Journal of the Formosan Medical Association 121 (2022) 1798e1803

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Original Article

Antibiotic choice for the management of

preterm premature rupture of membranes
in Taiwanese women
Han-Ying Chen a, Kuan-Ying Huang b, Yi-Heng Lin a,c,
Shin-Yu Lin a,*, Chien-Nan Lee a

a
Department of Obstetrics and Gynecology National Taiwan University Hospital and College of
Medicine, Taipei, Taiwan
b
Department of Obstetrics and Gynecology National Taiwan University Hospital and College of
Medicine, Hsinchu Branch, Taiwan
c
Department of Obstetrics and Gynecology National Taiwan University Hospital and College of
Medicine, Yunlin Branch, Taiwan

Received 2 August 2021; received in revised form 14 March 2022; accepted 18 March 2022

KEYWORDS Background: Preterm premature rupture of membranes (PPROM) is one of the most common
Antibiotic; causes of preterm birth. Antibiotic treatment is recommended to prolong the pregnancy
Antibiotic resistance; course and reduce fetal morbidity in women with PPROM. However, the guidelines for anti-
Preterm birth; biotic selection are based on studies done years ago, mostly in Western countries, which
Preterm premature may not reflect the geographic, temporal, and ethnic variation in microbial colonization and
rupture of infection in other parts of the world. We aimed to understand whether the antibiotics recom-
membranes mended by the current guidelines were sufficient to eradicate the majority of pathogens
(PPROM) involved.
Methods: This is a single-center retrospective study at a tertiary medical center in Taiwan with
patients recruited from January 1, 2017, to December 31, 2019. All patient included had a
confirmed diagnosis of PPROM. In this study, we aimed to investigate which broad-spectrum
antibiotic was most suitable for PPROM cases in Taiwan.
Results: 133 women were included, and 121 women had positive culture results. Most of the
pregnant women had one positive result (35.5%). The most common pathogen was Lactoba-
cillus species (27.8%), followed by Streptococcus species (12.9%) and Staphylococcus species
(12.09%).
Conclusion: The most appropriate antibiotic therapy for PPROM was a combination of 1 g azi-
thromycin given orally on admission plus a third-generation cephalosporin administered intra-
venously in the first 48 hours and followed by amoxicillin 500 mg per os for another five days.

* Corresponding author. Department of Obstetrics and Gynecology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei,
Taiwan. Fax: þ886 2 2311 4965.
E-mail address: lin.shinyu@gmail.com (S.-Y. Lin).

https://doi.org/10.1016/j.jfma.2022.03.015
0929-6646/Copyright ª 2022, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 Journal of the Formosan Medical Association 121 (2022) 1798e1803
This recommended antibiotic regimen for women with PPROM needs further study under a ran-
domized clinical trial with a larger study population to evaluate its efficacy.
Copyright ª 2022, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Introduction
Preterm birth is defined as any delivery before 37 weeks of
gestation, and it has an incidence of approximately 12% of
the live birth rate in the USA and 5e9% in many other
developed countries.1 Preterm birth is one of the leading
causes of prolonged hospitalization, pediatric neurologic
impairment, and neonatal death, costing more than 10
times the usual medical cost of patient care.2e4 Preterm
birth due to preterm premature rupture of membranes
(PPROM) remains one of the greatest challenges in modern
obstetrics.5 When PPROM occurs, efforts are made to pre-
vent infection-related complications and to prolong the
latent period between PPROM and the onset of labor when
appropriate, in order to decrease preterm-related
morbidity and mortality. The concept of administering an-
tibiotics in order to reduce morbidity in PPROM was first
published in 1997.6 Current practice guidelines are docu-
mented in the Overview of the Role of Antibiotics in Cur-
tailing Labor and Early Delivery (ORACLE) study which
recommends administering erythromycin to women with
PPROM. These guidelines have been credited with being
effective at reducing the occurrence of major neonatal
disease and may therefore have a substantial health benefit
on the long-term respiratory and neurologic function of
many children.
Administering antibiotic treatment in women with
PPROM is suggested by numerous guidelines with slight
differences in the proposed regimen. The recommendations
are mostly made on the basis of ORACLE study, a random-
ized clinical trial that was published in 2001.7 Moreover,
according to recent research, vaginal bacterial infections
are usually highly epidemiologic and species related. Due to
the general overuse of antibiotics, the rates of antibiotic
resistance have been increasing in recent years. Ali Por-
mohammad et al.8 reported that amoxicillin had the high-
est resistance ratedup to 70.5%din isolated human strains
of Escherichia coli. We hypothesize that, the previous
studies have overlooked the epidemiologic, racial, and
ethnic differences in addition to the increasing rates of
antibiotic resistance in bacteria.
It is essential to have a comprehensive understanding of
vaginal pathogenic bacteria in order to provide standard-
of-care treatment for patients with PPROM. In this study,
we collected and identified the composition and resis-
tance rate of vaginal bacteria in patients with PPROM.
Through this study, we aimed to have a greater under-
standing of the bacterial spectrum involved in PPROM and
whether the antibiotics recommended by the current
guidelines were sufficient to eradicate the majority of
pathogens involved.
1799
Materials and methods
This was a retrospective cohort study conducted in a ter-
tiary medical center in Taiwan from January 1, 2017, to
December 31, 2019. The patients with International Clas-
sification of Diseases, ninth revision (ICD-9) and tenth
revision (ICD-10) codes of PPROM were selected from the
electronic medical record system. The clinical data
collected included maternal age, parity, gravidity, under-
lying medical history, rupture of membrane gestational
age, antibiotic regimen, and gestational age at delivery,
among other variables. We included all pregnant women
diagnosed with PPROM before 34þ6 weeks of gestational age
and delivered after 24þ0 weeks of gestational age. These
patients were diagnosed with PPROM, which was supported
by their clinical history and confirmed by either a Nitrazine
pH test or an immunochromatographic dipstick test such as
Amnisure (Amnisure International LLC) or Actim PROM
(Actim). Women with pregnancy documented as less than
34 weeks’ gestation received microbiology analysis via
cervical culture upon admission. We did not include the
culture results of repeated examinations performed after
administrating antibiotics. All the women with PPROM were
admitted for inpatient care along with intensive
fetalematernal monitoring. The routine empirical anti-
biotic regimen in our hospital was 1 g of cefazolin every 8
hours until either delivery or no bacterial growth in the
cervical culture. If the patient was allergic to cefazolin,
alternatively, clindamycin 900 mg every 8 hours was
administered intravenously. Cefazolin was chosen as the
empirical antibiotic used in our facility for PPROM because
of its wide coverage of gram-positive and some commonly
seen gram-negative pathogens according to experts’ clin-
ical experience. The mode of delivery depended on the
patients’ clinical obstetric needs and physician prefer-
ences. If the predicted neonatal birth body weight is less
than 1500 g, delivery could be by cesarean section because
of preterm labor. We excluded women who did not have a
cervical culture performed and those who did not deliver in
our facility. Patient clinical data were retrieved from the
hospital database. The pathogens from the same group
were recorded as a whole (e.g., Streptococcus species)
rather than dividing into many subgroups. The exception
was coagulase-positive Staphylococcus species (“Staphylo-
coccus species” for short) and coagulase-negative staphy-
lococci. Coagulase-negative staphylococci are part of
normal human skin flora and do not have much to do with
serious infection. The ManneWhitney U-test was performed
to determine statistical significance in differences for
continuous variables between the groups. A statistical sig-
nificance level of 5% (p < 0.05) was adopted.
 H.-Y. Chen, K.-Y. Huang, Y.-H. Lin et al.

Table 1 Patient characteristics of 133 pregnant women. Table 2 Non-inflammatory versus inflammatory group.
Variables Mean [SD]/ 95% Confidence Characteristics Non- Inflammatory p-
Number (%) interval inflammatory group (N Z 23) value
Maternal age (years) 34.95 [5.35] [34.04e35.86] group (N Z 110)
WBC(K/mL) 10,815 [4497] [10050.72 Maternal age 35.4 [34.4, 36.3] 33.0 [30.2, 0.144
e11579.28] (years)a 35.9]
Neutrophil (%) 78.20 [8.13] [76.82e79.58] Gestational age at 28.94 [27.8, 30] 26.88 [24.7, 0.009*
C-reactive protein (mg/ 0.64 [0.82] [0.50e0.78] PPROM 28.5]
dL) (weeks)a
Body temperature 36.69 [0.51] [36.60e36.78] Time from PPROM 3.64 [2.44, 4.83] 2.12 [0.8, 3.4] 0.652
(degree Celsius) to delivery
Gravidity (day)a
1 50 (38%) Cesarean section 64, 58.2 16, 69.6 0.311
2 45 (34%) rate (N, %)
3 24 (18%) *p < 0.05.
4 3 (2%) a
Values are given as mean [95% Confidence interval].
S5 10 (7%)
Parity
0 76 (58%)
(3.8%) had a previous preterm history, and 2 (1.5%) under-
1 46 (35%)
went cervical cerclage during the current pregnancy. The
2 9 (7%)
cesarean section rate was 60.2% (80 of 133 patients); this
3 1 (1%)
was compatible with a study by Pasquier and colleagues,9
Route of delivery
who reported a 60% cesarean rate in PPROM women. The
Cesarean section 80 (60%)
most common cause of cesarean section was twins with
Normal spontaneous 50 (38%)
malpresentation (25%) followed by malpresentation
delivery
(21.3%). Among all the PPROM cases, we screened out
Vaginal birth after 3 (2%)
women with fever (body temperature >38  C), elevated C-
Cesarean section
reactive protein (>1.5 mg/dL)10 or leukocytosis (>16 K/
Cesarean section indication
mL)11 in the “inflammatory group”. The comparison be-
Twins with 20 (25%)
tween the inflammatory group and non-inflammatory group
malpresentation
is shown in Table 2. Women in the inflammatory group had
Malpresentation 17 (21.3%)
shorter time from rupture of membranes to delivery, but
Estimated birth weight 11 (13.8%)
this was not statistically significant (p value Z 0.652).
<1500 gm
Moreover, the women in the inflammatory group had
Fetal distress 10 (12.5%)
rupture of membranes significantly earlier than did the
Previous CS 9 (11.25%)
non-inflammatory group (p value Z 0.009). Higher cesarean
Placenta previa 5 (6.25%)
section rate was noted in the inflammatory group but failed
Placenta accreta 2 (2.5%)
spectrum
Others 6 (7.5%)
Table 3 The composition of microorganisms from cervical
culture of PPROM women.
Result of culture, n (%)a
Results
Lactobacillus species 69 (27.8%)
Streptococcus species 32 (12.9%)
There were 178 women recruited during the study period;
Staphylococcus species 30 (12.1%)
eight women were excluded because of loss to follow-up,
Candida albicans 19 (7.7%)
and 37 women were excluded because they did not have a
Enterococcus faecalis 19 (7.7%)
cervical culture. In addition, 12 women had a negative
Escherichia coli 17 (6.9%)
culture result. In total, 133 women were included, and 121
Burkholderia cepacia 9 (3.6%)
women had positive culture results. The mean age among
Coagulase-negative staphylococci 9 (3.6%)
133 women was 34.9 years old. The mean time from PPROM
Prevotella amnii 9 (3.6%)
to delivery was 3.37 (95%CI: 2.35, 4.39) days. The patient
Corynebacterium amycolatum 6 (2.4%)
characteristics are presented in Table 1. Multi-gestation
Enterobacter aerogenes 4 (1.6%)
pregnancies accounted for 10.5% (13 twin pregnancies and
Atopobium vaginae 3 (1.2%)
one triplet pregnancy) of all pregnancies, and 28 patients
Yeast-like organism 3 (1.2%)
(21.1%) had a previous medical history including preterm
Others 19 (7.7%)
delivery, diabetes mellitus, hypertension, rheumatologic
a
diseases, and concurrent urinary tract infection. Two pa- Values are given as number of the specific microorganism/
tients (1.5%) had previous cervical excisional surgery, 5 positive culture cases (%).

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 Journal of the Formosan Medical Association 121 (2022) 1798e1803

to show statistical significance (p value Z 0.311). The most
common reason for cesarean section in the inflammatory
group was estimated birth weight <1500 gm (4 out of 13
patients, 30%) and fetal distress (3 out of 13 patients,
23.1%). As for the non-inflammatory group, the most com-
mon reason for cesarean section was malpresentation (33
out of 63 patients, 52.4%)
More than one pathogen might be found in the cervical
culture; therefore, there were a total of 248 culture re-
sults. Most of the pregnant women only had one positive
result (35.5%), followed by two positive results (29.8%),
and then three positive results (28.9%). The results
showed that the most common pathogen was Lactoba-
cillus species (27.8%), followed by Streptococcus species
(12.9%) and Staphylococcus species (12.09%) (Table 3).
Among the cultures that only yielded one pathogen,
Lactobacillus species (56.1%) was the most common, fol-
lowed by Streptococcus species (19.5%). Among the cul-
tures that yielded more than one pathogen, Lactobacillus
species (22.4%) was most commonly seen, followed by
Staphylococcus (14.1%) and Streptococcus (11.7%) species.
The antibiotic resistance rates of the pathogens are listed
in Table 4. Ampicillin showed a high resistance rate in
gram-negative pathogens. A second-generation cephalo-
sporin at least is needed to cover gram-negative patho-
gens. Erythromycin demonstrated a high resistance rate in
the gram-positive group. Ampicillin or a second-
generation cephalosporin at least is needed to cover
gram-positive pathogens.
Discussion
There are several well-known guidelines regarding prophy-
lactic antibiotic regimens for women with PPROM (Table
5).12e14 Ampicillin plus erythromycin is one of the most
commonly recommended combinations.15 Recently, azi-
thromycin was reported to be equivalent to erythromycin in
these clinical scenarios; erythromycin is easier to administer,
costs less than other antibiotics, and has a better side effect
profile.16 For those patients who could not tolerate
erythromycin, penicillin was recommended. The current
guidelines are based on the antibiotic recommendation as
detailed in the Overview of the Role of Antibiotics in Cur-
tailing Labor and Early Delivery (ORACLE) study which was
published two decades ago. In addition, the ORACLE study
did not include a vaginal culture, nor was the antibiotic
resistance rate evaluated. The selection of an antibiotic
regimen was based solely on the provision of broad-spectrum
coverage. However, bacterial resistance to antibiotics has
increased substantially in recent years, and the pathogen
composition in vaginal cultures may have changed as well.8 It
is important to note that previous studies on PPROM have
taken place primarily in Western countries and have
recruited Caucasian women.7 According to Gupta et al.,17
community-acquired vaginal pathogens vary between
races, ethnicities, and countries. To our knowledge,
research on vaginal pathogens has not been performed spe-
cifically among the Taiwanese people. Further study is
needed to determine if prolonged antibiotic administration
would be beneficial to pregnancy outcomes in patients with
PPROM and to ascertain how frequently cervical cultures
should be repeated.
Other previous studies
A Hong Kong study18 analyzed the vaginal cultures of
women with PPROM during the 2013 to 2017 time period.
The study concluded that erythromycin with or without
ampicillin was insufficient to control gram-positive and
gram-negative bacterial growth in women with PPROM.
Their study also revealed that early neonatal sepsis was
frequently associated with gram-negative bacteria, and the
authors proposed intravenous cefuroxime for prophylactic
use.18 Another study from Israeli19 evaluated women with
fever, chorioamnionitis, or PPROM and concluded that
early-onset neonatal sepsis was caused by E. colidnot
group B Streptococcusdin 80% of the neonates.19 These
studies12,13 suggest that although infection by group B
Streptococcus is prevented with prophylactic antibiotics,

Table 4 Antibiotic resistance percentage of cultured bacteria.

Gram- Ampicillin Ampicillin-sulbactam First generation Second generation Third generation
negative resistance (SAM) resistance cephalosporin cephalosporin resistance cephalosporin resistance
bacteria resistance
Escherichia 1/1 (100%) 11/18 (61%) 7/14 (50%) 2/17 (12%) 3/15 (20%)
colia
Gram-positive Ampicillin Ampicillin- 1st generation of 2nd generation of 3rd generation of Erythromycin
bacteria resistance sulbactam (SAM) cephalosporin cephalosporin cephalosporin resistance
resistance resistance resistance resistance
Enterococcus 0/8 (0%) 0/1 (0%) 2/2 (100%) 2/3 (67%) 3/14 (21%) 1/2 (50%)
speciesa
Streptococcus 0/5 (0%) 1/2 (50%) 0/1 (0%) 0/2 (0%) 3/7 (43%) 4/13 (30%)
speciesa
Staphylococcus 0/2 (0%) 0/1 (0%) 1/3 (33%) 1/1 (100%)
speciesa
a
Values are given as number of resistant cases/positive culture cases (%).

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 H.-Y. Chen, K.-Y. Huang, Y.-H. Lin et al.

not sufficient to control 52.9% of patients with positive

Table 5 Different antibiotic regimens suggested for
cultures.
women with PPROM.
Associations Recommendation of Azithromycin as an empirical regimen
antibiotic regimens From the ORACLE trial, the results showed that erythro-
Society of Obstetricians and (1) Ampicillin2g IV every 6 mycin could prolong pregnancy in women with PPROM. As a
Gynaecologist of Canada hours and erythromycin result, erythromycin has been and continues to be pre-
(SOGC) 250 mg IV every 6 hours for 48 scribed for women with PPROM. In an effort to avoid side
hours followed by amoxicillin effects, curtail expense, and have a formulary medication
250 mg orally every 8 hours that is readily available, some hospitals have replaced
and erythromycin 333 mg erythromycin with azithromycin. Navathe et al.16 compared
orally every 8 hours for 5 days intravenous erythromycin for 2 days followed by erythro-
(2) Erythromycin 250 mg mycin per os for 5 days and azithromycin administered with
orally every 6 hours for 10 different protocols in 453 women with PPROM, and they
days found no difference in primary outcome (latency from
The National Institute for Oral erythromycin 250 mg 4 PPROM to delivery) or other secondary outcomes (cho-
Health and Care times a day for a maximum of rioamnionitis, stillbirth, neonatal sepsis, neonatal death,
Excellence (NICE) 10 days oral penicillin for a and necrotizing enterocolitis). One gram of azithromycin
maximum of 10 days per os given once on admission is sufficient to show benefits
American College of 2 days of Ampicillin plus in PPROM women. The human uterus is highly permeable to
Obstetricians and erythromycin followed by azithromycin, particularly the placental tissue and mem-
Gynaecologists (ACOG) Amoxicillin and Erythromycin brane. In this study, our hospital did not perform a sensi-
in oral from for 5 days tivity test for azithromycin because of the high resistance
Royal College of ObstetriciansAn antibiotic (preferably rate of bacterial pathogens for azithromycin. The effec-
and Gynaecologists erythromycin) should be given tiveness of azithromycin in the management of Ureaplasma
(RCOG) for 10 days or until the infection, which may aid in prolonging gestation, has been
women is in established labor reported by many studies.22 Therefore, one gram of azi-
Collège National des Amoxicillin, third-generation thromycin administered orally on admission is recom-
Gynécologues et cephalosporin and mended for patients with PPROM.
Obstétriciens Franҫais erythromycin (professional
(CNGOF) consensus) can be used Limitation of this study
individually or erythromycin There were some limitations in our study. First, this was a
and amoxicillin can be retrospective study from a single tertiary medical center
combined (professional and as such may only reflect regional bacterial composition.
consensus) for a period of 7 Multicenter studies with larger study populations would be
days. more ideal to overcome this limitation. Secondly, the lab-
oratory in our hospital did not perform sensitivity testing
for all of the isolated pathogens if those pathogens did not
exhibit substantial growth. Therefore, the denominator of
we now need to focus the coverage on gram-negative the same species for different antibiotics might be
bacteria as well. different. Third, tests for Ureaplasma and Chlamydia spe-
cies are not routine examinations in our hospital. There-
Insufficient bacterial coverage with erythromycin fore, we may lack the incidence, antibiotic resistance rate,
The widespread use of erythromycin for PPROM is based on and sensitivity rate of these two pathogens. Fourth, due to
the ORACLE trial. Theoretically, erythromycin inhibits the retrospective nature of this study, it was difficult to
neutrophil migration, oxidative burst, cytokines, and met- survey the incidence of neonatal sepsis, hypoxic ischemic
alloproteinase. The anti-inflammatory effect of erythro- encephalopathy, neurologic deficit, and other outcomes
mycin is the key factor in its role as a management option correlating with preterm perinatal morbidity. Future
for PPROM.20 To our knowledge, there have been few studies of neonatal outcomes in the setting of PPROM
studies on the drug sensitivity of various vaginal pathogens. should be evaluated using well-designed randomized clin-
In our analysis, there were a total of 248 positive culture ical trials.
results, where 153 positive cultures (61.7%) involved gram-
negative and gram-positive bacteria. Streptococcus species
were the most common bacterial pathogens, followed by Conclusion
Staphylococcus species. The resistance rate of these path-
ogens for erythromycin was high. Results showed that 50% Most of the international practice guidelines recommend
of Enterococcus faecalis and 100% of Staphylococcus spe- the use of prophylactic antibiotics for the management of
cies were resistant to erythromycin. This result is similar to PPROM based on the ORACLE trial, a study that was done
that of a previous study by Tuem et al.,21 who did not many years ago and did not investigate epidemiologic dif-
recommend erythromycin as a first-line single empirical ferences.7 Considering that bacteria tend to be epidemio-
antibiotic because administering erythromycin alone was logic and evolve over time, our study presented regional

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 Journal of the Formosan Medical Association 121 (2022) 1798e1803
analyses in Taiwan in order to provide further information
on the more suitable prophylactic antibiotic regimens
specifically for Taiwanese women with PPROM.
The results of our study showed that the most common
bacterial pathogens in PPROM are Streptococcus species, E.
coli, and Staphylococcus species. The cultured pathogens
exhibited a high resistance rate to the current recom-
mended antibiotics for prophylaxis: ampicillin and eryth-
romycin. Changes are needed for current published
guidelines. Referencing the established guidelines, we
suggest a third-generation cephalosporin be administered
intravenously in the first 48 hours followed by amoxicillin
500 mg every 8 hours in oral form for another 5 days. One
gram of azithromycin per os given once on admission in
PPROM women is suggested to cover Ureaplasma infection
and prolong pregnancy. This recommended antibiotic
regimen for women with PPROM needs further study under
a randomized clinical trial with a larger study population to
evaluate its efficacy.
Declaration of competing interest
The authors have no conflicts of interest relevant to this
article.
Acknowledgements
This work was supported by the National Taiwan University
Hospital [grant number 110-005081].
The authors would like to express their thanks to the
staff of National Taiwan University Hospital-Statistical
Consulting Unit (NTUH-SCU) for statistical consultation
and analyses.
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