Pediatric pneumonia death caused by community-acquired methicillin-resistant Staphylococcus aureus, Japan.

To the Editor: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), which carries genes for Panton-Valentine leukocidin (PVL), has become a major concern worldwide (1-3). CA-MRSA is mainly associated with skin and soft tissue infections in young, otherwise healthy, persons in the community (3) and also with life-threatening sepsis and community-acquired pneumonia (preceded by influenza) (1,3,4). The role of PVL in the pathogenesis of staphylococcal infections is controversial. Whereas Labandeira-Rey et al. (5) provided data that PVL, in combination with staphylococcal protein A, destroys respiratory tissue and bacteria-engulfing immune cells, Voyich et al. (6) and Bubeck Wardenburg et al. (7) showed that PVL was not essential for the pathogenesis of skin disease, sepsis, or pneumonia in a mouse model.

Several types of CA-MRSA clones exist, e.g., CA-MRSA belonging to multilocus sequence type (ST) 1 (called the USA400 clone) and ST8 (called the USA300 clone), which have been major clones in North America (recently, USA300 is becoming more prominent); CA-MRSA belonging to ST80, which has been a major clone in Europe; and CA-MRSA belonging to ST30, which is distributed worldwide, including Japan (2,8). MRSA carrying the PVL gene (a marker of CA-MRSA [ST30]) comprises 0.1% of MRSA isolated in hospitals in Japan (9). We describe a fatal case of pediatric pneumonia and septic shock from CA-MRSA in Japan.

A 16-month-old, previously healthy boy was admitted to the hospital for fever and shortness of breath on August 30, 2006. He had had cold-like symptoms for 14 days and fever for the 2 previous days. On examination, hordeolum of the right eyelid and cyanosis were observed; the patient's blood pressure was 106/ (undetectable) mm Hg, tachycardia 185 beats/ min, tachypnea 72 breaths/rain, and temperature 39.8[degrees]C. He had bilateral coarse breath sounds, and bronchovesicular breath sounds over the right lung. Chest radiography indicated lobar consolidation and pleural effusion on the right side. Laboratory analysis showed leukocytopenia, thrombocytopenia, elevated C-reactive protein level, and hypoxemia.

Intravenous administration of sulbactam/ampicillin and cefotaxime, and oxygen inhalation was started. Oxygen saturation did not improve, and laboratory values of disseminated intravascular coagulation (DIC) were observed: platelet count 121 K/[mm.sup.3], fibrinogen level 528 mg/dL, fibrin degradation products 37.7 [micro]g/mL, prothrombin time 1.86 international normalized ratio, and D-dimer 37.7 [micro]g/mL. The condition was considered septic shock, and consequently the boy was transferred to the pediatric intensive care unit, where he required intubation and mechanical ventilation.

Sulbactam/ampicillin was switched to meropenem, and cefotaxime was continued. On day 2 after admission, chest radiography showed bilateral consolidation. On day 3, blood culture yielded MRSA, and cefotaxime was changed to vancomycin. Meropenem therapy was continued to cover possible mixed bacterial infection. Immunoglobulin therapy and DIC syndrome treatment (nafamostat mesilate, ulinastatin, freeze-dried concentrated human antithrombin III) were also started. On day 4, computed tomographic examination detected pneumothorax and athelectasis. Because laboratory data confirmed the presence of only MRSA, meropenem was changed to flomoxef (which belongs to the oxacephem family of [beta]-lactam antimicrobial agents) on the expectation that a possible synergistic effect of flomoxef and vancomycin might occur. No major changes occurred on days 5 and 6. On day 7, in addition to bilateral infiltrates on chest radiography, the oxygen index was 65 (partial pressure of arterial oxygen/ fraction of inspired oxygen), and the patient was considered to have acute respiratory distress syndrome. A percutaneous cardiopulmonary support system (a portable heart-lung machine that provides temporary circulatory support) was used, but in spite of treatment, there was no improvement, and the child died on day 10 after admission (September 8). An autopsy was not performed.

Molecular characterization of MRSA isolated from the blood was performed as described previously (8,9). Isolated MRSA (strain NN32) was positive for PVL, belonging to ST30:spa 19:staphylococcal cassette chromosome mec (SCCmec)IVa, and was resistant to only [beta]-lactam antimicrobial agents (Table).

To date, all cases of PVL-positive CA-MRSA infections officially reported in Japan were caused by strains belonging to ST30 (9). All these strains can be classified into 2 types on the basis of spa type (Table), for example, ST30:spal9:SCCmecIVc. This type includes strain NN1, isolated from an 11-month-old patient with bullous impetigo (8); strain NN 12, isolated from a 17-year-old patient with cutaneous abscess/osteomyelitis (8); strain NN31, isolated from an 18-year-old patient with pelvic abscesses (9); and strain EB00449, isolated from a 27-year-old patient with cutaneous abscesses (9). Another type is ST765 (single locus variant of ST30):spa43:SCCmecIVx. This type includes strain DB00319, isolated from a 61-year-old hospital inpatient (9).

The molecular characteristics of strain NN32 were similar to those of strain NN 1, except for SCCmecIV subtypes (Table). Moreover, pulsed-field gel electrophoresis patterns (data not shown) and the PVL gene sequences of the 2 strains (NN32 and NN1) were identical (Table).

This case of CA-MRSA ST30 infection in a child represents a progression from common cold-like symptoms (occurring outside the influenza season) to fatal pneumonia, despite intensive therapy, including the administration of sensitive antimicrobial agents. CA-MRSA ST30 contains several genes that mediate adhesion (e.g., cna and bbp) and toxin genes (PVL and egc, which encode for at least 5 superantigens, including staphylococcal enterotoxin G, I, M, N, and O). The gene cluster egc is associated with septic shock (10). Further studies are needed to clarify the pathogenesis of community-acquired pneumonia caused by CA-MRSA.

Acknowledgments

We thank Yasuhisa Ueda, Yuki Bando, and Keisuke Sunagawa for clinical suggestions and Wataru Higuchi, Hirokazu Isobe, Soshi Dohmae, Hassan Zaraket, Shizuka Yabe, Misao Takano, and Kyoko Ozaki for technical assistance.

This study was supported by a grant from the Japan Science and Technology Agency, Japan.

References

(1.) Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus--Minnesota and North Dakota, 1997-1999. JAMA. 1999;282:1123 5. DOI: 10.1001/jama. 282.12.1123

(2.) Tristan A, Bes M, Meugnier H, Lina G, Bozdogan B, Courvalin P, et al. Global distribution of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus, 2006. Emerg Infect Dis. 2007; 13:594-600.

(3.) Zetola N, Francis JS, Nuermberger EL, Bishai WR. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis. 2005;5:275 86. DOI: 10.1016/S14733099(05)70112-2

(4.) Hageman JC, Uyeki TM, Francis JS, Jernigan DB, Wheeler JG, Bridges CB, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12:8944.

(5.) Labandeira-Rey M, Couzon F, Boisset S, Brown EL, Bes M, Benito Y, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315:1130-3. DOI: 10.1126/ science.1137165

(6.) Voyich JM, Otto M, Mathema B, Braughton KR, Whitney AR, Welty D, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J Infect Dis. 2006;194:1761-70. DOI: 10.1086/509506

(7.) Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med. 2007;13:1405-6. DOI: 10.1038/nm1207-1405

(8.) Takizawa Y, Taneike I, Nakagawa S, Oishi T, Nitahara Y, Iwakura N, et al. A Panton-Valentine leucocidin (PVL)-positive community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strain, another such strain carrying a multiple-drug resistance plasmid, and other more-typical PVL-negative MRSA strains found in Japan. J Clin Microbiol. 2005;43:3356-63. DOI: 10.1128/JCM.43.7.3356-3363.2005

(9.) Yamamoto T, Dohmae S, Saito K, Otsuka T, Takano T, Chiba M, et al. Molecular characteristics and in vitro susceptibility to antimicrobial agents, including the desfluoro(6) quinolone DX-619, of PantonValentine leucocidin-positive methicillin-resistant Staphylococcus aureus isolates from the community and hospitals. Antimicrob Agents Chemother. 2006;50:4077-86. DOI: 10.1128/AAC.00847-06

(10.) Ferry T, Thomas D, Genestier AL, Bes M, Lina G, Vandenesch F, et al. Comparative prevalence of superantigen genes in Staphylococcus aureus isolates causing sepsis with and without septic shock. Clin Infect Dis. 2005;41:771-7. DOI: 10.1086/432798

Takashi Ito,* Makiko Iijima,* Takayoshi Fukushima,* Masato Nonoyama,* Masahiro Ishii, * Tatiana Baranovich, ([dagger]) Taketo Otsuka, ([dagger]) Tomomi Takano, ([dagger]) and Tatsuo Yamamoto ([dagger])

* Kitasato University School of Medicine, Kanagawa, Japan; and ([dagger]) Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

DOI: 10.3201/eid 1408.070391

Address for correspondence: Tatsuo Yamamoto, Division of Bacteriology, Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences, 757 Ichibanchou, Asahimachidori, Niigata, Japan; email: [e-mail]

Table. Characteristics of PVL-positive MRSA strains reported
in Japan since 2000 *

                                                    Present
                                                    strain

Type, gene,
or resistance                                    NN32    NN1

Types                          cc                 30     30
                               ST                 30     30
                               spa                19     19
                               agr                3       3
                             SCCmec              IVa     IVc
                            Coagulase             IV     IV

Toxins
  Leukocidins      lukS-PV, lukF-PV ([dagger])    +       +
                         lukE-lukD, lukM          -       -
  Hemolysins              hla, hlg, hld           +       +
                               hlb                -       -
                              hlg-v               -       -
  Staphylococcal               sea                -       -
  enterotoxins           tst, seb, sec,           -       -
                         sed, see, seh,
                          sej, sek, sep
                      egc ([double dagger])       +       +
                               seu                +       +
  Exfoliative             eta, etb, etd           -       -
  toxins                       set                +       +
  Others                      edin                -       -

Adhesins
                        icaA, sdrD, sdrE          -       -
                     icaD, cna, ([section])       +       +
                           eno, fnbA,
                           fnbB, ebpS,
                        clfA, clfB, fib,
                     sdrC, bbp ([paragraph])

Drug resistance          Aminoglycosides
and penicillinase
plasmid
                           Macrolides
                          Lincosamides
                          Tetracycline
                      Penicillinase plasmid       +       +
                              (kb)               (33)   (33)

                                                   PVL-positive MRSA

                                                    Previous strains

Type, gene,                                     NN12,    EB      DB
or resistance                                    NN31   00449   00319

Types                          cc                 30     30      30
                               ST                 30     30      765
                               spa                19     19      43
                               agr                3       3       3
                             SCCmec              IVc     IVc    IVx *
                            Coagulase             IV     IV      IV

Toxins
  Leukocidins      lukS-PV, lukF-PV ([dagger])    +       +       +
                         lukE-lukD, lukM          -       -       -
  Hemolysins              hla, hlg, hld           +       +       +
                               hlb                -       -       +
                              hlg-v               -       -       -
  Staphylococcal               sea                -       -       +
  enterotoxins           tst, seb, sec,           -       -       -
                         sed, see, seh,
                          sej, sek, sep
                      egc ([double dagger])       +       +       +
                               seu                +       +       +
  Exfoliative             eta, etb, etd           -       -       -
  toxins                       set                +       +       +
  Others                      edin                -       -       -

Adhesins
                        icaA, sdrD, sdrE          -       -       -
                     icaD, cna, ([section])       +       +       +
                           eno, fnbA,
                           fnbB, ebpS,
                        clfA, clfB, fib,
                     sdrC, bbp ([paragraph])

Drug resistance          Aminoglycosides         GEN#          GEN **
and penicillinase                               KAN# *         KAN **
plasmid                                                        STR **
                           Macrolides                          ERY **
                          Lincosamides                         CLI **
                          Tetracycline           TET#
                      Penicillinase plasmid       +       +       +
                              (kb)               (33)   (33)   (40) **

* PVL, Panton-Valentine leukocidin; MRSA, methicillin-resistant
Staphylococcus aureus; SCCmec IVx, staphylococcal cassette chromosome
mec type IV with unknown subtypes; +, positive; -, negative; GEN,
gentamicin; KAN, kanamycin; STIR, streptomycin; ERY, erythromycin;
CLI, clindamycin; TET, tetracycline.

([dagger]) GenBank accession nos. for the PVL gene sequences from
strains NN32 and NN1 are AB286959 and AB186917, respectively.

([double dagger]) egc, enterotoxin gene cluster, including seg,
sei, sem, sen, and sea genes.

[section]) cna, gene encoding for collagen binding protein (adhesin).

[paragraph]) bbp, gene encoding for bone sialoprotein binding protein
(adhesin).

# Drug resistance encoded by a conjugative drug resistance plasmid
(pGKT1) (8).

** Multidrug-resistant penicillinase plasmid encoding for resistance
to GEN, KAN, STR, ERY, and CLI, in addition to penicillin
resistance (9).