A Chronic Respiratory Pasteurella Multocida Infection Is Well-Controlled by Long-Term Macrolide Therapy

□ CASE REPORT □

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

Masafumi Seki 1, Tomomi Sakata 2, Masahiro Toyokawa 2,IsaoNishi2 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 susceptibility, 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 infection 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)

be successfully controlled by long-term macrolide therapy. Introduction Case Report Pasteurella species are highly prevalent among animals and have become one of the most important opportunistic A 57-year-old woman visited our university hospital in pathogens that are associated with epizootic outbreaks in hu- December 2011 with a cough, chronic sputum, and mild re- mans (1). Among these species, P. multocida is the most current exertional dyspnea. She had a previous history of se- prevalent in human infections, and it is usually acquired vere pneumonia when she was 10 years old and bronchiec- through contact with animals; including bites, scratches, or tasis that affected both lungs (Fig. 1A, D). contact with mucous secretions derived from dogs, cats, and Physical examination showed a thin, slightly febrile birds (2, 3). woman, with slight clubbing of the fingers and no cyanosis. Common symptoms of pasteurellosis on human skin are Coarse breath sounds and scattered inspiratory rhonchi were swelling, diffuse or localized inflammation with redness and heard throughout both lung fields. Laboratory data included pain, and bloody or purulent exudate at the animal bite a WBC count of 6,320/μL (neutrophils 70.3%) and a C- sites (1, 4). However, it is possible that a respiratory infec- reactive protein (CRP) level of 0.37 mg/dL. tion can develop in patients with chronic pulmonary dis- P. multocida, which is known to colonize dogs, was iso- ease (1, 4, 5). In these cases, pasteurellosis can also present lated from her sputum (Fig. 2), and it demonstrated suscep- as a severe bilateral pneumonia and cause lymphadenopathy, tibility to antibiotics at that time (Table). Phagocytosis of epiglottitis, and abscess formation with increased sputum the bacilli was observed, and P. multocida was semi- and chest pain (5). quantitatively cultured as (3+), which suggested >107 cfu/mL. In this report, a case of chronic respiratory infection due No mycobacterial species or Pseudomonas species were col- to P. multocida with bronchiectasis is described. Bacteria lected from her sputum during the follow-up period. Her isolated from the patient’s sputum showed a decrease in an- condition was generally good, but she developed frequent tibiotic susceptibility after the patient had received treatment exacerbations every one or two months after the first visit. for frequent exacerbations, but the patient’s condition could 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, [email protected]

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

A B C

D E F

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.

centrilobular granular shadows with mucoid impaction, and cystic bronchiectasis (Fig. 1B, E). Due to concerns about the increase in antibiotic resistance, 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 erythromycin 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- Figure 2. Gram staining of the sputum from a 57-year-old served, and the chest imaging results did not reveal a pro- woman with chronic Pasteurella multocida infection with bron- gression of symptoms in December 2014 (Fig. 1C, F). chiectasis. Many small, Gram-negative, rod-shaped bacilli (arrows) are observed with neutrophils (arrowheads). ×1,000. Discussion

Pulmonary infections with P. multocida are uncommon, nate and minocycline, from December 2011 to 2012 in the but there has been a recent increase in the number of such outpatient department and became afebrile each time, but cases being reported (1). The patients are usually middle- she required home oxygen therapy that started in July 2012. aged men with a clinical diagnosis of chronic respiratory In December 2012, P. multocida was continuously iso- diseases, including bronchiectasis. In addition, about 80% of lated from her sputum and semi-quantitative culture results the reported patients have a history with antecedent expo- still indicated an abundant amount of P. multocida (3+), even sure to infected animals and pets. Although the present pa- though she ceased being a pet owner. P. multocida drug sus- tient was a woman, her age, underlying pulmonary disease, ceptibility decreased, especially to penicillin (Table). Her and pet history were consistent with previously reported chest radiography also showed increased consolidations, cases (2, 4).

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

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 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S 0.5, S /Trimethoprim 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 treatment. many animals, but the most common human infection with Furthermore, it has been shown that macrolides control P. multocida is a local cellulitis following animal-inflicted the cell-to-cell communication or quorum-sensing system in wounds that are related to dogs or cat bites and chronic Pseudomonas aeruginosa infections by regulating scratches (1, 3). Recognition of clinical disease with P. m u l - the expression of P. aeruginosa virulence factors (10). In tocida requires a knowledge of its pathogenicity because a Pasteurella species including P. multocida, these bacilli also delay in diagnosis may result in the progression of severe have similar quorum-sensing systems, and the bacterial cul- pneumonia and abscess formation (1). ture supernatants have active molecules that regulate the The present patient ceased being a pet owner and received autoinducers of their quorum-sensing systems (14). These antibiotics after it was discovered that she had a P. multo- data suggest that macrolides might also be able to effec- cida infection, but P. multocida continued to be isolated tively treat P. multocida-infected patients by mediating the from her sputum in high numbers (3+) and was resistant to regulation of quorum-sensing systems in this pathogen. antibiotics, which made her condition worse. Therefore, a In conclusion, a case of chronic pulmonary P. multocida treatment strategy using something other than antimicrobials infection with bronchiectasis was herein described. P. multo- was needed. cida developed drug-resistance because of recurrent antibi- It is known that 14 or 15-membered ring macrolides, in- otic administration, and furthermore, it was isolated persis- cluding erythromycin, clarithromycin, and azithromycin, not tently and abundantly. However, the patient’s condition sta- only have antibacterial effects, but also immunomodulatory bilized after erythromycin was administered. Macrolides effects, which frequently result in more host effects rather may also be useful for P. multocida infection, similar to than effects against the targeted microorganisms (6-10). The chronic Pseudomonas infection and inflammatory lung dis- effects of long-term treatment with macrolide antibiotics eases, including DPB and CF, as immunomodulatory agents, have been demonstrated in clinical and basic research, and in addition to their antibiotic effects. the use of macrolide antibiotics for chronic pulmonary diseases and infections, including diffuse panbronchiolitis The authors state that they havenoConflictofInterest(COI). (DPB) (11), as well as other inflammatory airway disorders, such as cystic fibrosis (CF) are currently being estab- Masafumi Seki and Tomomi Sakata contributed equally to this lished (12). work. Macrolides are considered to reduce mucus hypersecretion References and cytokine expression in host factors. Tamaoki et al. reported that macrolides inhibit mucus viscosity by chloride 1. Wilson BA, Ho M. Pasteurella multocida: from zoonosis to cellu- channel inhibition (13). In addition, we previously reported lar microbiology. Clin Microbiol Rev 26: 631-655, 2013. the mechanisms of action and effectiveness of these agents 2. Beyt BE Jr, Sondag J, Roosevelt TS, Bruce R. Human pulmonary pasteurellosis. JAMA 242: 1647-1648, 1997. in DPB, lipopolysaccharide (LPS)-related pulmonary disor- 3. Holst E, Rollof J, Larsson L, Nielsen JP. Characterization and dis- ders, and influenza (6, 8, 9). Macrolides may inhibit the tribution of Pasteurella species recovered from infected humans. J overproduction of mucin and cytokines in airways, which is Clin Microbiol 30: 2984-2987, 1992. mediated through upstream molecules, including NF-kappa 4. Rollof J, Johansson PJ, Holst E. Severe Pasteurella multocida in- B and the related mitogen-activated protein (MAP) kinases fections in pregnant women. Scand J Infect Dis 24: 453-456, 1992. in the infected lungs, which decreases inflammation after

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

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