastatin (n,%)	35 (13.46)	2 (3.85)	33 (15.87)	0.022
Dexamethasone (n,%)	26 (10)	1 (1.92)	25 (12.02)	0.036

Data were represented as number (percentage).

Univariate logistic regression analysis of tigecycline is associated with acute pancreatitis

Univariate logistic regression analysis was performed to identify factors potentially associated with TAAP. Male sex showed no significant association with TAAP (OR = 0.695, 95% CI: 0.371–1.323, p = 0.260). Other variables with a p-value <0.1 in univariate analysis were considered candidate factors for inclusion in the multivariate model (Table S2).

Multivariate logistic regression analysis of tigecycline is associated with acute pancreatitis

The final model demonstrated moderate discriminative ability, with a C-statistic of 0.817 (95% CI: 0.749–0.886). The results of multivariate logistic regression analysis showed that organ transplantation (OR = 7.643, 95%CI: 1.475–42.226), serum phosphorus levels (OR = 2.211, 95%CI: 1.101–4.610), serum urea level (OR = 1.057, 95%CI: 1.006–1.107), AST/ALT ratio (OR = 1.833, 95%CI: 1.205–2.970), serum GGT level (OR = 1.005, 95%CI:1.000–1.011), and concomitant use of esomeprazole (OR = 3.019, 95% CI:1.362–6.641) were factors associated with TAAP (Table 4).

Table 4.

Multivariate logistic regression analysis of variables associated with TAAP

Variables	β	SE	Wald χ2	p-value	OR	95% CI
Organ transplantation	2.034	0.839	5.876	0.015	7.643	1.475–42.226
Phosphorus (mmol/L)	0.794	0.362	4.818	0.028	2.211	1.101–4.610
Urea (mmol/L)	0.055	0.024	5.378	0.020	1.057	1.006–1.107
AST/ALT ratio	0.606	0.227	7.129	0.008	1.833	1.205–2.970
GGT (U/L)	0.005	0.002	4.739	0.029	1.005	1.000–1.011
Esomeprazole	1.105	0.402	7.557	0.006	3.019	1.362–6.641
Intercept	−3.254	0.839	15.031	0.000	–	–

AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; GGT, Gamma-Glutamyl Transferase.

Sensitivity analysis

Sensitivity analyses confirmed the robustness of our primary findings. Bootstrap internal validation, conducted with 1,000 repetitions, demonstrated minimal overfitting, yielding an optimism-corrected C-statistic of 0.776 compared to the original C-statistic of 0.817 (optimism = 0.042). The assessment of continuous predictors using restricted cubic splines indicated no significant deviations from linearity for serum phosphorus (P for nonlinearity = 0.25), serum urea (P for nonlinearity = 0.59), or serum GGT (P for nonlinearity = 0.26). The number and proportion of missing data for all variables were detailed in Table S3. Conditional logistic regression analysis performed on 20 multiply imputed datasets produced results consistent with the primary model (Table S4).

Discussion

In China, tigecycline is classified as a special-use drug within the management of antibacterial agents. This medication is prescribed for complex intra-abdominal infections, intricate skin and soft structure infections, as well as community-acquired bacterial pneumonia caused by susceptible bacteria. To enhance the safety of tigecycline for future medical applications, it is essential to identify the factors associated with its adverse effects.

This study demonstrated an incidence of TAAP of 0.75% in adult patients, categorizing it as “uncommon” (0.1% ≤ incidence <1%), consistent with rates reported in phase 3 and 4 clinical trials of tigecycline. Notably, this incidence was slightly higher than the 0.56% reported in a previous single-center study involving 3910 patients, a discrepancy that may be attributed to our larger sample size and multicenter design. Each center involved established prescription review protocols to guarantee that tigecycline was dosed appropriately according to set guidelines. The duration of tigecycline treatment did not differ significantly between case and control groups. Among the 52 cases, clinical pharmacists assessed the correlation of adverse reactions as either “possible” or “probable.” A majority of the patients (59.62%, 31/52) experienced mild or moderate acute pancreatitis, while 21 patients (40.38%) developed severe or critical forms of the condition, highlighting the potential clinical significance of this adverse event. No apparent differences in the associations were observed between male and female patients.

This multicenter analysis provides systematic evidence that supports organ transplantation as a significant factor associated with TAAP, consistent with earlier suggestions from case reports and small sample research.^5,19,20 The statistical association was significant (OR = 7.643), although it carries a degree of uncertainty (95% CI: 1.475–42.226), which might be due to the limited number of transplant recipients in our study group. This limitation constrained our ability to conduct detailed subgroup analyses based on transplant type. We proposed that organ transplantation serves as a composite indicator, reflecting not only exposure to immunosuppressants but also the cumulative effects of end-organ failure, surgical stress, potential viral infections, and complex polypharmacy, all of which contribute to a high-risk scenario for TAAP.

Current evidence has identified numerous biomarkers associated with acute pancreatitis development, including age, comorbid diseases, mental status, pulmonary infiltrates, procalcitonin (PCT), neutrophil percentage (Neu%), levels of ALT/AST, the ratio of albumin to globulin, cholinesterase, urea, glucose, AST, and serum total cholesterol.²¹ Predictive models for severe acute pancreatitis incorporate age, body mass index, white blood cell count, PCT, serum calcium levels, and a computed tomography severity index of 4 or higher.²² Consistently, our study also showed elevated serum phosphorus levels, increased serum urea levels, elevated serum GGT levels, and elevated AST/ALT ratio as factors associated with TAAP. Furthermore, emerging research has indicated that metabolic pathways involving phospholipids and glycerolipids could act as diagnostic markers for acute pancreatitis.²³ Our study identifies hyperphosphatemia as an underlying factor associated with TAAP. While previous research has indicated that elevated phosphate levels may promote inflammatory responses,²⁴ and tigecycline has been hypothesized to induce mitochondrial dysfunction²⁵; these mechanisms remain speculative and were not directly investigated in our observational study.

According to real-world practices, we documented the frequent concomitant use of multiple drug classes alongside tigecycline, including antibacterials, gastrointestinal agents, and hepatoprotectants, as well as drugs that may induce acute pancreatitis.¹² Given that tigecycline is a bacteriostatic antibiotic with limited efficacy when used as monotherapy, the use of guideline-recommended combination therapy is prevalent. Notably, our analysis revealed that standard antibacterial combination regimens did not increase the incidence of acute pancreatitis.

This study demonstrated an association between concomitant esomeprazole use and TAAP. Esomeprazole, a common proton pump inhibitor (PPI), is the L-isomer of omeprazole and is metabolized by enzymes CYP3A4 and CYP2C19. Although a direct interaction between esomeprazole and tigecycline has not been previously reported, several hypotheses could explain this finding. It is plausible that esomeprazole may enhance the effects of tigecycline by increasing its concentration or slowing its metabolism through yet-undefined mechanisms. Previous research indicated that PPIs could enhance the bactericidal properties of tigecycline in a concentration-dependent manner,²⁶ providing some indirect support for this pharmacokinetic hypothesis. However, confounding by indication represents a compelling alternative explanation, as proton pump inhibitors are frequently prescribed for the prevention and treatment of gastrointestinal bleeding in critically ill patients.²⁷ This patient population inherently carries a higher baseline risk for complications, including pancreatitis, due to greater illness severity, hemodynamic instability, and systemic inflammatory response. Although our analysis showed esomeprazole as a factor, our model could not fully adjust for all aspects of disease severity (e.g., ICU admission and specific severity scores). Thus, the observed association may reflect either a direct drug effect, the underlying critical illness, or both. Consequently, we recommend increased vigilance when tigecycline is administered alongside proton pump inhibitors (PPIs), particularly in vulnerable populations such as transplant recipients. Furthermore, we emphasize the necessity for future studies to elucidate this relationship. It is important to note that, given the observational design of our study, the identified associations do not establish causality and should be interpreted as hypothesis-generating for future research.

As the first multicenter study on this topic, our research systematically evaluated the incidence and factors associated with TAAP, expanding on earlier findings that primarily relied on case reports and meta-analyses. We analyzed a comprehensive dataset spanning seven years from multiple centers, incorporating a wide range of variables, including patient demographics, laboratory indices, and concomitant medications. This study identified several factors associated with TAAP, including organ transplantation, elevated serum phosphorus, urea, GGT, AST/ALT ratio, and concomitant esomeprazole therapy. Clinicians should remain vigilant regarding these parameters when prescribing tigecycline, particularly for high-risk populations. These findings establish a foundation for optimizing the safe clinical use of tigecycline.

Limitations of the study

There are several limitations in this study. First, the absence of therapeutic drug monitoring for tigecycline across various centers hampered our ability to conduct concentration-effect evaluations effectively. Additionally, protopathic bias cannot be ruled out for the association observed with concomitant medications such as esomeprazole, which may reflect the treatment of prodromal symptoms, a direct drug effect, confounding by indication, or a combination of these factors. Furthermore, while we accounted for numerous potential confounding factors, including sex, which showed no significant association with TAAP in our analyses, it is important to note that some residual confounding may still be present. Our multivariate model demonstrated strong discrimination, evidenced by a C-statistic of 0.817; however, the events per variable ratio was suboptimal due to the limited number of outcome occurrences (n = 52). This relatively small number of events also constrained our statistical power to detect modest associations, such as potential sex-related differences, despite our comprehensive reporting of sex-stratified incidence and regression analyses. Lastly, despite employing a multicenter approach, the overall sample size, particularly for subgroup analyses, remained constrained.

Resource availability

Lead contact

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Hong Cheng (chenghong@znhospital.cn).

Materials availability

This study did not generate new unique reagents.

Data and code availability

• •The data reported in this study cannot be deposited in a public repository because the patient-level data from this multi-center study are not publicly available due to ethical restrictions and data use agreements with the participating institutions. To request access, contact Hong Cheng (chenghong@znhospital.cn, Zhongnan Hospital of Wuhan University).
• •All original code has been deposited and is publicly available at Zenodo [https://doi.org/10.5281/zenodo.17523590] as of the date of publication.
• •Any additional information required to reanalyze the data reported in this article is available from the lead contact upon request.

Acknowledgments

This work was supported by the Special Clinical Research Fund of Wu Jieping Medical Foundation (No. 320.6750.2022-20-23).

Author contributions

H.C. and F.S.: conceptualization. W.L., S.G., K.Y., W.H., G.C., N.D., W.L., W.G., F.Y., and X.K.: data curation. C.W. and X.M.: formal analysis. H.C. and Y.L.: funding acquisition. C.W. and X.M.: methodology. H.C. and F.S.: project administration, resources, software, and supervision. A.D., L.C., J.Z., Q.Z., L.Z., and P.L.: validation. Y.L. and C.W.: visualization. Y.L. and C.W.: writing original draft. All authors reviewed the manuscript.

Declaration of interests

The authors declare no competing interests.

STAR★Methods

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Software and algorithms
R (version 4.2.2)	The R Foundation	https://cran.r-project.org/bin/windows/base/old/4.2.2/

Experimental model and study participant details

Study participant details

This multicenter, retrospective nested case-control study included human participants admitted to seven tertiary hospitals in central China between January 2015 and January 2022. All participants were of Asian ethnicity (Han Chinese) and were over 18 years of age, comprising 4801 males and 2141 females. Patients were identified from electronic medical records based on receipt of tigecycline therapy. No experimental animals, cell lines, or microbial strains were used in this study. All participants received standard medical care during hospitalization according to institutional protocols.

Ethics statement

This study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (Approval No. 2022160K), with reciprocal approval obtained from each participating center. Written informed consent was waived due to the retrospective design of the study.

Method details

Study design

This study employed a multicenter, retrospective nested case-control design. It was conducted within a base cohort comprising all patients who received tigecycline with standard-dose (a loading dose of 100 mg, followed by 50 mg every 12 h) across seven participating centers from 2015 to 2022. Cases of acute pancreatitis that occurred following tigecycline therapy were identified from this cohort. A control group was subsequently selected for comparative analysis based on same center and age. This design effectively utilizes extensive clinical data to investigate the factors associated with uncommon or rare adverse drug reactions.

Data collection

The demographic, laboratory, and drug therapy characteristics of patients in the case and control groups during hospitalization were evaluated, and all data were extracted from the hospital’s electronic medical records database. Sex, age, length of hospital stay, surgery, death, and comorbidities were recorded together with other demographic details. The comorbidities included diabetes, hypertension, cancer, chronic kidney disease, chronic obstructive pulmonary disease (COPD), and organ transplantation. Critically, main laboratory variables analyzed as potential factors were collected within 24–48 h after admission, but before the initiation of tigecycline therapy (T0), thereby serving as baseline values that reflect pre-existing risk rather than the consequence of drug exposure or acute pancreatitis onset. The complete blood count was performed on whole blood, coagulation tests on plasma, and other laboratory tests on serum, including white blood cells, neutrophils, red blood cells, platelets, D-dimer, activated partial thromboplastin time (APTT), fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), cholesterol, low-density lipoprotein (LDL), triglyceride, triglyceride, high-density lipoprotein (HDL), hepatic function: aspartate aminotransferase (AST), alanine transaminase (ALT), AST/ALT, Alkaline phosphatase, direct bilirubin, gamma-glutamyl transferase (GGT), renal function: urea, uric acid, creatinine, estimated glomerular filtration rate (eGFR) and electrolytes (sodium, potassium, calcium, and phosphorus), as well as serum amylase and lipase. In addition, the following categories of infection sites for tigecycline therapy were determined by reviewing the medical records: central nervous system blood, pulmonary, blood, urinary tract, intra-abdominal, skin and soft tissue and bone and joint. All information regarding the concurrent medications administered to the patient during the period of tigecycline treatment while hospitalized was collected.

Study population

The exclusion criteria were as follows: (1) Patients aged <18 years; (2) Patients with prior history of acute or chronic pancreatitis, radiological evidence of cholelithiasis or microlithiasis, alcohol abuse history, serum triglycerides >1000 mg/dL, ERCP, or documented anatomical pathologies predisposing to acute pancreatitis (e.g., pancreatic annular abnormalities); (3) Individuals presenting with acute or chronic pancreatitis from other etiologies prior to tigecycline administration; (4) Pregnant women; (5) Cases with incomplete clinical documentation.

Cases were diagnosed by meeting two of the three clinical criteria while ruling out other pancreatic disorders following tigecycline administration: (1) acute abdominal pain with tenderness in the upper abdomen; (2) serum amylase and/or lipase levels exceeding 3×ULN which was applied using the center-specific ULN from each patient’s treating hospital (Table S5); (3) abnormal findings indicative of acute pancreatitis on imaging studies such as abdominal CT or abdominal ultrasound.⁶

Case patients were matched 1:4 with controls through individual matching based on same center and age. Controls were selected using incidence density sampling from the same cohort, ensuring synchronized initiation timelines for tigecycline and follow-up durations. The index date for cases corresponded to the date of TAAP diagnosis. For each case, eligible controls were those from the base cohort who were receiving tigecycline and had not developed acute pancreatitis by the same index date, ensuring temporal alignment of exposure assessment. The balance achieved through this matching protocol was formally assessed using the tableone package in R, which confirmed excellent covariate balance across not only matched variables, but also hospital stay, with absolute standardized mean differences (SMDs) < 0.1.

Definitions

The association between tigecycline and acute pancreatitis was evaluated using the Naranjo adverse drug reaction probability scale,²⁸ with the following key criteria²⁹: (1) Development of acute pancreatitis following tigecycline administration; (2) Temporal consistency between drug exposure and symptom onset, aligning with documented latency patterns; (3) Clinical resolution of acute pancreatitis manifestations after tigecycline discontinuation; (4) The reappearance of acute pancreatitis symptoms upon re-exposure to the drug.

The severity and relevance of TAAP in our study were evaluated using a scale to more accurately grade the condition and measure the correlation between acute pancreatitis and tigecycline.³⁰ In terms of severity,³¹ mild cases are defined as mild symptoms with only interstitial changes in the pancreas without local or systemic complications; moderate cases are defined as transient local or systemic complications or transient organ failure (<48 h); severe cases are defined as persistent organ dysfunction (>48 h) or infectious necrosis; and critical cases are defined as persistent organ dysfunction (>48 h) or infectious necrosis and death due to acute pancreatitis.

Quantification and statistical analysis

Statistical methods

All statistical analyses were conducted using R (version 4.2.2). Descriptive statistics are presented as counts and percentages for categorical variables, and as medians with interquartile ranges for continuous variables, which were found to be non-normally distributed. Missing data for continuous variables were addressed using median imputation. Group comparisons between cases and controls were performed using the Wilcoxon test for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate.

Variables included in the multivariate model were selected based on their clinical relevance and results from univariate analysis, applying a screening threshold of p < 0.1. Given the 1:4 matching ratio and our interest in evaluating the effects of the matching variables themselves, the final multivariate model was fitted using unconditional logistic regression, adjusting for the matching factors (center and age). This approach is statistically valid for matched designs and offers greater flexibility for multivariable modeling. Results are reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Multicollinearity was assessed in this final model using variance inflation factors (VIF), with no significant collinearity detected, as all VIF values were below 2.0 (Table S6). To account for potential clustering of data at the center level, all regression models incorporated cluster-robust standard errors. A two-sided p < 0.05 was defined as statistically significant.

We conducted three sensitivity analyses to evaluate the robustness of the primary model. First, we performed internal validation of the final multivariable logistic regression model through bootstrap resampling with 1,000 repetitions. This approach allowed us to obtain an optimism-corrected C-statistic and to evaluate potential overfitting. Second, we examined the linearity of the relationship between continuous predictors (serum phosphorus, urea, and GGT) and the log-odds of the outcome by employing restricted cubic splines with three knots within logistic regression models. The statistical significance of the nonlinear components was assessed using likelihood ratio tests. Furthermore, we conducted an integrated sensitivity analysis that simultaneously addressed the matched study design and potential missing data. We performed conditional logistic regression on 20 multiply imputed datasets, with results pooled using Rubin’s rules.

Additional resources

This research is registered at www.chictr.org.cn (registered No. ChiCTR2300072484).

Published: March 3, 2026