methicillin - resistant staphylococcus aureus ( mrsa ) strains are well known to be hospital - associated or healthcare - associated pathogens . however , within the past two decades , the incidence of infections due to community - acquired methicillin - resistant s. aureus ( ca - mrsa ) strains have been rapidly increasing worldwide .
similar to hospital - acquired mrsa ( ha - mrsa ) , ca - mrsa can cause severe infections such as soft - tissue infection ( including necrotizing fasciitis ) , necrotizing pneumonia , severe sepsis , and disseminated infection .
moreover , s. aureus can produce many exotoxins such as toxic shock syndrome toxin-1 ( tsst-1 ) and staphylococcal enterotoxin b ( seb ) .
exotoxins of s. aureus are associated with a severe illness that includes shock and multiple organ failure and is called toxic shock syndrome ( tss ) .
specifically , in women of childbearing age , an insanitary ectocervical environment ( e.g. , long - term tampon - use or post - partum period ) is associated with bacterial growth , including the growth of s. aureus , and the risk of tss .
we herein report 2 cases of tss due to ca - mrsa in japanese women .
a literature review of cases from japan revealed that transvaginal invasion is a very rare portal of entry of ca - mrsa .
the population of ca - mrsa in japan is relatively low compared with that in other countries . despite this fact
, we assert that the initiating treatment for tss with vancomycin and clindamycin , even in japan . informed consent was obtained from the patients for the publication of their respective case reports .
case 1a 46-year - old japanese woman was admitted to our hospital after a 1-day history of fever , shaking chills , and diarrhoea .
she previously was seen at another clinic on the same day of admission ( day 1 ) , and fosfomycin was prescribed
she did not have any relevant past history and had not been prescribed any medications .
she had never been abroad , and she had not eaten any raw foods in the previous month .
a 46-year - old japanese woman was admitted to our hospital after a 1-day history of fever , shaking chills , and diarrhoea .
she previously was seen at another clinic on the same day of admission ( day 1 ) , and fosfomycin was prescribed
she did not have any relevant past history and had not been prescribed any medications .
she had never been abroad , and she had not eaten any raw foods in the previous month .
her vital signs on the day of admission were as follows : blood pressure , 67/47  mmhg ; heart rate , 118 beats per minute ; body temperature , 39.4  c ; respiratory rate , 30 breaths per minute ; and peripheral capillary oxygen saturation level on room air , 98% .
physical examination showed capillary refilling time of 12  s , and generalized rash on her chest and abdomen .
laboratory data revealed white blood cell ( wbc ) count of 12,300/l , c - reactive protein ( crp ) level of 15.4  mg / dl , blood urea nitrogen ( bun ) of 26.4  mg / dl , serum creatinine ( s - cre ) level of 3.3  mg / dl , serum total protein level of 7.1  g / dl , serum albumin level of 3.4  g / dl , and procalcitonin level of 69.8  ng / ml .
results of liver function tests were normal except for a lactate dehydrogenase ( ldh ) level of 328 iu / l .
urine dipstick examination revealed 2 + protein and 2 + occult blood . a microscopic examination detected 510 red blood cells ( rbcs ) per high - power field and 510 wbcs per high - power field . at first , we diagnosed severe bacterial colitis and hypovolemic shock and started large volumes of hydration , dopamine infusion , and intravenous ciprofloxacin ( 300  mg , 2 times daily )
, we learned that she had begun menstruating 4  days prior to admission , and that she kept a tampon inserted 3  days until the day of admission .
additional testing of her vaginal discharge showed the following ; polymorphonuclear leukocytes 2 + , and nugent score , 1 .
we suspected tss or septic shock of unknown origin and changed the antibiotics to vancomycin ( 1  g , 2 times daily , intravenously ) , clindamycin ( 600  mg , 4 times daily , intravenously ) , and meropenem ( 500  mg , 4 times daily , intravenously ) . on day 4
, community - acquired s. aureus was detected from the tampon and vaginal discharge and her vital signs gradually recovered enough to stop the dopamine infusion , and her diarrhoea stopped .
we diagnosed staphylococcal tss owing to tampon use , discontinued meropenem on day 11 , and continued antibiotic treatment with the combination of vancomycin and clindamycin for 14  days . on day 14
, the patient was found to have peeling skin at the end of her fingers ( fig .
the patient was discharged on day 18 , without any damage to her organs or deterioration in activities of daily living.case 2a 40-year - old japanese woman was admitted to our hospital after a 5-day history of yellowish vaginal discharge , and 3-day history of fever , shaking chills , and appetite loss .
she did not have any relevant past medical history and had not been prescribed any medications , including antibiotics .
she had never been abroad and had not had any raw foods in the previous month .
1 a 40-year - old japanese woman was admitted to our hospital after a 5-day history of yellowish vaginal discharge , and 3-day history of fever , shaking chills , and appetite loss .
she did not have any relevant past medical history and had not been prescribed any medications , including antibiotics .
she had never been abroad and had not had any raw foods in the previous month .
her vital signs on the day of admission were as follows : blood pressure , 86/49  mmhg ; heart rate , 121 beats per minute ; body temperature , 39.8  c ; respiratory rate , 36 breaths per minute ; and peripheral capillary oxygen saturation level on room air , 96% .
results of cardiovascular , respiratory , and abdominal examinations were normal , except tenderness on the right costal - vertebral angle .
laboratory data revealed wbc of 19,200/l , crp level of 14.5  mg / dl , bun level of 28.4  mg / dl , s - cre level of 1.7  mg / dl , serum total protein level of 6.0  g / dl , serum albumin level of 3.3  g / dl , and procalcitonin level of 5.4  ng / ml .
results of liver function tests were normal except for an ldh level of 328 iu / l .
a microscopic examination detected 5 to 10 rbcs per high - power field and more than 100 wbcs per high - power field .
testing of her vaginal discharge showed the following : polymorphonuclear leukocytes , 4 + ; and nugent score , 4 .
gram stain of both urine and vaginal discharge showed clustered gram - positive cocci . at first , we diagnosed severe urinary tract infection and septic shock .
we started large volumes of hydration , dopamine infusion , and intravenous ampicillin ( 2  g , 3 times daily ) and gentamicin ( 120  mg , once daily ) .
however , her vital signs did not recover and she experienced diarrhoea . on day 2 , s. aureus was detected from urine and vaginal discharge .
we suspected staphylococcal tss or septic shock of unknown origin , and changed the antibiotics to vancomycin ( 1  g , 2 times daily , intravenously ) , clindamycin ( 600  mg , 4 times daily , intravenously ) , and meropenem ( 1  g , 3 times daily , intravenously ) for covering enteric bacteria and anaerobes like bacteroides spp . on day 3
, community - acquired s. aureus was detected from both urine and vaginal discharge , and she recovered adequately enough to discontinue dopamine and large volumes of hydration .
gynaecological examination revealed narrowing of the vaginal opening caused by vulvar lichen sclerosus , a chronic and progressive dermatologic disorder of genital skin that can cause vulvar pruritus , dysuria , and sexual dysfunction due to cleft narrowing .
we diagnosed staphylococcal tss caused by vaginitis and discontinued meropenem on day 9 and continued vancomycin in combination with clindamycin for 14  days . on day 14 , we noted peeling skin at the end of her fingers ( fig .
the following 13 antimicrobials were tested : ampicillin , cefazolin , imipenem , gentamicin , gentamicin , erythromycin , clindamycin , telithromycin , levofloxacin , minocycline , vancomycin , teicoplanin , arbekacin , and trimethoprim / sulfamethoxazole . according to m100-s20 , published by the clinical and laboratory standards institute , the isolates from case 1 and case 2 were resistant to ampicillin , cefazolin , imipenem , and gentamicin , but were susceptible to erythromycin , clindamycin , and minocycline .
the 2 isolates were tested for genes encoding selected exotoxins including tsst-1 , exfoliative toxins a and b ( eta and etb ) , staphylococcal enterotoxins a to e ( enta , entb , entc , entd , and ente ) , and panton - valentine leukocidin ( pvl ) by multiplex real - time polymerase chain reaction ( pcr ) analysis . both isolates contained genes encoding for the toxins eta , etb , and tsst-1 , but were negative for other exotoxins , including pvl .
the isolates were also typed to determine their staphylococcal cassette chromosome mec ( sccmec ) type by multiplex pcr targeting the cassette chromosome recombinases ( ccr ) and mec gene complex .
both isolates were identified as the group st8-mrsa with sccmec type iv , which has recently been one of a major genotype in the community in japan .
the following 13 antimicrobials were tested : ampicillin , cefazolin , imipenem , gentamicin , gentamicin , erythromycin , clindamycin , telithromycin , levofloxacin , minocycline , vancomycin , teicoplanin , arbekacin , and trimethoprim / sulfamethoxazole . according to m100-s20 , published by the clinical and laboratory standards institute , the isolates from case 1 and case 2 were resistant to ampicillin , cefazolin , imipenem , and gentamicin , but were susceptible to erythromycin , clindamycin , and minocycline .
the 2 isolates were tested for genes encoding selected exotoxins including tsst-1 , exfoliative toxins a and b ( eta and etb ) , staphylococcal enterotoxins a to e ( enta , entb , entc , entd , and ente ) , and panton - valentine leukocidin ( pvl ) by multiplex real - time polymerase chain reaction ( pcr ) analysis .
both isolates contained genes encoding for the toxins eta , etb , and tsst-1 , but were negative for other exotoxins , including pvl .
the isolates were also typed to determine their staphylococcal cassette chromosome mec ( sccmec ) type by multiplex pcr targeting the cassette chromosome recombinases ( ccr ) and mec gene complex .
both isolates were identified as the group st8-mrsa with sccmec type iv , which has recently been one of a major genotype in the community in japan .
we described 2 cases of tss due to ca - mrsa from transvaginal invasion , which are the first case reports of this kind in japan .
appropriate antibiotics , including clindamycin or linezolid , and vancomycin or teicoplanin , have to be started immediately for the patients with staphylococcal tss .
however , we did not administered these antibiotics initially because of clinical misjudgment and subsequently , each case had a severe clinical course .
we identified the reasons for the misjudgment in each case . in case 1 , we were unable to obtain information about tampon use at admission , which is an essential clue for the diagnosis of tss .
therefore , it is important to obtain a detailed history regarding tampon use in female patients with septic shock of unknown origin . in case 2
, we did not consider ca - mrsa as a causative pathogen of septic shock at admission , although the gram stain of vaginal discharge samples showed clustered gram - positive cocci .
ca - mrsa strains accounts a certain percentage of staphylococcus aureus strains in japan and ca - mrsa can cause tss as our cases .
the prevalence of ca - mrsa isolation in japan has been reported as 4.3%   overall and 3.7% among children .
we have to administer appropriate combination of antibiotics to cover ca - mrsa immediately in cases of suspected staphylococcal tss even though they have no risk factors for ha - mrsa infection .
learning points from the 2 cases are as follows : 1 ) taking a detailed history about genital symptoms and female hygiene practice is essential for the diagnosis of females with sepsis of unknown cause , 2 ) even in japan , we have to administer a combination of antibiotics including antibiotics with toxin - suppressing properties and anti - mrsa antibiotics to the patients with suspected staphylococcal tss .
there have been no previous reports about the prevalence of tss due to ca - mrsa in japan , and only a few case reports have ever been reported in japan .
we extensively reviewed the literature for past studies and case reports about tss due to ca - mrsa in japan .
based on our search of medline and igaku chuo zasshi ( a tool for searching japanese biomedical publications ) , no case series or controlled studies were identified .
we could identify 8 cases ( 3 male and 5 female ) ; 4 case reports were written in english , and 4 were written in japanese and had been cited by both japanese and english studies ( age range : 1677 years ; median age : 44 years ) ( table 1 ) , , , , , , , . among these cases , skin and soft tissue infections and necrotizing pneumonia were the main portal of entry .
this is similar to the results of a previous study in another country other than the proportion of menstrual tss .
gynaecologic ca - mrsa infections as the primary cause of tss have not been reported in japan . on the other hand ,
we consider that lower prevalence of menstrual tss in japan is probably related to the lower proportion of tampon use in japan . in only 1 case ,
bacteraemia due to ca - mrsa was detected , and in another case , the patient died .
most of the ca - mrsa strains , which had been examined for staphylococcal cassette chromosome mec ( sccmec ) typing , had sccmec iv ( 5 cases in 6 evaluated cases ) , and tsst-1 production was confirmed in 8 of 10 cases , including the present 2 cases .
according to previous data from japan , the majority of ca - mrsa strains have sccmec iv or v , and 46% of ca - mrsa strains are tsst-1-producing strains .
this is the first literature review about tss due to ca - mrsa in japan , and our results are consistent with the results of previous studies regarding the epidemiology of ca - mrsa in japan .table 1literature review of cases of toxic shock syndrome caused by community - acquired mrsa reported in japan.table 1no.agesexunderlying diseasefocusoutcomeblood culturesccmecexotoxinspvlref.english publications159fnecrotizing pneumoniasurvivednatsst-1na11262mbipolar depressionnecrotizing pneumoniadiednaiitsst-112316ftype a influenzanecrotizing pneumoniasurvivedivseb+13474fdmsstisurvived+ivsecselpselltsst-114japanese publications577fra , ntmi , burnsstisurvivednatsst-1na15631mburnsstisurvivedivtsst-116727msstisurvivednanatsst-1na17821fsstisurvivednanasebna18our cases946fmenstrual tsssurvivedivetaetbtsst-1case 11040fvaginitissurvivedivetaetbtsst-1case 2abbreviations : ra  =  rheumatoid arthritis ; ntmi  =  nontuberculous mycobacterial infection ; dm  =  diabetes mellitus ; ssti  =  skin and soft tissue infections ; sec  =  staphylococcal enterotoxin c ; selp  =  staphylococcal enterotoxin - like p ; sell  =  staphylococcal enterotoxin - like l ; na  =  not available , ref
literature review of cases of toxic shock syndrome caused by community - acquired mrsa reported in japan .
abbreviations : ra  =  rheumatoid arthritis ; ntmi  =  nontuberculous mycobacterial infection ; dm  =  diabetes mellitus ; ssti  =  skin and soft tissue infections ; sec  =  staphylococcal enterotoxin c ; selp  =  staphylococcal enterotoxin - like p ; sell  =  staphylococcal enterotoxin - like l ; na  =  not available , ref . 
, the authors described 2 cases of tss due to ca - mrsa associated with a vaginal portal of entry , which represent the first case reports of its kind in japan .
appropriate antibiotics , including vancomycin and clindamycin , should be initiated when tss is suspected in patients .
in addition , the literature review suggested that tss due to ca - mrsa in japan has similar characteristics to those reported in other countries .
 community - acquired methicillin - resistant staphylococcus aureus has been spreading worldwide , including in japan . 
 however , few cases of toxic shock syndrome caused by community - acquired methicillin - resistant staphylococcus aureus have been reported in japan . 
 we report 2 cases , in middle - aged women , of toxic shock syndrome due to community - acquired methicillin - resistant staphylococcus aureus via a vaginal portal of entry . 
 the first patient had used a tampon and the second patient had vaginitis due to a cleft narrowing associated with vulvar lichen sclerosus . 
 both patients were admitted to our hospital with septic shock and severe acute kidney injury and subsequently recovered with appropriate antibiotic treatment . in our review of the literature , 
 8 cases of toxic shock syndrome caused by community - acquired methicillin - resistant staphylococcus aureus were reported in japan . in these 8 cases , 
 the main portals of entry were the skin and respiratory tract ; however , the portal of entry of community - acquired methicillin - resistant staphylococcus aureus from a vaginal lesion has not been reported in japan previously . 
Introduction
Case report
Microbiological test
Discussion
Conflict of interest
Funding