368

CASE REPORT
A puerperal patient with agranulocytosis during
tazobactam / piperacillin administration : A case report
Haruna Iwazawa1, Hiroaki Tanaka1, Takakiyo Tatsumichi1, Kazunori Yamaguchi1, Koichi Takahashi1, Kiyo Suzuki1,Takahiro Motoki1, Kenji Kanenishi2, and Shinji Kosaka1
Department of Pharmacy, Kagawa University Hospital, Ikenobe, Miki, Kagawa, Japan, 2Department of Perinatology and Gynecology, Kagawa
University Graduate School of Medicine, Ikenobe, Miki, Kagawa, Japan1

Abstract : Tazobactam / piperacillin (TAZ / PIPC) is an injectable combination drug consisting of a broad-spectrum penicillin and a β-lactamase inhibitor. This antimicrobial has a wide spectrum of efficacy against both
Gram-positive bacteria and anaerobes. Adverse events usually present as diarrhea or liver dysfunction ; agranulocytosis has not been reported in Japanese patients with puerperal disorders. However, we report a 32-year-oldJapanese woman who received TAZ / PIPC to treat an intraperitoneal infection that developed after complications related to transvaginal delivery. Within 14 days of beginning TAZ / PIPC therapy, the patient developed
agranulocytosis, indicated by a white blood cell count of 1900 cells / µL and a neutrophil count of 475 cells / µL. We
discontinued TAZ / PIPC at this point and changed the antimicrobial to meropenem. Seven days later, her whiteblood cell count increased to 3700 cells / µL (neutrophil count : 1684 cells / µL), and the intraperitoneal infection
resolved. Patients receiving TAZ / PIPC should be monitored periodically for agranulocytosis as well as for diarrhea and liver dysfunction. J. Med. Invest. 68 : 368-371, August, 2021Keywords : piperacillin-tazobactam, agranulocytosis, neutropenia, puerperium

INTRODUCTION

CASE PRESENTATION

Tazobactam / piperacillin (TAZ / PIPC) is a combination antibiotic preparation for injection consisting of a β-lactamase
inhibitor, tazobactam (TAZ), and a penicillin antibiotic, piperacillin (PIPC), at a ratio of 1 : 8 (1). As TAZ / PIPC has a broad
antimicrobial spectrum against Gram-positive bacteria, such as
Staphylococcus, gram-negative bacteria, including Pseudomonas
aeruginosa, and anaerobic bacteria (2), it is routinely used clinically to treat many infectious diseases (3). In Japan, the drug’s
indications for pneumonia, pyelonephritis, and peritonitis arecovered by health insurance. In the Guidelines for the Treatmentof Respiratory Infectious Diseases, TAZ / PIPC is recommended
as a first-choice drug for hospital-acquired pneumonia (HAP),nursing- and healthcare-associated pneumonia (NHCAP), andsevere pneumonia (4). In the United States, TAZ / PIPC andcarbapenem preparations are recommended as drugs for monotherapy in the guidelines for the management of intraperitonealinfectious diseases collaboratively announced by the Surgical
Infection Society and Infectious Diseases Society of America in2010. As primary adverse reactions, diarrhea and liver dysfunction have been reported, but no case report of agranulocytosis asa serious adverse event has been published in Japanese patientswith puerperal disorders. We report a patient in whom the administration of TAZ / PIPC for intraperitoneal infection during
puerperium may have induced agranulocytosis.

Patient : A 32-year-old female patient.
Complaint : Delivery.
Medical history : Hypothyroidism.
Therapeutic drug : Levothyroxine sodium hydrate.
Family history : Not contributory.
Obstetric history : gravidity, 0 ; parity, 0.
Allergy : Not contributory.
Present illness : She was admitted due to premature ruptureof the fetal membranes (Day 5 in Week 39 of pregnancy).
Laboratory data on admission : The laboratory data on admission are presented in the Table.
Physical examination on admission : The patient’s height,
body weight, body temperature, heart rate, and blood pressure

Received for publication September 25, 2020 ; accepted March 14,2021.
Address correspondence and reprint requests to Hiroaki Tanaka, Department of Pharmacy Kagawa University Hospital, 1750-1 Ikenobe,
Miki, Kagawa 761-0793, Japan and Fax : +81-87-891-2318.

Table. Laboratory data on Day 4WBC

98.40×102 / µL

TP

6.4

g / dL

Seg

83.2％

ALB

3.0g / dL

Eosin

0.0％

AST

16U/L

Baso

0.2％

ALT

8U/L

Lymph

11.7％

LDH

184

U/L

Mono

4.9％

BUN

5.6mg / dL
mg / dL

5RBC

40.4×10 / µL

Cr

0.37

HGB

10.8g / dLeGFR

157.3mL / min

PLT

20.3×10 / µL

CRP

5.68

mg / dL4

WBC : white blood cell count, Seg : segmented neutrophils, Eosin : eosinophils, Baso : basophils, Lymph : lymphocytes, Mono : monocytes,RBC : red blood cells, HGB: hemoglobin, PLT : platelets, TP : total
protein, ALB : albumin, AST : aspartate aminotransferase, ALT : alanine aminotransferase, LDH : lactate dehydrogenase, BUN : bloodurea nitrogen, Cr : creatinine, eGFR : estimated glomerular filtration
rate, CRP : C-reactive protein

The Journal of Medical Investigation Vol. 68 2021

The Journal of Medical Investigation Vol. 68 August 2021
were 155.8 cm, 54.5 kg, 37.2°C, 115 beats / min, and 130 / 87
mmHg, respectively.
Course after admission : After admission, delivery was induced using oxytocin, and on Day 4, a neonate was born bytransvaginal delivery. After delivery, placental separation-related hemorrhage persisted, making management by ligation
and blood transfusion difficult ; therefore, total hysterectomy
was performed on the same day. From Day 8, fever ( ≥ 38°C)
persisted, and blood culture revealed Bacterioides fragilis on Day
9, suggesting intraperitoneal infection as an etiological factor.
TAZ / PIPC therapy (4.5 g, every 8 hours) was started. Subsequently, the leukocyte count gradually decreased to 1900 / µL
on Day 23 (neutrophil count : 475 / µL), leading to a diagnosis ofagranulocytosis. There was no change in the red blood cell count(RBC). There was a slight decrease in the platelet count (PLT),
but the value did not meet the diagnostic criterion for thrombopenia. In addition, there were no changes in the eosinophil orbasophil count in comparison with the values at admission.
Drug-induced agranulocytosis was suspected, and TAZ / PIPC
administration was promptly discontinued. Considering thedrug susceptibility of Bacterioides fragilis and breast milk transfer, TAZ / PIPC was changed to meropenem (MEPM) (1 g every
8 hours). Subsequently, granulocyte-colony stimulating factor(G-CSF) was not used, and the leukocyte count returned to3920 / µL on Day 27 (neutrophil count : 1784 / µL). Concerning
the intraperitoneal infection, a reduction in the inflammatory
response and fever resolution were noted 2 weeks after confirming a negative blood culture. MEPM therapy ended on Day 30.
Subsequently, there was no recrudescence of agranulocytosis or
intraperitoneal infection, and the patient was discharged on Day38 (Fig.).

DISCUSSION
We report a patient with agranulocytosis related to TAZ / PIPC
administration during puerperium. Agranulocytosis related to369

drugs, excluding anticancer drugs, is characterized by a neutrophil count of ≤ 500 / µL, and this adverse event is rare (5). Its
incidence is 1–5 person-years per 1,000,000 persons (6). Drugs
are involved in the etiology of agranulocytosis in approximately
70% of patients (7).
As drugs that frequently cause agranulocytosis, anti-thyroiddrugs, antibiotics, and antipsychotics are known, but only afew patients with TAZ / PIPC-induced agranulocytosis havebeen reported (8-12) ; no puerperal patient has been reported.
A definitive diagnosis of drug-induced agranulocytosis can bemade if there is a decrease in the granulocyte count after drug
administration in the absence of other factors causing granulocytopenia. However, a decrease in the granulocyte count is notrare in severe-status patients, especially those with infection.
Conditions to be differentiated from acute agranulocytosis areviral / bacterial infection, bone marrow failure syndrome, hypersplenism, and drug-induced agranulocytosis (13). In the present
case, we were unable to definitively conclude that TAZ / PIPC induced the granulocytopenia. However, considering the reductionin the abscess after the start of TAZ / PIPC therapy and the patient’s recovery from protracted leukopenia to a leukocyte countof 5480 / µL (neutrophil count : 3162 / µL) 12 days after discontinuing TAZ / PIPC administration despite few imaging findings
suggestive of infection, TAZ / PIPC may have been etiologicallyinvolved in the protracted granulocytopenia in the present case.
In addition to TAZ / PIPC, levothyroxine sodium was administered before admission to treat hypothyroidism ; however, nostudy has reported agranulocytosis related to levothyroxine
sodium. Moreover, hematology on admission revealed no abnormalities in the leukocyte or neutrophil counts. Therefore, thepossibility of levothyroxine sodium-induced agranulocytosis wasexcluded, and TAZ / PIPC may have induced the agranulocytosis.
However, bone marrow examination was not conducted and adefinitive diagnosis was not made, being a limitation.
Although the etiology of drug-induced agranulocytosis remains unclear, two mechanisms, direct toxicity and an immune
mechanism, have been proposed (14).

Figure. Leukocyte, neutrophil, red blood cell and platelet counts, C-reactive protein, and body tempurature
throughout the patient’s hospitalization period

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H. Iwazawa, et al. TAZ / PIPC agranulocytosis in puerperal

In Japan, the reported incidences of TAZ / PIPC- and PIPC-induced agranulocytosis are 0.1 to 5% and unclear, respectively,in the package inserts. We searched for “agranulocytosis” usinga system to search for adverse reactions to drugs based on the“Japanese Adverse Drug Event Report database” announced
on the Pharmaceuticals and Medical Devices Agency (PMDA)
homepage, Drug Information Finding Outcomes (DRIFOs). For
the respective drugs, 30 and 14 patients were found, respectively. There was no puerperal disorder in either series. TAZ / PIPCused in the present case is a combination drug that may induce
adverse reactions. However, there is no commercially available
product consisting of TAZ alone and no study has reported thatthe addition of TAZ to PIPC increases the risk of adverse reactions ; therefore, comparison may be difficult. On the other hand,
penicillin-induced agranulocytosis has been reported ; therefore,
in the present case, the adverse reaction may have been related
to PIPC.
Regarding the cross-reactivity of TAZ / PIPC and MEPM, theprobability of cross-reactions with carbapenems in patients withpenicillin allergy was previously considered to be approximately
50%. However, this was based on a single study involving a small
number of patients (15). A recent study reported that cross-reactions with carbapenems occurred in <1% of patients withpenicillin allergy (16).
Concerning direct toxicity, antiepileptic and-psychotic drugs
were reported to directly act on myeloid cells. The toxicity is
induced by the drug itself, a toxic metabolite, or an accessory
product. Leukopenia related to direct toxicity develops slowly. In
comparison, an immune mechanism is termed a “drug allergy”
in some cases, and drug adsorption / immune complex / autoimmune mechanisms are known to occur. The onset of a drug
allergy is more rapid than a toxicity. Antibody is produced
within 1 hour to 1 day in patients previously sensitized to thedrug, and in 7–10 days in non-sensitized patients. Concerning
penicillin antibiotics, an immune mechanism may be involved in
the onset of agranulocytosis. In the present case, leukocytopenia
and neutropenia were observed 14 days after the administrationof TAZ / PIPC. This is consistent with the timing of agranulocytosis onset possibly related to an immune mechanism, which
is supported by previous studies stating that adverse reactions
developed 11–17 days after the use of TAZ / PIPC (11, 17). Furthermore, the risk factors for agranulocytosis are advanced age,female sex, renal hypofunction, and autoimmune diseases (18,19). However, in the present case, the patient was 32 years old,
and the creatinine clearance (Ccr) (Cockcroft–Gault equation)
was 165.58 mg / dL ; there was no renal hypofunction. There wasalso no history of autoimmune disease.
The agranulocytosis-related mortality rate with TAZ / PIPC isapproximately 10%, and agranulocytosis accounts for 20%–30%
of drug-related deaths, and is the most frequent causative factor.
As protracted / severe neutropenia increases the mortality rate,
initial management is important. Therefore, when administering TAZ / PIPC to puerperal patients, neutrophil counts should
be monitored to detect agranulocytosis, in addition to monitoring for diarrhea and evaluating liver function.
In the present case, bacteremia due to hospital-onset intraperitoneal infection was noted. To cover the Gram-positive bacteria
suspected to be the causative bacteria in addition to Bacterioides
fragilis, which was detected on blood culture, CFPM + CLDM orMNZ, a quinolone + CLDM or MNZ, or carbapenem antibiotics
are considered options. In the present case, it was necessary toselect a highly safe drug with low breast milk transfer, considering lactation. CLDM may affect the intestinal flora of children
fed breast milk. The carcinogenicity of MNZ in animals and its
mutagenicity in humans were previously demonstrated ; therefore, healthy infants may be exposed to metronidazole via breast

milk (20). Considering the safety, according to these studies,
MEPM with its low-level breast milk transfer was proposed as
an alternative to TAZ / PIPC (21), preventing the unnecessary
discontinuation of lactation.
In conclusion, we reported a patient with agranulocytosis
related to TAZ / PIPC administered during the puerperal period.
On the basis on the patient’s previous drug administration history, we considered that agranulocytosis was related to TAZ / PIPC
and discontinued the drug, resulting in recovery. When administering TAZ / PIPC, neutrophil counts should be monitored todetect agranulocytosis, in addition to monitoring for diarrhea
and evaluating liver function. Furthermore, drug administration should be discontinued at the onset of agranulocytosis, andTAZ / PIPC should be changed to other drugs, if necessary.

ETHICS APPROVALThis study was performed according to the guidelines of theDeclaration of Helsinki, and approved by the ethics committee ofKagawa University (Approval No. 2019-137). Written informed
consent was received from the patient for publication of this casereport.

CONFLICT OF INTEREST
None of the authors have any potential conflicts of interest
associated with this research.

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