What this study adds
The overall prevalence of tigecycline-induced pancreatitis (TIP) was
relatively low in a real-world setting. Serum amylase and lipase
levels should be closely monitored in patients with comorbid renal
insufficiency during tigecycline treatment.
Comorbid renal insufficiency was identified as an independent risk
factor for TIP.
Tigecycline significantly decreased the infection indices in non-TIP
patients without worsening pancreatitis. Tigecycline is safe and
efficient for treatment of pancreatitis with intra-abdominal
infection.
1 | INTRODUCTION
Tigecycline is the first member of the glycylcycline class of
antimicrobials to be a derivative of minocycline, having a
9-t-butylglycylamido group added the first carbon of the minocycline D
ring.1 This new antibiotic inhibits bacterial protein
synthesis by binding to the 30S ribosomal subunit,2and overcomes the two main mechanisms of bacterial resistance: ribosomal
protection and efflux pump.3 The increasing incidence
of multidrug-resistant (MDR) and extensively drug-resistant (XDR)
bacterial pathogens is a major public health concern. Owing to its
broad-spectrum antibacterial activity, tigecycline is widely used for
treatment of complicated skin and soft tissue infections,
intra-abdominal infections, and community-acquired pneumonia caused by
MDR pathogens, especially carbapenem-resistant
bacteria.4,5
Tigecycline was approved by the US Food and Drug Administration in June
2005 and by Chinese government in 2011. With the increasing clinical use
of tigecycline, adverse effects, such as nausea, vomiting, and diarrhea,
have become inevitable. Acute pancreatitis (AP) has been reported in a
limited number of case reports and can be fatal if
unrecognized.6,7 In 2006, AP was added to the list of
side effects for tigecycline after post-marketing surveillance.
Currently, there are no predictive factors for AP occurrence and no
sensitive identification methods for AP prevention during tigecycline
treatment. The purpose of this study was to analyze the risk factors and
clinical characteristics of tigecycline-induced pancreatitis (TIP) and
to evaluate the safety and efficiency of tigecycline use in patients
with previously diagnosed pancreatitis before tigecycline use.
2 | METHODS
2.1 | Study design
This single-center retrospective case-control study was conducted at
Tongji Hospital, Tongji Medical College, Huazhong University of Science
and Technology, a 4600-bed tertiary hospital. The study was approved by
the Ethics Committee of Tongji Hospital. The need for informed consent
from the patients was waived because of the retrospective nature of the
study.
2.2 | Patients
Consecutive patients treated with intravenous tigecycline for
>3 days in our hospital were screened from January 1, 2017,
to December 31, 2020. The patients were divided to juveniles
(<18 years of age) and adults (≥18 years of age). Data for the
screened patients were exported from the Department of Computer Center
and evaluated by two independent researchers. The inclusion criteria
were: patients with duration of tigecycline therapy for at least 3 days.
The exclusion criteria were: (1) patients who lacked complete medical
records and laboratory examination results; (2) patients who were
readmitted to our hospital several times and treated with tigecycline
(only first admission was included); (3) patients with history of AP
episode, chronic pancreatitis, autoimmune pancreatitis, or pancreatic
cancers; and (4) patients administered definite or probable drugs
associated with pancreatitis (such as acetaminophen,
azathioprine)8 during tigecycline treatment, with
exception of octreotide because most patients with pancreatitis were
administered octreotide. The selection of the patients is depicted in
Figure 1. Patients were evaluated for the prevalences of comorbid
diseases including hypertension, coronary heart disease, diabetes
mellitus, chronic obstructive pulmonary disease, bronchial asthma, renal
insufficiency (including acute and chronic renal insufficiency), liver
insufficiency (including hepatitis, cirrhosis, and autoimmune liver
disease), solid organ tumor, and autoimmune disease based on the
diagnoses in their discharge records.
2.3 | AP evaluation
Patients with a discharge diagnosis of AP were evaluated for the
following common causes: biliary stones, alcohol exposure, endoscopic
retrograde cholangiopancreatography (ERCP), trauma,
hypertriglyceridemia, hypercalcemia, tumor, and autoimmune disease. AP
patients who had one of the common causes and developed AP before
tigecycline treatment were classified as non-tigecycline-induced
pancreatitis (non-TIP). For these patients, we recorded length of
hospital stay, cause of AP, severity of AP,9 any
surgery performed to treat AP, modified computed tomography (CT)
severity index score,10 amylase and lipase levels, and
infection indices before and after tigecycline treatment. These data
were used to examine the safety and efficiency of tigecycline treatment
in non-TIP patients.
Patients who did not have the above causes were evaluated for the
presence of TIP using a probability assessment scale for drug-induced
pancreatitis based on the Naranjo scale that was developed by Weissman
et al11 in 2020. According to the requirements for the
scale, we completed a form involving 10 questions for each patient
without the common causes and obtained a summative score
(>9, highly probable; 6–8, probable; 3–5, possible; and
≤2 doubtful). Patients with TIP were evaluated for the Naranjo score,
clinical symptoms, severity of AP,9 modified CT
severity index score,10 average time from tigecycline
therapy to symptom onset, serum amylase and lipase levels, and times for
symptoms and amylase and lipase levels to return to their normal ranges.
Patients without a discharge diagnosis of AP were classified as
non-pancreatitis.
2.4 | Data collection
The following data were extracted from the electronic medical records:
sex, age, admission department, main and secondary diagnoses, baseline
routine blood tests (white blood cell count, percentage of neutrophils,
red blood cell count, hemoglobin, platelet count), liver function tests
(alanine aminotransferase, aspartate transaminase, albumin, globulin,
total bilirubin, direct bilirubin, alkaline phosphatase [ALP],
γ-glutamyl transpeptidase), renal function tests (blood urea nitrogen,
serum creatinine, uric acid, bicarbonate radical, estimated glomerular
filtration rate), serum lipid parameters (total cholesterol,
triglyceride, low-density lipoprotein), electrolyte indices (potassium,
sodium, calcium, corrected calcium), infection indices (high-sensitivity
C-reactive protein, erythrocyte sedimentation rate, procalcitonin),
coagulation markers (prothrombin time [PT], fibrinogen, activated
partial thromboplastin time [APTT], d-dimer), amylase, and lipase.
Tigecycline treatment data (loading dose, maintenance dose, treatment
duration) and combination therapy information were recorded. The total
dose of tigecycline was calculated for each patient. Based on the
discharge diagnoses and medical records, sites of infection or
indications for tigecycline therapy were classified as follows: lung,
chest, cranium, endocarditis, skin or soft tissue, abdomen, intestine,
biliary tract, liver abscess, urogenital tract, mixed infections,
sepsis, septicemia, septic shock, agranulocytosis, hemophagocytic
syndrome, multiple organ failure, trauma, and major surgery-related
infection.
2.5 | Statistical analysis
All statistical analyses were performed using SPSS version 22.0 (IBM
Corporation, Somers, NY, USA). Presence of a parametric distribution was
evaluated by the Kolmogorov–Smirnov test. Parametric and categorical
data were presented as mean ± standard deviation (SD) and rate,
respectively. Non-parametric data were presented as median and
interquartile range (IQR). Comparisons between two groups were made by
Student’s t-test for parametric data and the Mann–Whitney test or
Wilcoxon test for non-parametric data. The chi-square test was used for
categorical variables. Univariate and multivariate analyses were
performed using logistic regression models to identify independent risk
factors for TIP. All biologically plausible variables that showed
significance at P < .10 in univariate analyses were
entered into a multivariate forward logistic regression analysis. A
value of P < .05 was considered to indicate statistical
significance.
3 | RESULTS
3.1 | Demographic data
After the screening process, a total of 3910 patients were included in
the study. The enrolled patients comprised 3823 adult patients aged ≥18
years and 87 juvenile patients aged <18 years. Among the adult
patients, there were 103 patients with a discharge diagnosis of AP.
Based on the medical records, 82 patients were diagnosed with AP before
tigecycline therapy and classified as non-TIP, 21 patients were
classified as TIP, and 3720 patients were classified as
non-pancreatitis.
In the adult patients, tigecycline was most commonly used in the
hematology department followed by the intensive care unit and the organ
transplantation department (Supplementary Figure 1). The demographic
data for TIP and non-pancreatitis are shown in Table 1. The median
length of hospital stay was longer and the prevalence of comorbid renal
insufficiency was higher in the TIP group compared with the
non-pancreatitis group. There were no significant differences in the sex
distribution and prevalences of other comorbid diseases between the two
groups.
The juvenile patients comprised 49 boys (56.3%) and 38 girls (43.7%)
with a mean age of 11.74 ± 6.0 years.
3.2 | Indications for tigecycline
In the adult patients, the most common indication for tigecycline
therapy was pneumonia, followed by agranulocytosis and major
surgery-related infection. There were no significant differences in the
classifications of the indications for tigecycline therapy between the
TIP group and the non-pancreatitis group (Supplementary Table 1).
For the juvenile patients, the most common indication for tigecycline
therapy was agranulocytosis (36.8%), followed by pneumonia (11.5%) and
sepsis (10.3%).
3.3 | Prevalence of TIP
In the adult patients, the prevalence of TIP was 21/3741 (0.56%). The
prevalences of TIP in the hematology department, intensive care unit,
and organ transplantation department were 7/879 (0.80%), 2/501
(0.43%), and 5/392 (1.28%), respectively. Compared with the total
patients, there were no significant differences in the prevalences of
TIP in the hematology department (0.80% vs. 0.56%, P = .419) or
intensive care unit (0.43% vs. 0.56%, P = .722), while the
prevalence in the organ transplantation department showed a tendency to
be higher (1.28% vs. 0.56%, P = .087).
For the juvenile patients, the prevalence of TIP was 1/87 (1.15%).
3.4 | Clinical characteristics of TIP
The detailed characteristics of the patients with TIP are summarized in
Table 2. Of the 21 patients with TIP, 57.1% received a loading dose and
the majority had a maintenance dose of 50 mg q12h. Most patients
presented with overt abdominal symptoms, while five patients had no
clinical symptoms. The mean time from tigecycline use to symptom onset
was 7.2 days. All patients had mild pancreatitis, and the median
modified CT severity score was 2. No patients were re-administered
tigecycline. Abdominal symptoms were relieved soon after tigecycline
withdrawal (mean time: 3.6 days). The amylase and lipase levels returned
to their normal ranges at a mean time of 7.1 days after tigecycline
withdrawal.
3.5 | Risk factors for TIP
We compared the laboratory data and therapeutic regimens between the TIP
group and the non-pancreatitis group (Table 3). The ALP level in the TIP
group was significantly higher than that in the non-pancreatitis group,
while the PT and APTT levels in the TIP group tended to be lower. There
were no significant differences in the data for blood routine tests,
other liver function tests, serum lipid level, electrolyte indices,
renal function tests, or infection indices between the two groups. The
therapeutic regimens, including loading dose, maintenance dose,
treatment duration, and total dose of tigecycline, were similar between
the two groups.
The following variables with significant differences (P< .1) between the TIP group and the non-pancreatitis group
were included in the multivariate analysis: age, length of hospital
stay, percentage of comorbid
renal insufficiency, multiple organ failure as indication for
tigecycline, ALP, PT, and APTT. In the multivariate analysis, comorbid
renal insufficiency was identified as an independent risk factor for TIP
with an odds ratio (OR) of 3.032 (Table 4).
3.6 | Safety and efficiency of tigecycline
therapy in non-TIP
In the study cohort, 82 patients were diagnosed with pancreatitis before
tigecycline therapy and classified as non-TIP. The detailed information
for these patients is shown in Table 5. The most common cause of
pancreatitis was biliary stones, followed by hypertriglyceridemia. There
were two cases of pancreatitis in pregnancy in the hypertriglyceridemia
group, 81.7% of patients had severe pancreatitis, and 22% of patients
underwent surgery for removal of necrotic tissue. Acute necrotizing
pancreatitis was noted in 39 (47.6%) patients. Finally, 63.4% of
patients showed improvement. The modified CT score after tigecycline use
did not differ from that before tigecycline use (5.3 ± 1.8 vs. 5.3 ±
2.0, P = 1.0). The amylase and lipase levels after tigecycline
use did not increase compared with those before tigecycline use, but
significantly decreased as the pancreatitis improved (Figure 2A, B).
After a median 8 days of tigecycline treatment, infection indices
including white blood cell count (Figure 2C), percentage of neutrophils
(Figure 2D), high-sensitivity C-reactive protein (Figure 2E), and
procalcitonin (Figure 2F) were significantly decreased compared with the
indices before drug use.
4 | DISCUSSION
In the present study, we retrospectively analyzed patients administered
tigecycline for at least 3 days in our hospital during a 4-year period.
We enrolled both adult patients and juvenile patients with the aim of
analyzing the prevalences of TIP in this real-world setting and
identifying risk factors for TIP. We also created a detailed summary for
information related to tigecycline use in 82 non-TIP patients.
Tigecycline is a vital antibiotic treatment option for infections caused
by MDR and XDR bacteria, especially in the intensive care unit. Our
findings showed tigecycline was most commonly used in the hematology
department, followed by the intensive care unit. Tigecycline was also
commonly used for immunosuppressed recipients in the organ
transplantation department. Regarding the indications for tigecycline,
the most common indication was pneumonia, consistent with the finding in
a previous study (>60%).12
The prevalences of TIP in the adult and juvenile patients were 0.56%
and 1.15%, respectively. The prevalence for patients in the organ
transplantation patients was slightly higher compared with those in the
other patients. A study involving phase 3 and 4 tigecycline trials
revealed that only 0.24% of 3,788 tigecycline-treated patients
developed pancreatitis.13 In the second Periodic
Safety Update Report for tigecycline, the incidence of pancreatitis was
estimated at 1‰ and 1%, with 3 cases of necrotizing pancreatitis and 2
cases of fatal pancreatitis.14 However, all 21
patients with TIP in the present study had mild pancreatitis and their
main CT feature was edema of the pancreas. Our results were similar to
those of a secondary analysis involving 19 studies on
tigecycline-induced AP, in which edematous infiltrate was the main
imaging feature in patients and most cases had mild
AP.15 We further found that the mean time from
tigecycline use to symptom onset was 7.2 days, while previous studies
reported 8.5 days14 and 12.5 days.16In our patients, abdominal symptoms were relieved at a mean of 3.6 days
after tigecycline withdrawal and the enzyme levels returned to their
normal ranges at a mean of 7.1 days, similar to the findings in a
previous study (4 days and 5 days, respectively).15 We
also noted that five patients had no obvious symptoms, consistent with
the previous study.15 The possible reasons for TIP may
be the high elimination rate of tigecycline by the biliary
tract17 and the similar mechanism to
tetracycline-induced pancreatitis (reaction with 30S ribosomal units and
blockade of protein synthesis leading to triglyceride accumulation in
the pancreas).18
The mean Naranjo score in our patients was 7.2. Possible reasons why the
mean Naranjo score did not reach 9 (highly probable for drug-induced
pancreatitis) may be that none of the patients were re-administered
tigecycline (relevant question: if a drug re-challenge was performed,
did AP recur?) and that all patients had infections (relevant question:
does the patient have or was the patient recently diagnosed with an
infection [bacterial, fungi, or viral] which could cause AP?).
Our multivariate analyses identified comorbid renal insufficiency as an
independent risk factor for TIP (OR = 3.032). However, the renal
function indices did not differ significantly between the TIP group and
the non-pancreatitis group. This inconsistency may be explained by the
small number of TIP patients (n = 21). Nevertheless, our results
indicated that TIP is an uncommon event and that serum amylase and
lipase levels should be closely monitored in patients with comorbid
renal insufficiency during tigecycline treatment.
Acute necrotizing pancreatitis is a severe and life-threatening disease,
and infection occurs in about 30% of cases as the most important
prognostic factor.19 In AP patients, the major cause
of death, after early organ failure, was secondary infection of
pancreatic or peripancreatic necrotic tissue, leading to sepsis and
multiple organ failure.20 In the present study, we
evaluated the safety of tigecycline use in 82 AP patients. We found that
the modified CT score after tigecycline use was similar to that before
tigecycline use and that the amylase and lipase levels significantly
decreased as the pancreatitis improved. The infection indices were also
significantly decreased, indicating that tigecycline was efficient in
controlling infection in patients with pancreatitis. Previous studies
demonstrated that tigecycline was good at penetrating necrotic
pancreatic tissue21 and was both safe and effective
for treatment of infected necrotizing pancreatic fluid collection and
sepsis caused by infected pancreatic necrosis.4 There
is also evidence for efficacy of tigecycline use in treatment of complex
intra-abdominal infection or abscess after AP.4 Our
results further confirmed that tigecycline was suitable and safe for
treatment of AP, especially severe necrotizing pancreatitis, with
abdominal infection.
There were some limitations to the present study. First, it was a
retrospective case-control study and may have a selection bias. Second,
the dose of tigecycline used in each patient was not adjusted by the
body weight because many patients had severe disease and their body
weight could not be obtained.
In summary, the overall prevalence of TIP was low, most of the AP cases
were mild, and withdrawal of tigecycline as early as possible usually
permitted quick recovery and avoidance of severe complications. Comorbid
renal insufficiency was identified as an independent risk factor for
TIP. Tigecycline is safe and efficient for treatment of AP, especially
necrotizing pancreatitis, with intra-abdominal infection.