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71（ 21 ）〈Case Report〉

A case of necrotizing pneumonia caused by co-infection
with influenza B and a Panton–Valentine leucocidin
negative community acquired methicillin–resistant
Staphylococcus aureus strain
Keiji Mouri1, Yoshihiro Kobashi1, *, Shigeki Kato1,
Tetsuo Yamaguchi2 and Mikio Oka1
1

Department of Respiratory Medicine, Kawasaki Medical School2
Department of Microbiology and Infectious Diseases,
Toho University School of Medicine(Received for publication January 25, 2018)

A 63-year-old woman visited our hospital complaining of fever and dyspnea. Her
inﬂammatory response was strongly positive, with hyperglycemia, severe hypoxia, ahigh level of procalcitonin, and an inﬂuenza B antigen-positive result. Chest
computed tomography (CT) on admission showed multiple nodules with inﬁltrative
shadows in the bilateral lung ﬁelds, and gram-positive coccus with phagocytosis byneutrophils was observed in a sputum sample. Although treatments using sulbactam/
ampicillin (SBT/ABPC) and azithromycin (AZM) plus peramivir were initiated, theclinical effect was poor due to the delay of administration of linezolid (LZD).
Because methicillin-resistant Staphylococcus aureus (MRSA) was isolated fromsputum, treatments were changed to LZD plus AZM. Molecular analysis of the
MRSA isolate showed as follows: multilocus sequence typing (MLST) 8,
staphylococcal cassette chromosome mec (SCCmec) typeIV, spa type t1767, PantonValentine leucocidin (PVL)-negative, arginine catabolic mobile element (ACME)negative, and toxic shock syndrome toxin-1 (TSST)-1-positive. Inﬂuenza B and
TSST-1 produced by community acquired MRSA (CA-MRSA) may have been
involved in the formation of necrotizing pneumonia in this patient. However, she
improved following the administration of peramivir and LZD.

*Correspondence to Yoshihiro Kobashi, Department of Respiratory Medicine, Kawasaki Medical School, 577 Matsushima,

Kurashiki, 701–0192, Japan
Tel.: ＋81–86–462–1111, Fax: ＋81–86–464–1041, E-mail: yoshihiro@med.kawasaki-m.ac.jp

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Introduction
Methicillin-resistant Staphylococcus aureus (MRSA), which has the staphylococcal cassettechromosome mec (SCCmec), has been a known nosocomial pathogen since 19611). Another class of
MRSA, known as community-acquired MRSA (CA-MRSA), ﬁrst emerged in the community from1997 to 1999, and has since become a major concern worldwide2). CA-MRSA is mainly associatedwith skin and soft tissue infections, but sometimes with unusual and severe infections such as bacteremia, sepsis, and necrotizing pneumonia in healthy individuals without risk factors2, 3).
CA-MRSA has type IV or V SCCmec, which exhibits low minimum inhibitory concentration(MIC) values for oxacillin or imipenem, is resistant to β-lactam agents only, and often produces
Panton-Valentine leucocidin (PVL), a toxin acting against polymorphonuclear neutrophils andmonocytes2) in western countries. The PVL-positive sequence type (ST) 8/SCCmecIV MRSA in
the United States (USA300) is one of the most common and best characterized forms of CAMRSA4). USA300 carries the arginine catabolic mobile element (ACME), which is considered topromote the colonization and survival of USA3004). In Japan, most CA-MRSA consists of ST8
CA-MRSA, which is negative for PVL and ACME5–7). We report a rare case of necrotizing pneumonia due to co-infection of inﬂuenza B and CA-MRSA, showing negative responses for PVL
and ACME, but a positive response for toxic shock syndrome toxin-1 (TSST-1).

Case Report
A 63-year-old woman with diabetes mellitus (receiving no medication) was admitted to our
hospital complaining of fever and dyspnea that had started three days earlier (April 1, 2014). She
had a smoking history (30 cigarettes per day for 40 years), but there were no other potentiallycontributing factors excluding diabetes mellitus. She was not received inﬂuenza vaccine inoculation in 2013–2014. She had never been abroad. Her consciousness level was 1 on the Japan Coma
Scale (14 on the Glasgow Coma Scale) on arrival and her vital signs were as follows: blood pressure 150/76 mmHg, pulse 130/min (regular), respiratory rate 30/min, oxygen saturation 95% (O2
5 L mask), body temperature 38.6°C. On physical examinations, coarse crackles and rhonchi wereauscultated in both lung ﬁelds. Laboratory examinations on admission are shown in Table 1. Inﬂammatory response including WBC and CRP were markedly elevated. Glucose and HbA1c, related to diabetes mellitus, were also markedly elevated. Mild liver dysfunction was also recognized. Arterial blood showed respiratory and metabolic acidosis, elevation of AaDO2, anddegradation of PaO2/FIO2. Concerning serological examinations, elevation of procalcitonin and apositive response to inﬂuenza B antigens were noted. Although the blood cultures for common
bacteria, urinary pneumococcal antigens, and urinary legionella antigens were negative, Gram

Table 1. Laboratory examination data on admission

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Fig. 1. Chest radiograph on admission showing inﬁltration shadowsin the right middle and left middle and lower lung ﬁelds

staining of purulent sputum (Miller-Jones classiﬁcation: P3) revealed many inﬂammatory cells
phagocytizing gram-positive coccus bacilli.
Regarding the radiological ﬁndings on admission, inﬁltrative shadows appeared in the right
middle and left middle and lower lung ﬁelds on chest radiograph (Figure 1). Inﬁltrative shadowsand centrilobular nodular shadows were recognized in the right upper and lower lobes and left
upper and lower lobes on chest computed tomography (CT) (Figure 2).
We showed the clinical course of this case in Figure 3. Although antibiotic therapy using sulbactam/ampicillin (SBT/ABPC), azithromycin (AZM) and peramivir was immediately initiatedafter admission, respiratory failure advanced and necessitated mechanical ventilation support on
day 1. From the sputum culture on admission and aspiration sputum culture of a bronchoscopic
specimen, MRSA was detected. The antimicrobial susceptibility of the isolated MRSA is shownin Table 2. Under the diagnosis of CA-MRSA pneumonia according to the deﬁnition described by
Naimi et al.8), the antibiotic therapy was changed to combination therapy consisting of Linezolid(LZD) and AZM on day 6. Although the respiratory condition gradually improved, several cavitary lesions appeared in both lungs with atelectasis of the left lower lobe on chest CT on day 10(Figure 4). We considered that the pneumonia due to CA-MRSA had deteriorated to a pulmonary
abscess due to the delay of administration of LZD. However, because Pseudomonas aeruginosa
and Klebsiella pneumoniae were newly detected from the sputum culture, tazobactam/piperacillin(TAZ/PIPC) was added as antibiotic therapy. The clinical course of this patient gradually improved, and she was discharged on day 22.
Whole-genome sequencing of the MRSA isolate (strain TUM 14604) was carried out by

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75（ 25 ）Fig. 2. Chest CT on admission showing inﬁltrative shadows and centrilobular shadows in theright lower lobes and left upper and lower lobes

Fig. 3. The clinical course of this case showing with drugs for treatment, the transitional changeof respiratory conditions and inﬂammatory responses

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Table 2. Antimicrobial susceptibility of isolated MRSA

next-generation sequencing using MiSeq (Illumina, San Diego, CA, USA). The draft genome sequence data were assembled using CLC Genomics Workbench v 9.5.1 software (Qiagen, Aarhus,
Denmark). Multilocus sequence typing (MLST) was performed using 7 housekeeping genes, andan allelic proﬁle was obtained from the MLST website (http://www.mlst.net/). SCCmectype andspa type were determined, and the presence of virulence genes was checked. The sequence type
was ST 8/SCCmec typeIV, and the spa type was t1767. The results for virulence genes were as
follows: PVL (lukSF-pv)-negative, ACME (arcA)-negative, exfoliative toxin (ET)(eta, etb)-negative, and TSST-1 (tst-1)-positive.

Discussion
We encountered a patient with diabetes mellitus without medication who showed necrotizing
pneumonia caused by co-infection with inﬂuenza B and PVL-negative CA-MRSA. Although
there was a report that the frequency of MRSA increased among elderly patients with community-acquired pneumonia (CAP)9), there are few reports concerning necrotizing pneumonia due toco-infection with inﬂuenza B and CA-MRSA in Japan.

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77（ 27 ）Fig. 4. Chest CT on day 10 admission showing several newly observed cavity lesions in both
lungs with atelectasis of the left lower lobe

CA-MRSA corresponds to MRSA infection occurring in patients without risk factors for
MRSA infection, such as a past history of admission to a hospital or nursing home, surgery, hemodialysis, and use of an intravenous reservoir8, 10). Naimi et al. deﬁned CA-MRSA as satisfying
the following criteria: (1) the detection of MRSA in clinical specimens obtained from an outpatient or inpatient within 48 hours after admission with infectious signs, (2) no past history of
MRSA detection in clinical specimen cultures, (3) no past history of admission to a hospital or
nursing home within the last one year, surgical operation, or hemodialysis, and (4) no use of areservoir such as an intravenous catheter8). Because our case satisﬁed the above four criteria andshowed a positive response for the inﬂuenza B antigen, we diagnosed the patient with necrotizing
pneumonia due to co-infection with inﬂuenza B and CA-MRSA.
Regarding the selection of antibiotics for this patient, we considered Gram-positive coccus
bacilli as the causative microorganism because a Gram-positive coccus was isolated from the purulent sputum and aspiration sputum bronchoscopic specimens on day 1. Therefore, we initiatedantibiotic therapy using SBT/ABPC and AZM combined with peramivir for inﬂuenza B infection.
On day 6, the culture examination results for the gram-positive coccus identiﬁed MRSA. While
CA-MRSA showed resistance to penicillin and cephem antibiotics, it showed sensitivity to anti-78（ 28 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Apr. 2018MRSA drugs such as vancomycin (VCM), arbekacin (ABK), teicoplanin (TEIC), LZD, daptomycin (DAP), minocycline (MINO), levoﬂoxacin (LVFX), and sulfamethazole-trimethoprim (ST).
The MRSA of this patient showed a susceptibility pattern different from hospital-acquired MRSA
(HA-MRSA). It was reported that sensitivity of CA-MRSA to erythromycin (EM) has not beenpreserved in Asia11), but the CA-MRSA of this patient showed sensitivity to both EM andclindamycin (CLDM) (Table 2). Finally, we changed SBT/ABPC to LZD from day 6. The reason
was that treatment was not clinically effective with VCM or TEIC and was more effective with
LZD or CLDM, which suppressed the production of Staphylococcus aureus toxin in previous reports8–12). Otherwise, we administered LZD considering both the comparatively high MIC(2 μg/mL) for VCM in this patient and excellent transmission to the lung tissue compared to
VCM or TEIC for the treatment of CA-MRSA13). However, the patientʼs condition slightly worsened, with a newly detected infection due to the gram-negative bacilli (Klebsiella pneumoniae
and Pseudomonas aeruginosa). Radiologically, several cavity lesions appeared in both lung ﬁelds
adding to inﬁltration shadows on day 10 (Figure 3). Therefore, we initiated combined therapy of
TAZ/PIPC, CAM and LZD. Finally, this patient showed improvement on day 22.
As for the molecular analysis, in this case the CA-MRSA revealed the following ﬁndings: ST
8/SCCmec/t1767, PVL gene-negative, ACME-negative, ET-negative, and TSST-1-positive. Finally, this clone differed from the USA300 clone, and was the same genotype as CA-MRSA/J,
the Japanese dominant CA-MRSA clone6). While most cases of CA-MRSA isolated in the USA
are PVL gene-positive, CA-MRSA isolated in Japanese cases is PVL gene-negative7,14). Among
PVL-positive CA-MRSA, it was reported that PVL was associated with the strength of pathogenesis and even healthy young adults developed fatal necrotizing pneumonia or sepsis in previous
studies15,16). However, PVL-negative CA-MRSA caused necrotizing pneumonia (cavity formation) and was associated with a poor prognosis in Japan2,16, 18–20). Considering these ﬁndings, thepathogenicity and prognosis associated with CA-MRSA may be unrelated to the PVL gene andmay be related to other factors. In this case, the CA-MRSA was only TSST-1 positive. TSST-1 isa superantigen that suppresses the motility of polymorphonuclear neutrophils by inhibiting theexpression of MRSA exoproteins2). Orii et al. reported a fatal case of necrotizing fasciitis due to a
PVL-negative MRSA strain that expressed TSST-119) and Otera et al. also reported a fetal case of
necrotizing pneumonia due to a PVL-negative and TSST-1 positive MRSA strain20). They suggested that the pathogenesis is the result of a factor other than PVL. The difference between thepatient reported by Otera et al.20) and our case could have been inﬂuenza B virus infection. The
synergistic effect due to TSST-1 and the products from inﬂuenza B infection may affect the formation of necrotizing pneumonia. It is necessary to perform epidemiological research involving
severe cases of CA-MRSA infection and clarify pathogenetic factors other than PVL gene analysis.
Defres et al. reported ﬁndings suggesting CA-MRSA infection as follows: inﬂuenza-likeApr. 2018

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79（ 29 ）syndrome, severe respiratory symptoms with rapidly progressive pneumonia, fever over 39°C,
hemoptysis, hypotension, leukopenia, chest radiograph showing multilobar inﬁltrates that may
have cavitated, recent travel to an endemic area and recent contact with CA-MRSA, belonging toa group associated with increased rates of CA-MRSA colonization, and a previous family historyof recurrent furuncles or skin abscess9).
Based on this CA-MRSA case, when Staphylococcus aureus is detected in a case of CAP for
which standard antibiotic treatment is refractory, we must consider CA-MRSA as a causative microorganism and initiate combined chemotherapy, including anti-MRSA antibiotics, at an earlystage.
Conﬂict of Interest
The authors declare that they have no conﬂict of interest.

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