Original Studies

Effect of Macrolides and β-lactams on Clearance of

Bordetella pertussis in the Nasopharynx in Children With
Whooping Cough
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Yu-Mei Mi, MM,* Chun-Zhen Hua, MD,* Chao Fang, MM,† Juan-Juan Liu, MM,* Yong-Ping Xie, MM,*
Luo-Na Lin, MM,* and Gao-Liang Wang, MM*
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Objective: The purpose of the current study is to investigate the bactericidal

effect of macrolides and β-lactams on Bordetella pertussis (B. pertussis)
P ertussis (whooping cough) is a highly contagious respiratory
disease caused by Bordetella pertussis (B. pertussis). The inci-
dence of pertussis has reemerged in many countries despite the
in the nasopharynx and provide guidance for treating macrolides-resistant
B. pertussis infections.
high-vaccine coverage worldwide,1–3 which presents a great threat
Methods: Patients with whooping cough was diagnosed by culture of naso-
to children’s health. Antibiotic treatment eliminates B. pertussis
pharynx swabs between January 2016 to December 2018. B. pertussis was
from an infected child and thus controls the transmission between
identified using specific antisera against pertussis and parapertussis. Drug
contacts. In addition, antibiotics can reduce the duration of illness
susceptibility test was carried out using the E-test method. The clearance
and the severity of disease in children if treatment started early after
of B. pertussis in nasopharynx at 7 and 14 days into and posttreatment with
infection.4,5 The first choice of antibiotic for pertussis children is
macrolides, and β-lactams was compared.
macrolides;6,7 however, macrolides-resistant B. pertussis (MRBP)
Results: A total of 125 B. pertussis samples were collected from patients
has increased in recent years worldwide, especially in some regions
who received single antibiotic treatment. Among those isolates, 62.4%
of China.8–10 Therefore, there is an urgent need to find an antibiotic
(78/125) had high resistance with minimum inhibitory concentrations
with bactericidal activity against B. pertussis. We have shown that
greater than 256 mg/L for erythromycin and azithromycin. The MIC90 of while cefuroxime has a relatively high minimum inhibitory con-
piperacillin, cefoperazone-sulbactam, meropenem, ampicillin, ceftriax- centration (MIC) against B. pertussis (12 mg/L), ampicillin, pipera-
one, ceftazidime and trimethoprim-sulfamethoxazole for these isolates cillin, ceftriaxone and cefoperazone-sulbactam have much lower
was <0.016, 0.094, 0.094, 0.19, 0.19, 0.25 and 0.75 mg/L, respectively. MICs, which are in the range of 0.047 to 0.38 mg/L.11 Thus, those
The clearance rate with β-lactams treatment (68.8%, 44/64) was signifi- antibiotics with lower MICs could be bactericidal against B. pertus-
cantly higher than that with macrolides treatment at 14 days posttreat- sis in vivo. In the current study, we compared the clearance rate of
ment (50.8%, 31/61) (χ2 = 4.18, P = 0.04). Macrolides had a better clear- β-lactams and macrolides against B. pertussis in the nasopharynx
ance rate at 7 days posttreatment than β-lactams (χ2 = 4.49, P = 0.03) for and provided references for treatment and recommendations for the
macrolides-sensitive isolates and a worse clearance rate for macrolides- quarantine period for pertussis children.
resistant isolates.
Conclusion: B. pertussis isolates had a high-resistant rate for macrolides MATERIALS AND METHODS
in our study. Macrolides are the first choice for treating pertussis caused
by macrolides-sensitive strains, and some β-lactams such as piperacillin Enrollment
should be considered as alternative antibiotics for treatment of macrolides- Patients enrolled in this study were children receiving
resistant B. pertussis infection. treatment for pertussis in the Children’s Hospital of Zhe Jiang
University from January 2016 to December 2018. Inclusion cri-
Key Words: Bordetella pertussis, children, nasopharynx, β-lactams, mac- teria included as follows: (1) Culture positive for B. pertussis in
rolides nasopharynx during admission; (2) antibiotics (including those
(Pediatr Infect Dis J 2021;40:87–90) received before admission) were only macrolides (erythromycin,
azithromycin or clarithromycin), and treatment had lasted 2 weeks
(2–3 curses of treatment when using azithromycin, and 3–4 days
treatment gap between courses) and (3) antibiotics (including those
Accepted for publication August 23, 2020. used before admission) were only β-lactams (except the first and
From the *Division of Infectious Diseases, The Children’s Hospital, Zhejiang
University School of Medicine, National Clinical Research Center for Child
second generation of cephalosporins).11 Exclusion criteria included
Health, Hangzhou, Zhejiang, P.R. China; †Department of Clinical Labora- as follows: (1) The duration of antibiotics treatment was less than 2
tory, The Children’s Hospital, Zhejiang University School of Medicine, weeks, or antibiotics treatment was not continuous even if the total
National Clinical Research Center for Child Health, Hangzhou, Zhejiang, treatment period reached 2 weeks. (2) A combination of antibiotics
P.R. China.
Supported by Natural Science Foundation of Zhejiang Province, China (LGF was used. (3) Patients did not finish once-a-week nasopharyngeal
18H010001). swab culture during treatment. (4) Lost contact and unable to finish
The authors have no conflicts of interest to disclose. follow-up swab culture after discharge from the hospital.
This study was approved by the Ethics Committee and the Institutional Board
of Privacy and Security at the hospital (2016-IRB-014) and was performed
under the institution’s opt-out passive consent policy. Bacterial Culture and Antibiotics Susceptibility Test
This manuscript has not been published previously and is being submitted only The collection of nasopharyngeal swab, inoculation and
to The Pediatric Infectious Disease Journal.
Address for correspondence: Chun-Zhen Hua, MD, Division of Infectious Dis- bacteria culture was performed as described previously.11 B. per-
eases, The Children’s Hospital, Zhejiang University School of Medicine, tussis strains were confirmed by positive slide agglutination with
National Clinical Research Center for Child Health, 57 Zhugan Lane, Hang- specific antisera against B. pertussis and negative reaction with B.
zhou 310003, P.R. China. E-mail: [email protected]. parapertussis antiserum (Remel Europe Ltd., United Kingdom).
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/21/4002-0087 Samples that were positive for both sera were further analyzed by
DOI: 10.1097/INF.0000000000002911 high-throughput whole-genome sequencing.

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 Mi et al The Pediatric Infectious Disease Journal • Volume 40, Number 2, February 2021

Treatment treatment, and 5 were from the group of β-lactams treatment. There
Nasopharyngeal swabs were taken from patients upon was no significant difference for relapse rates between macrolides
admission. Antibiotics were prescribed before culture results were group (11/61, 18.0%) and β-lactams group (9/64, 14.1%, χ2 = 0.37,
obtained as follows: (1) For those patients who had been prescribed P = 0.55).
with macrolides or β-lactams (except the first and second gener- The clearance rate in these 125 patients and the drug resist-
ation of cephalosporin) and had a short course of treatment (for ance of isolates is shown in Table 2. There was also no significant
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erythromycin and β-lactams, shorter than 7 days; for azithromy- difference in the clearance rate from the nasopharynx when treat-
cin, shorter than 5 days), or whose symptom was getting better, the ment started within 7 days or after 7 days of infection (χ2 = 0.89,
same antibiotics were prescribed. (2) For patients who have been on P = 0.34). The clearance rate in the group received macrolides for 14
macrolides and other β-lactams (except the first and second genera- days was significantly lower than that in group received β-lactams
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tion of cephalosporin) for more than 7 days and symptoms have (χ2 = 4.18, P = 0.04); treatment with macrolides had higher clear-
not improved, cefoperazone-sulbactam or piperacillin-tazobactam ance rate for macrolides-sensitive B. pertussis (MSBP) than MRBP
(if cefoperazone-sulbactam was not working) was prescribed. (3) (7 days into treatment, χ2 = 9.35, P = 0.002; 14 days into treatment
Erythromycin or azithromycin was prescribed if no antibiotics have χ2 = 20.11, P < 0.001; 7 days posttreatment χ2 = 15.99, P < 0.001;
been prescribed before admission. Patients with positive bacte- 14 days posttreatment χ2 = 6.79, P = 0.009). There was no differ-
ria cultures were treated with antibiotics for 14 days,11 and naso- ence for clearance rate against MSBP by β-lactams or macrolides
pharyngeal swabs were taken at 7 and 14 days into treatment, and treatment (7 days starting treatment χ2 = 0.50, P = 0.48; 14 days
7 and 14 days postdischarge from hospital during follow-up visits. into treatment χ2 = 1.49, P = 0.22; 14 days posttreatment χ2 = 3.09,
P = 0.08) except β-lactams treatment has a lower clearance rate at 7
Statistical Analysis days posttreatment (χ2 = 4.49, P = 0.03). The clearance rate against
Enumeration data were shown as number (percentage, %). MRBP was significantly higher in the β-lactams group than that in
Comparisons of enumeration data between groups were analyzed the macrolides group (7 days into treatment, χ2 = 7.57, P = 0.006;
using χ2 test or Fisher’s exact test. Normal distribution data were 14 days into treatment χ2 = 18.55. P < 0.001; 7 days posttreatment
presented as mean ± standard deviation. A comparison of nor- χ2 = 16.12, P < 0.001; 14 days posttreatment χ2 = 5.95, P = 0.01).
mal distribution data between groups was analyzed using t-test.
Abnormal distribution data were presented using the median with DISCUSSIONS
interquartile range. A comparison of abnormally distributed data There were increased reports on MRBP in recent years, espe-
between groups was analyzed using the Mann-Whitney U test. cially in China that had the highest rate of resistant isolates with
P < 0.05 was considered as statistically different. the highest MICs.8–11 Our results showed that 62.4% of the isolates
had MICs greater than 256 mg/L, which was consistent with our
RESULTS previous finding (75.4%) and a study from Shanghai (57.5%).9,11
Nonetheless, the current recommendation for treating B. pertussis
Demographic Information is still macrolides.6,7 Treatment with macrolides for MSBP infec-
We have recruited a total of 125 pertussis children that fit tion could reduce symptoms and shorten disease duration if treat-
our criteria in our study. There were 64 males (51.2%, 64/125). ment was started at an early stage after infection.5 Symptoms in
Age distribution was between 15 days and 9 years, 1 month with a some patients with MRBP infection were improved by macrolides
median age of 4.4 months (3.03, 9.51). There were 48.8% (61/125) treatment, probably by inhibiting toxin production from bacteria by
of patients that received macrolides, which included 50 cases of macrolides.12 However, relapse of infection was very common. We
erythromycin and 11 cases of azithromycin. The other 51.2% also found that most bacteria colonies recovered from nasopharyn-
(64/125) of patients received β-lactams, which included 23 cases of geal swabs appeared dusty like after antibiotics treatment, which
cefoperazone-sulbactam, 11 cases of piperacillin-tazobactam and indicates that antibiotics treatment may have changed the physiol-
30 others that received ceftriaxone, cefodizime, cefdinir, cefixime, ogy of these bacteria.
amoxicillin-clavulanate or ampicillin-sulbactam. There were no Pertussis is a highly contagious respiratory disease and can
significant differences in age (z = 1.21, P = 0.23), sex (χ2 = 1.78, spread from respiratory droplets containing bacteria colonized in
P = 0.18) or period before admission (z = 1.85, P = 0.06) between
the 2 groups treated with macrolides and β-lactams.

Drug Susceptibility Tests TABLE 1. MIC Values for 10 Antibiotics in 125

As shown in Table 1, we determined MICs in these 125 iso- B. Pertussis Isolates
lates for 10 antibiotics. There were 62.4% (78/125) isolates that had
MIC Min MIC Max MIC50* MIC90†
MICs higher than 256 mg/L to erythromycin and azithromycin. On Antimicrobial Agent (mg/L) (mg/L) (mg/L) (mg/L)
the other hand, all isolates were sensitive to piperacillin and had
MICs lower than 0.016 mg/L. Erythromycin (125) 0.023 >256 >256 >256
Azithromycin (125) <0.016 >256 >256 >256
SXT (125) 0.002 1.5 0.19 0.75
Treatment Outcomes Ampicillin (94) 0.023 0.5 0.094 0.19
Symptoms, including paroxysmal cough, posttussive vomit- Piperacillin (125) <0.016 <0.016 <0.016 <0.016
ing, and apnea, became better in 80.0% (100/125) patients after Cefuroxime (33) 2 16 6 12
treatment for 2 weeks. There was no significant difference in the Ceftazidime (31) 0.023 0.5 0.094 0.25
rate of improvement between the group received macrolides (47/61, Ceftriaxone (125) 0.047 0.38 0.094 0.19
Cefoperazone-sulbactam (125) <0.016 0.38 0.032 0.094
77.0%) and those received β-lactams (53/64, 82.8%) (χ2 = 0.65, Meropenem (125) 0.006 0.25 0.047 0.094
P = 0.42). Twenty patients (20/125, 16.0%) had worse paroxysmal
*MIC50, MIC at which 50% of the isolates tested are inhibited.
cough within 1 week after finishing the first treatment and had been †MIC90, MIC at which 90% of the isolates tested are inhibited.
readmitted into the hospital. Fifteen of these 20 (75.0%) patients had MIC indicates minimum inhibitory concentration; SXT, trimethoprim-sulfameth-
MRBP infections, in which 10 were from the group of macrolides oxazole.

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 The Pediatric Infectious Disease Journal • Volume 40, Number 2, February 2021 Effect of Antibiotics Against B. pertussis

TABLE 2. Drug Resistance Rate and Clearance Rate of B. Pertussis by Treatment With Different Antibiotics

Clearance Rate in Nasopharynx % (n)

Antibiotics Age Median Days of History 7 d Into 14 d Into 7d 14 d

for Treatment Isolates (n) Male (n) (IQR), mo Median (IQR) Treatment Treatment Posttreatment Posttreatment
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Macrolides 61 28 4.0 (2.8, 6.3) 8 (6, 12) 18.0 (11) 50.8 (31) 73.7 (45) 86.9 (53)
Macrolides-sensitive (30)* 14 3.9 (2.8, 5.8) 8 (6, 11) 33.3 (10) 80.0 (24) 96.7 (29) 100 (30)
Macrolides-resistant (31)† 14 4.0 (2.7, 6.9) 9.5 (6.5, 25.3) 3.2 (1) 22.6 (7) 51.2 (16) 74.2 (23)
β-lactams 64 38 4.4 (3.0, 9.5) 8 (8, 14) 26.6 (17) 68.8 (44) 85.9 (55) 92.2 (59)
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Macrolides-sensitive (17)‡ 9 4.7 (3.4, 5.2) 10 (8, 11) 23.5 (4) 58.8 (10) 70.6 (12) 82.4 (14)
Macrolides-resistant (47)§ 29 4.8 (3.3, 10.24) 10 (8, 25) 27.7 (13) 72.3 (34) 91.5 (43) 95.7 (45)
*Longest carriage time 35 d.
†Longest carriage time 81 d.
‡Longest carriage time 49 d.
§Longest carriage time 56 d.
IQR indicates interquartile range; MSBP, macrolides-sensitive B. pertussis; MRBP, macrolides-resistant B. pertussis.

the nasopharynx. Thus, we have evaluated the outcome of treat- present study, and only half of those were cefoperazone-sulbactam
ments by the clearance rate of B. pertussis in the nasopharynx. We and piperacillin. It also suggested that cefoperazone-sulbactam
found that the clearance rate for MSBP by macrolides at 7 days and piperacillin might be better for clearing B. pertussis than other
and 14 days into treatment was 33.3% and 80.0%, respectively. In β-lactams in nasopharynx. In addition, the limited sample number
contrast, the clearance rate for MRBP was only 3.2% and 22.6% might have also had an effect on our results.
at the same time points. It suggests that macrolides should not be It has been shown that the prescription of antibiotics at an
prescribed for pertussis caused by MRBP. For MSBP, macrolides early stage of infection (less than 7 days) could significantly reduce
had better bactericidal activity than β-lactams in vivo; however, the symptoms of pertussis patients and shorten disease duration.4,5
7-day course of macrolides is not enough to clear all B. pertussis We tested whether early antibiotics prescription can eliminate
strains in the nasopharynx and will lead to relapse.13–15 Of the 20 B. pertussis faster from colonization. It turned out that there was
patients whose symptoms relapsed after the first 14 days of treat- no difference in the clearance rate when antibiotics were prescribed
ment, 3 were positive for B. pertussis again after the second admis- within or after 7 days of disease onset. There were also patients
sion, which also showed that adequate course of treatment is very who had mild symptoms but were still positive for B. pertussis by
important for bacteria clearance. Therefore, a treatment plan for at nasopharyngeal swab. Some patients even carried B. pertussis for
least 14 days is advised strongly. 35 to 81 days. The presence of symptomless patients with coloniz-
There were very few β-lactams susceptibility tests against ing B. pertussis suggested that antibiotics might have reduced the
B. pertussis worldwide. Our study showed that MICs of ampicillin, toxin production in B. pertussis, which needs to be investigated in
ceftriaxone, ceftazidime, cefoperazone-sulbactam and meropenem future studies.
were lower than that of other antibiotics tested here. Piperacillin In conclusion, isolates of B. pertussis are highly resistant
had a MIC lower than 0.016 mg/L for all strains. Furthermore, we to macrolides in our region. Treatment with macrolides is the first
showed that the clearance rate of the group received a combina- choice for MSBP infection, and it needs to be used for at least 2
tion of these β-lactams was higher against B. pertussis at 14 days weeks to clear colonization of B. pertussis in the nasopharynx.
into treatment comparing to that of the group received macrolides, β-lactams, such as cefoperazone-sulbactam or piperacillin, should
suggesting that these β-lactams can be used to treat pertussis in be prescribed as alternative antibiotics for treating MRBP infec-
children in regions like China where MRBP is circulating. There tion in regions with a high prevalence of MRBP isolates. B. pertus-
was no difference in the clearance rate for β-lactams against MSBP sis culture of nasopharyngeal swabs should be considered as one
and MRBP. Piperacillin, which had high antibacterial activity in of the standards to evaluate treatment outcomes. Limitations of our
vitro, also cleared B. pertussis in nasopharynx very well.11 It is study were that the research was only carried out in a single center,
worth considering a multicenter study to test whether piperacillin the number of patients was small, and many types of β-lactams
should be used as the first choice of antibiotics in areas with a lot have been used, which limited the analysis of the treatment effect
of MRBP isolates. Trimethoprim-sulfamethoxazole is not suitable from a single antibiotic. Piperacillin showed the strongest in vitro
for infants younger than 2 months.16 The MIC of trimethoprim-sul- effect; however, we had to replace it with piperacillin-tazobactam
famethoxazole in our study was higher than that of other β-lactams. in our treatment due to a lack of piperacillin in the hospital. A
Nevertheless, there is no reference for the MIC values of trimeth- future study has been planned to investigate the effect of differ-
oprim-sulfamethoxazole in the Clinical and Laboratory Standards ent β-lactams on pertussis in children in multicenter with more
Institute; thus, the effect of this antibiotic against B. pertussis still samples.
needs to be studied.17
As shown in Table 2, the clearance rate of β-lactams was ACKNOWLEDGMENTS
lower against MSBP, but significant higher against MRBP than that We thank Ying-Jie Lu, Boston Children’s Hospital, for his
of macrolides. Thus, it is important to promote the effectiveness of critical reading of this article.
β-lactams, such as piperacillin against B. pertussis in China, where
there are many MRBP isolates. We have shown previously that a REFERENCES
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