Results and Discussion
We extracted 72,723 reports of suspected AEs related to antibiotic
treatment among the 1,048,576 reports in the JADER database between
April 2004 and January 2021. The number of reports of agranulocytosis
was 3,221. As shown Table 1, 10 of 60 antibiotics were detected as
signals; the RORs (95% CIs) for ampicillin/sulbactam, amikacin,
cefmetazole, cefozopran, clindamycin, ciprofloxacin,
imipenem/cilastatin, kanamycin, teicoplanin, and vancomycin were 2.65
(1.79–3.80), 2.49 (1.91–4.34), 4.48 (2.27–6.92), 2.77 (1.88–3.95),
1.64 (1.04–2.47), 2.01 (1.40–2.82), 2.78 (2.11–3.60), 6.05
(2.16–13.7), 2.05 (1.31–3.07), and 3.54 (2.73–4.54), respectively.
Because neutrophils are produced in bone marrow, we speculated that
antibiotics with high migration to bone marrow may have a high risk of
inducing agranulocytosis before data mining. However, signals were not
detected for antibiotics with high cerebrospinal fluid transferability,
such as ceftriaxone [10] and cefotaxime [11], whereas
teicoplanin [12], an antibiotic with poor cerebrospinal fluid
transferability, was detected. Therefore, these findings suggested that
the risk of agranulocytosis could not be clarified by analysis of
migration to the bone marrow only. A retrospective study reported that
the development of vancomycin-induced neutropenia was not associated
with the dosage, trough concentration, or administration period
[13]. Although other antibiotics also need to be investigated,
antibiotic-induced agranulocytosis may not be a cumulative toxicity.
The incidence of neutropenia induced by vancomycin is approximately
2–18% [14, 15]. In contrast, Smith et al. reported that linezolid,
an anti-methicillin-resistant Staphylococcus aureus (MRSA) agent,
may be safe and effective for the treatment of febrile neutropenia
[16]. In addition, carbapenems targeting Pseudomonas
aeruginosa are empirically used for the treatment of febrile
neutropenia [17], indicating that when using antibiotics with
anti-Pseudomonas aeruginosa or anti-MRSA activity in the
empirical treatment of high-risk patients, such as those with febrile
neutropenia, it may be better to preferentially use antibiotics with the
same spectrum for which no signal was detected in this study.
In the clinical setting, aminoglycosides are often administered withβ -lactam antibiotics to induce synergistic effects [18, 19].
Moreover, infective endocarditis caused by MRSA may be treated with
vancomycin or teicoplanin in combination with aminoglycosides [20].
In the current study, because amikacin and kanamycin were detected as
signals, we speculate that it may be better to use gentamicin as the
aminoglycoside in combination therapy.
In recent reports of SRS data mining, WSP analysis has been performed to
evaluate the time-to-onset data for target AEs [9]. For the
time-to-onset analysis, we extracted 292 cases for the 10 antibiotics
with signal detection (Table 2). The median durations (interquartile
ranges) of agranulocytosis onset following treatment with amikacin,
cefmetazole, ciprofloxacin, and kanamycin were within 1 week of the
first treatment. The difference in the onset time may have been related
to the variations in pharmacokinetics of each antibiotic and the onset
mechanism of agranulocytosis; however, the details are unknown, and
further research is needed. Although the 95% CIs of WSP β for
eight antibiotics (excluding amikacin and ciprofloxacin) were over and
excluded 1, indicating a wear out failure type, the profiles of amikacin
and ciprofloxacin were consistent with the random failure type (Table
2). Accordingly, time-to-onset analysis using WSP is likely to be a
useful tool for determination of the specific safety monitoring period
for agranulocytosis.
Data mining using the JADER database has some limitations that should be
considered because the JADER database has several biases. First, because
the JADER database does not contain information for control patients,
the intensity of RORs cannot be quantified and compared among
antibiotics. Second, there are also some reporting biases, such as
under-reporting and lack of data. Third, the number of reports was small
and may have been underestimated because the PT codes 10018687
(granulocytopenia) and 10018681 (granulocyte count decreased) were not
included in the current study. Fourth, because agranulocytosis may be
induced by severe infections [21], the agranulocytosis reported by
SRS may not be caused by administration of antibiotics.
In conclusion, this comprehensive analysis was the first report
evaluating the incidences of antibiotic-induced agranulocytosis. Despite
the various limitations of using the JADER database, we identified 10
antibiotics that may be associated with high risk of agranulocytosis,
suggesting that absolute neutrophil counts in patients taking these
drugs should be monitored carefully in the clinical setting. Finally,
further clinical studies are needed to verify the mechanisms through
which ampicillin/sulbactam, amikacin, cefmetazole, cefozopran,
clindamycin, ciprofloxacin, imipenem/cilastatin, kanamycin, teicoplanin,
and vancomycin may induce agranulocytosis.