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□ CASE REPORT □

A Chronic Respiratory Pasteurella multocida Infection IsWell-Controlled by Long-Term Macrolide Therapy

Masafumi Seki 1, Tomomi Sakata 2, Masahiro Toyokawa 2, Isao Nishi 2 and Kazunori Tomono 1

Abstract

A 57-year-old woman with severe bronchiectasis frequently received antibiotics, including penicillin, for

acute exacerbations due to Pasteurella multocida. Although the bacteria showed a decrease in antibiotic sus-

ceptibility, her symptoms and X-ray findings became stable, and severe exacerbations were not observed for

the last few years after a low-dose erythromycin treatment was started. The development of a respiratory in-

fection with Pasteurella multocida is relatively uncommon, but it can be controlled by immunomodulation

which is associated with long-term macrolide therapy.

Key words: chronic respiratory infection, macrolides, Pasteurella multocida, opportunistic pathogen

(Intern Med 55: 307-310, 2016)(DOI: 10.2169/internalmedicine.55.4929)

Introduction

Pasteurella species are highly prevalent among animals

and have become one of the most important opportunistic

pathogens that are associated with epizootic outbreaks in hu-

mans (1). Among these species, P. multocida is the most

prevalent in human infections, and it is usually acquired

through contact with animals; including bites, scratches, or

contact with mucous secretions derived from dogs, cats, and

birds (2, 3).

Common symptoms of pasteurellosis on human skin are

swelling, diffuse or localized inflammation with redness and

pain, and bloody or purulent exudate at the animal bite

sites (1, 4). However, it is possible that a respiratory infec-

tion can develop in patients with chronic pulmonary dis-

ease (1, 4, 5). In these cases, pasteurellosis can also present

as a severe bilateral pneumonia and cause lymphadenopathy,

epiglottitis, and abscess formation with increased sputum

and chest pain (5).

In this report, a case of chronic respiratory infection due

to P. multocida with bronchiectasis is described. Bacteria

isolated from the patient’s sputum showed a decrease in an-

tibiotic susceptibility after the patient had received treatment

for frequent exacerbations, but the patient’s condition could

be successfully controlled by long-term macrolide therapy.

Case Report

A 57-year-old woman visited our university hospital in

December 2011 with a cough, chronic sputum, and mild re-

current exertional dyspnea. She had a previous history of se-

vere pneumonia when she was 10 years old and bronchiec-

tasis that affected both lungs (Fig. 1A, D).

Physical examination showed a thin, slightly febrile

woman, with slight clubbing of the fingers and no cyanosis.

Coarse breath sounds and scattered inspiratory rhonchi were

heard throughout both lung fields. Laboratory data included

a WBC count of 6,320/μL (neutrophils 70.3%) and a C-

reactive protein (CRP) level of 0.37 mg/dL.

P. multocida, which is known to colonize dogs, was iso-

lated from her sputum (Fig. 2), and it demonstrated suscep-

tibility to antibiotics at that time (Table). Phagocytosis of

the bacilli was observed, and P. multocida was semi-

quantitatively cultured as (3+), which suggested >107 cfu/mL.

No mycobacterial species or Pseudomonas species were col-

lected from her sputum during the follow-up period. Her

condition was generally good, but she developed frequent

exacerbations every one or two months after the first visit.

She received antibiotics, including oral amoxicillin/clavula-

１Division of Infection Control and Prevention, Osaka University Hospital, Japan and ２Laboratory for Clinical Investigation, Osaka University

Hospital, Japan

Received for publication January 9, 2015; Accepted for publication March 15, 2015

Correspondence to Dr. Masafumi Seki, sekimm-ngs@umin.ac.jp

Intern Med 55: 307-310, 2016 DOI: 10.2169/internalmedicine.55.4929

308

Figure　1.　Chest X-ray (A-C) and computed tomography (CT; D-F) images of a 57-year-old woman with chronic Pasteurella multocida infection with bronchiectasis. X-ray and CT images in December 2011 (A, D) show moderate bronchiectasis and granular shadows (arrows), but images in December 2012 (B, E) show severe changes after frequent exacerbations without erythromycin administration during this period. However, images in April 2014 (C, F) are similar to those in December 2012.

A B C

D E F

Figure　2.　Gram staining of the sputum from a 57-year-old woman with chronic Pasteurella multocida infection with bron-chiectasis. Many small, Gram-negative, rod-shaped bacilli (ar-rows) are observed with neutrophils (arrowheads). ×1,000.

nate and minocycline, from December 2011 to 2012 in the

outpatient department and became afebrile each time, but

she required home oxygen therapy that started in July 2012.

In December 2012, P. multocida was continuously iso-

lated from her sputum and semi-quantitative culture results

still indicated an abundant amount of P. multocida (3+), even

though she ceased being a pet owner. P. multocida drug sus-

ceptibility decreased, especially to penicillin (Table). Her

chest radiography also showed increased consolidations,

centrilobular granular shadows with mucoid impaction, and

cystic bronchiectasis (Fig. 1B, E).

Due to concerns about the increase in antibiotic resis-

tance, the patient was given oral erythromycin (400 mg/day)

in January 2013, which was half of the usual dose, but ap-

propriate for use as an immunomodulatory drug, although

the isolated P. multocida showed no susceptibility to eryth-

romycin from the start of follow-up for this patient (Table).

After she started to receive the erythromycin, the amount

of sputum did not change and it became serous, although

the number of P. multocida remained high (3+). Furthermore,

no exacerbations with respiratory symptoms had been ob-

served, and the chest imaging results did not reveal a pro-

gression of symptoms in December 2014 (Fig. 1C, F).

Discussion

Pulmonary infections with P. multocida are uncommon,

but there has been a recent increase in the number of such

cases being reported (1). The patients are usually middle-

aged men with a clinical diagnosis of chronic respiratory

diseases, including bronchiectasis. In addition, about 80% of

the reported patients have a history with antecedent expo-

sure to infected animals and pets. Although the present pa-

tient was a woman, her age, underlying pulmonary disease,

and pet history were consistent with previously reported

cases (2, 4).

Intern Med 55: 307-310, 2016 DOI: 10.2169/internalmedicine.55.4929

309

Table.　Drug Susceptibility of Pasteurella multocida Isolated from the Patient (sputum).

Date 2011 Dec 2012 Jul 2012 Dec 2013 Jan 2013 May 2013 Dec 2014 Apr Ampicillin 0.25, S 0.5, S 2, R 1, R 2, R >4, R 2, R

Penicillin G 0.12, S 0.5, S 1, R 1, R >4, R 1, R 2, R Ceftriaxon 0.12, S 0.12, S 0.12, S 0.12, S 0.12, S 0.12, S 0.12, S

AMPC/CVA 1, S 1, S 2, R 1, R 1, S 1, R 2, R

Erythromycin >1, R >1, R >1, R >1, R >1, R >1, R >1, R

Clarithromycin >1, R >1, R Azithromycin 2, R 1, S Tetracycline 0.5, S 1, S 0.5, S 0.5, S 2, R 2, R Levofloxacin 0.25, S 0.25, S 0.25, S 0.25, S 0.25, S 0.25, S 0.25, S

Sulfamethoxazole /Trimethoprim 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S

Each number indicates minimum inhibitory concentration (MIC) of each antibiotic for P. multocida.AMPC/CVA: amoxicillin/clavulanate, S: sensitive, R: resistant

P. multocida sometimes causes sepsis and bacteremia in

many animals, but the most common human infection with

P. multocida is a local cellulitis following animal-inflicted

wounds that are related to dogs or cat bites and

scratches (1, 3). Recognition of clinical disease with P. mul-tocida requires a knowledge of its pathogenicity because a

delay in diagnosis may result in the progression of severe

pneumonia and abscess formation (1).

The present patient ceased being a pet owner and received

antibiotics after it was discovered that she had a P. multo-cida infection, but P. multocida continued to be isolated

from her sputum in high numbers (3+) and was resistant to

antibiotics, which made her condition worse. Therefore, a

treatment strategy using something other than antimicrobials

was needed.

It is known that 14 or 15-membered ring macrolides, in-

cluding erythromycin, clarithromycin, and azithromycin, not

only have antibacterial effects, but also immunomodulatory

effects, which frequently result in more host effects rather

than effects against the targeted microorganisms (6-10). The

effects of long-term treatment with macrolide antibiotics

have been demonstrated in clinical and basic research, and

the use of macrolide antibiotics for chronic pulmonary dis-

eases and infections, including diffuse panbronchiolitis

(DPB) (11), as well as other inflammatory airway disorders,

such as cystic fibrosis (CF) are currently being estab-

lished (12).

Macrolides are considered to reduce mucus hypersecretion

and cytokine expression in host factors. Tamaoki et al. re-

ported that macrolides inhibit mucus viscosity by chloride

channel inhibition (13). In addition, we previously reported

the mechanisms of action and effectiveness of these agents

in DPB, lipopolysaccharide (LPS)-related pulmonary disor-

ders, and influenza (6, 8, 9). Macrolides may inhibit the

overproduction of mucin and cytokines in airways, which is

mediated through upstream molecules, including NF-kappa

B and the related mitogen-activated protein (MAP) kinases

in the infected lungs, which decreases inflammation after

treatment.

Furthermore, it has been shown that macrolides control

the cell-to-cell communication or quorum-sensing system in

chronic Pseudomonas aeruginosa infections by regulating

the expression of P. aeruginosa virulence factors (10). In

Pasteurella species including P. multocida, these bacilli also

have similar quorum-sensing systems, and the bacterial cul-

ture supernatants have active molecules that regulate the

autoinducers of their quorum-sensing systems (14). These

data suggest that macrolides might also be able to effec-

tively treat P. multocida-infected patients by mediating the

regulation of quorum-sensing systems in this pathogen.

In conclusion, a case of chronic pulmonary P. multocidainfection with bronchiectasis was herein described. P. multo-cida developed drug-resistance because of recurrent antibi-

otic administration, and furthermore, it was isolated persis-

tently and abundantly. However, the patient’s condition sta-

bilized after erythromycin was administered. Macrolides

may also be useful for P. multocida infection, similar to

chronic Pseudomonas infection and inflammatory lung dis-

eases, including DPB and CF, as immunomodulatory agents,

in addition to their antibiotic effects.

The authors state that they have no Conflict of Interest (COI).

Masafumi Seki and Tomomi Sakata contributed equally to this

work.

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