In vitro activity and clinical efficacy of macrolides, cefoperazone-sulbactam and piperacillin/piperacillin-tazobactam against Bordetella pertussis and the clinical manifestations in pertussis patients due to these isolates: A single-centre study in Zhejiang Province, China

https://doi.org/10.1016/j.jgar.2019.01.029Get rights and content

Highlights

  • Bordetella pertussis with high macrolide-resistance circulates in Hangzhou, China.

  • Piperacillin and cefoperazone-sulbactam are active in inhibiting Bordetella pertussis in vitro.

  • Piperacillin-tazobactam and cefoperazone-sulbactam are effective in treatig pertussis.

Abstract

Background and objective

Macrolides are the recommended antibiotics for treating pertussis and preventing transmission. The causative bacterium, Bordetella pertussis, has high macrolide resistance and has recently circulated in China. The objective of this study was to find effective alternative antibiotics for treatment by assessing the in vitro activity and clinical efficacy of antibiotics against Bordetella pertussis.

Methods

Bordetella pertussis was confirmed by agglutination with specific antisera and mass spectrometry. The MICs of antibiotics against isolates were determined using the Etest method. Treatment outcomes were clinically and microbiologically evaluated.

Results

A total of 126 pertussis patients were diagnosed based on culture, 69.8% of whom were aged ≤6 months and 72.1% were treated with previous macrolides. Leucocytosis and lymphocytosis were observed in 29.4% and 54.8% of all patients, respectively. Both MIC50 and MIC90 of erythromycin, azithromycin, and clindamycin were >256 mg/L, and 75.4% were highly macrolide resistant. The MIC90 of trimethoprim-sulfamethoxazole, ampicillin, ampicillin-sulbactam, cefuroxime, ceftriaxone and cefoperazone-sulbactam were 0.38 mg/L, 0.25 mg/L, 0.19 mg/L, 12 mg/L, 0.19 mg/L and 0.047 mg/L, respectively. The MICs of piperacillin in all of the isolations were <0.016 mg/L. Of the patients treated with single cefoperazone-sulbactam or piperacillin-tazobactam, 30 of 32 (93.8%) had significantly improved clinical symptoms and 24 of 25 (96%) had negative culture results after 2 weeks of therapy.

Conclusion

Macrolide resistance in Bordetella pertussis is a serious problem in Zhejiang Province, China. Piperacillin/piperacillin-tazobactam and cefoperazone-sulbactam have potent antibacterial activity in vitro and in vivo, and may become the alternative choice for treating pertussis caused by macrolide-resistant isolates.

Introduction

Pertussis, also known as whooping cough, is an acute respiratory tract infection caused by Bordetella pertussis (B. pertussis). Typical pertussis is characterised by severe, long-lasting, spasmodic, paroxysmal coughing after its initial onset in children, and it is particularly serious in neonates and infants [1], [2]. In recent years, the number of pertussis cases has significantly increased, and it is re-emerging as a public health problem, even in regions with high vaccine coverage [3], [4], [5]. However, antibiotics for treating pertussis are extremely limited, and macrolide antibiotics, such as erythromycin and azithromycin, remain the only recommended antibiotics for the treatment and prophylaxis of this disease [6]. Early intervention with sensitive antibiotics is beneficial and associated with a shortened duration of coughing and reduced risk of death in young infants [1]. Usually, macrolide resistance is not a major concern for pertussis [6], [7], although erythromycin resistance in B. pertussis has been described in some countries [8], [9], [10].

Recently, Wang [11] and Yang et al. [12] found that B. pertussis isolates with high levels of macrolide resistance are very common in some parts of China; thus, alternative antibiotics to treat paediatric pertussis caused by macrolide-resistant strains, or patients for whom treatment has failed, is urgently needed. This study sought to assess the in vitro activity and clinical efficacy of non-macrolide antibiotics – such as piperacillin/piperacillin-tazobactam and cefoperazone-sulbactam – against B. pertussis isolates to find effective alternative antibiotics for treatment.

Section snippets

Ethics

The study was approved by the Local Research Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine (2016-IRB-014), and informed consent was obtained for experimentation. This research was conducted in accordance with the Declaration of Helsinki and national and institutional standards.

Patients

The patients with suspected pertussis and enrolled in the study were those with a cough lasting >2 weeks, or had at least one of the symptoms of paroxysmal cough, whoop, or

Demographic information and clinical features

A total of 948 patients from Zhejiang Province with suspected pertussis and aged from 21 days to 14 years (median age 5 months and 21 days, 61.8% male) were enrolled between January 1 and December 31 2016. A total of 692 (73.0%) were aged <1 year. Nasopharyngeal swabs were positive for B. pertussis and Bordetella parapertussis by culture in 126 (13.3%) and four (0.4%) of all patients, respectively. The patients with positive culture results of B. pertussis were significantly younger than those

Discussion

Pertussis is a notifiable disease, and it is usually clinically diagnosed in China because laboratory methods – such as culture, PCA or ELISA – are not routinely used. The current institute is one of the few hospitals where culture for B. pertussis is available. The pertussis patients were culture confirmed in the present study, and most of the patients were aged <6 months and had not been vaccinated with diphtheria-pertussis-tetanus vaccine; thus, they were at risk of pertussis [6], [15], [16].

Funding

This work was supported by Natural Science Foundation of Zhejiang Povince, China (LGF 18H010001).

Competing interests

The authors have no conflicts of interest to declare.

Ethical approval

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.

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