Serotype 35B Streptococcus pneumoniae,Japan, 2002–2012

Among 641 pneumococcal isolates recovered from 2002 to 2012 in Japan, 19 (3.0%) were serotype 35B. Twelve of the 19 were ST558 (single-locus variant of Utah35B-24-ST377) and seven were ST2755. Continuous monitoring of serotypes and their clonal association is important, especially in Japan where PCV7 was licensed only in 2010.     

Recent trends in pediatric bacterial meningitis in Japan – A country where Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines have just been introduced

To investigate the trends in incidence and the characteristics of bacterial meningitis in Japan where Haemophilus influenzae type b (Hib) vaccine and 7-valent pneumococcal conjugated vaccine (PCV7) were introduced in 2008 and 2010, respectively, which was 5–20 years after their introduction in western countries. The nationwide Japanese survey of pediatric and neonatal bacterial meningitis was performed in 2011 and 2012. We analyzed the epidemiological and clinical data, and compared the information obtained in the previous nationwide survey database. We also investigated the risk factors for disease outcome.In the 2011–2012 surveys, 357 patients were evaluated. H. influenzae, Streptococcus pneumoniae, Streptococcus agalactiae and Escherichia coli were the main organisms. The number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.31 in 2009 to 0.43 in 2012 (p < 0.001). The incidence of H. influenzae and S. pneumoniae meningitis also decreased from 0.66 to 0.08 (p < 0.001), and 0.30 to 0.06 (p < 0.001), respectively. Only 0–2 cases with Neisseria meningitidis were reported each year throughout 2001–2012. The median patient age was 10–12 months in 2001–2011, and became lower in 2012 (2 month old) (p < 0.001). The fatality rate for S. agalactiae is the highest (5.9% (11/187)) throughout 2001–2012 among the four organisms. Risk factors for death and sequelae were convulsions at onset, low CSF glucose, S. agalactiae etiology, and persistent positive CSF culture.Hib vaccine and PCV7 decreased the rate of bacterial meningitis. Earlier introduction of these vaccines may have prevented bacterial meningitis among Japanese children.     

Penicillin- and third-generation cephalosporin-resistant strains of Streptococcus pneumoniae meningitis: Case report and literature review

BackgroundTreatment of patients with penicillin-resistant S. pneumoniae (PRSP) is complicated because of the relatively poor blood-brain barrier penetration of effective antimicrobials. Our case: A previously healthy 70-year-old woman, a traveler from China to Japan, was admitted to our hospital with fever and loss of consciousness. She has no history of pneumococcal vaccination. She was diagnosed with bacterial meningitis due to penicillin-and third-generation cephalosporin-resistant strains of S. pneumoniae. The patient was successfully treated with a combination therapy of vancomycin (VCM) and levofloxacin (LVFX) and recovered without any neurological sequelae. As the treatment of penicillin-and third-generation cephalosporin-resistant strains of S. pneumoniae meningitis remains unclear, we conducted a review of the reported cases of meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae.MethodWe performed a search using the keywords “penicillin-resistant Streptococcus pneumoniae,” “meningitis,” and “pneumococcal meningitis”. We searched the electronic databases PubMed, Embase, and Ichushi from their inception to March 2020. Subsequently, two authors independently reviewed the resulting database records, retrieved full texts for eligibility assessment, and extracted data from these cases.ResultWe identified 18 papers describing thirty-five cases of penicillin- and cephalosporin-resistant S. pneumoniae meningitis including our case. The patient's characteristics were; median age: 50 years, men:50%, 85% of cases received combination regimens of antibiotics: Ceftroriaxone (CTRX) plus VCM (20 cases), CTRX plus VCM plus rifampicin (RFP) (two cases), CTRX plus linezolid (one case), fluoroquinolones (two cases), carbapenems (six cases), Thirty-five percent received steroids. Twenty-four percent of patients died. Twenty-six percent of patients complicated neurological sequalae.ConclusionCombination therapy including VCM plus LVFX could be a treatment option.     

Rapid progressive destruction of the cochleae in an infant due to pneumococcal meningitis

The widespread adoption of pneumococcal conjugate vaccines has reduced the incidence of Streptococcus pneumoniae infections, but has also led to the emergence of infections due to non-vaccine serotypes. A 15-month-old girl was referred to our hospital with suspected meningitis. S. pneumoniae was isolated from her cerebrospinal fluid. She was initially treated with a combination of cefotaxime and vancomycin, followed by ampicillin and vancomycin. After 7 days, the patient's condition improved and she was transferred to the general ward; however, her mother noted signs of hearing difficulties. On the 16th day of admission, we performed an auditory brainstem response test, which suggested severe bilateral hearing impairment. This was confirmed using an auditory steady-state response test after consulting with otolaryngologists. Magnetic resonance imaging revealed fibrosis of both cochleae with labyrinthitis. The patient underwent emergency cochlear implantation at a different hospital. The S. pneumoniae isolate was later identified to be serotype 10A with a PBP2x mutation, which is not covered by the conjugate vaccine and has reduced cephalosporin susceptibility. This case was characterized by highly rapid cochlear destruction, and an earlier otolaryngologist consultation may have provided a more well-organized surgery plan. Pediatricians are urged to promptly consult with otolaryngologists for patients with similar indications.     

Genetic characteristics of piliated Streptococcus pneumoniae serotype 35B,increased after introduction of pneumococcal vaccines in Japan

IntroductionStreptococcus pneumoniae is a commensal bacterium of the human nasopharynx and a major causative pathogen of bacterial diseases worldwide. Pilus of S. pneumoniae is one of the virulence factors which enhance the adhesion to the host epitherial cells in the upper respiratory tract.MethodsWe analyzed the serotype distribution and presence of pilus genes, rrgC and sipA, among 785 S. pneumoniae isolates from specimens of patients with invasive or non-invasive disease in a regional Japanese hospital between October 2014 and August 2018. We next performed multilocus sequence typing and penicillin-resistant genotyping for 86 isolates of serotype 35B.ResultsSerotype 35B was the most frequent serotype which accounted for 11.0% of total isolates and had pilus genes at high rate (80.2%). Clonal complex (CC) 558 isolates accounted for 77.9% of serotype 35B and were highly positive for rrgC and gPRSP (98.5%). In contrast, all CC2755 isolates (19.8%) were rrgC-negative and gPISP.ConclusionsOur results suggest that CC558 may assist the prevalence of serotype 35B after the introduction of vaccines, as that clone has pili as adhesins in addition to non-susceptibility against penicillin. These results may be useful information for development of optimal preventive strategies. Continuous studies on serotype distribution and virulence factors of S. pneumoniae are necessary.     

Open-label study to evaluate the pharmacodynamics,clinical efficacy,and safety of meropenem for adult bacterial meningitis in Japan

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35–71]) were enrolled. Infection with Streptococcus pneumoniae (three patients), Streptococcus salivarius (one patient), and Staphylococcus aureus (one patient) was confirmed by cerebrospinal fluid culture. Meropenem (2 g every 8 h) was administered to all five patients. Treatment duration ranged from 14 to 28 days (mean 22.6 days). All the patients were successfully treated. The concentration of meropenem in cerebrospinal fluid ranged from 0.27 to 6.40 μg/ml up to 8.47 h and was over 1 μg/ml 3 h after starting meropenem infusion. In each patient, the present study confirmed for the first time that the concentration of meropenem in cerebrospinal fluid exceeded the minimal inhibitory concentration for these pathogens. Eleven clinical and laboratory adverse events considered to be related to meropenem were observed in all patients, but no serious adverse event and no discontinuance of treatment due to adverse events occurred. Thus meropenem appeared to be a well-tolerated and effective agent for Japanese adult patients with bacterial meningitis. 2 g every 8 h of meropenem was delivered to CSF and its concentration was exceed in MICs for the detected pathogens.     

A broad range assay for rapid detection and etiologic characterization of bacterial meningitis: performance testing in samples from sub-Sahara

This study aimed to conduct a pilot evaluation of broad-based multiprobe polymerase chain reaction (PCR) in clinical cerebrospinal fluid (CSF) samples compared to local conventional PCR/culture methods used for bacterial meningitis surveillance. A previously described PCR consisting of initial broad-based detection of Eubacteriales by a universal probe, followed by Gram typing, and pathogen-specific probes was designed targeting variable regions of the 16S rRNA gene. The diagnostic performance of the 16S rRNA assay in "127 CSF samples was evaluated in samples from patients from Togo, Africa, by comparison to conventional PCR/culture methods. Our probes detected Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Uniprobe sensitivity and specificity versus conventional PCR were 100% and 54.6%, respectively. Sensitivity and specificity of uniprobe versus culture methods were 96.5% and 52.5%, respectively. Gram-typing probes correctly typed 98.8% (82/83) and pathogen-specific probes identified 96.4% (80/83) of the positives. This broad-based PCR algorithm successfully detected and provided species level information for multiple bacterial meningitis agents in clinical samples.     

Clinical significance of cerebrospinal fluid inhibitory titers of antibiotics, based on pharmacokinetic/pharmacodynamic parameters, in the treatment of bacterial meningitis

The cerebrospinal fluid (CSF) inhibitory titer (CSF-IT) of an antibiotic, which can be used to estimate the duration of time above the agent’s MIC in the CSF, was introduced as one of the indices to evaluate the effectiveness of antibiotic selection in treating bacterial meningitis. The CSF-IT was determined via a microdilution method. A suspension of the causative organism was added to a tube containing twofold diluted CSF and double-concentrated Mueller-Hinton broth with supplement. The CSF-IT was determined by the maximum point without turbidity of medium after overnight incubation at 37°C. Concerning the strain of β-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR), the killing rates of both meropenem and piperacillin were compared in an in vitro pharmacokinetic (PK) model, in which human pharmacokinetics in CSF were simulated. Organisms recovered from the CSF in 37 treated clinical cases of bacterial meningitis were H. influenzae, Streptococcus agalactiae, Streptococcus pneumoniae, Escherichia coli, and Neisseria meningitidis; in these cases, the CSF-IT ranged from 1: 8 to as high as 1: 4 096. In the in vitro PK model, the concentrations of both drugs were higher than the MICs over a period of 24 h; however, the killing rate of piperacillin was higher than that of meropenem, and bacterial regrowth was observed after the administration of meropenem. A CSF-IT value higher than 1: 32 indicates that the antibiotic concentration in the CSF exceeds the MIC for 24 h. The effect of piperacillin on BLNAR depends not only on the time above MIC of 24 h but also on the maximum concentration in the CSF.     

Accuracy of clinical presentation for differentiating bacterial from viral meningitis in adults: a multivariate approach

Objective To determine whether bacterial (BM) and viral (VM) meningitis can be differentiated based on initial clinical presentation.Design and setting Retrospective cohort study in a medical emergency department and intensive care unit in a university hospital.Patients 144 adults, including 90 with confirmed BM and 54 unpretreated VM.Measurements and results Symptoms, examination findings, paraclinical data, and clinical outcome were assessed. Severity was defined by the presence at referral of one of the following criteria: altered consciousness, seizures, focal neurological findings, and shock. After univariate analyses we performed stepwise logistic regression to determine predictors for BM available at referral (except for CSF Gram stain) and logistic regression using previously validated CSF cutoffs. Univariate methods identified the presence of one sign of severity as the most important predictor for BM (sensitivity 0.989, specificity 0.981, positive predictive value 0.989, negative predictive value 0.981, odds ratio 4,770) and showed that CSF results differ in BM and in VM (except for CSF glucose). Logistic regression analysis revealed severity and CSF absolute neutrophil count as the two predictors of BM (R²=0.876). Logistic analysis showed that BM was related to severity (=6.46±1.27) and a CSF absolute neutrophil count above 1,000/mm³ whereas CSF glucose below 2 mmol/l and CSF protein higher than 2 g/l were not predictive.Conclusions The presence of at least one sign of severity at referral and a CSF absolute neutrophil count above 1,000/mm³ mm are predictive of BM.This article is discussed in the editorial available at:     

Urinary tract infection due to Group B Streptococcus: A case series from Eastern India

Group B Streptococcus (GBS) or Streptococcus agalactiae is an uncommon causative agent of urinary tract infection (UTI). We present a series of seven cases of UTI due to GBS from a tertiary care hospital of Eastern India, highlighting its emerging role in a hitherto less commonly described clinical entity.     

Fatal overwhelming postsplenectomy infection due to Streptococcus pneumoniae serotype 10A with atypical polysaccharide capsule in a patient with chromosome 22q11.2 deletion syndrome: A case report

We report the first case of a teenage patient with chromosome 22q11.2 deletion syndrome who died of overwhelming postsplenectomy infection (OPSI) by Streptococcus pneumoniae despite appropriate prevention by pneumococcal vaccine. He had congenital heart disease and underwent several surgeries. Immunodeficiency had not been noticed clinically. Two years prior to death, splenectomy was performed for a drug-resistant idiopathic thrombocytopenic purpura and he was immunized with 23-valent pneumococcal polysaccharide vaccine (PPV23) 4 months after splenectomy. He died suddenly after a mild flu-like symptom. Autopsy was performed and OPSI was diagnosed. Blood culture was positive for S. pneumoniae. This isolated S. pneumoniae strain was serotypically un-typable by polyvalent serum agglutination test. On the contrary, multilocus sequence typing followed by DNA sequencing indicated the molecular serotype as 10A. Additional testing using monovalent and factor-specific sera confirmed the strain as serotype 10A. Ultrastructural observation of this S. pneumoniae strain showed that the polysaccharide capsule was thin and sparse. We speculate that the abnormal morphology of the capsule may have accounted for the polyvalent serum agglutination failure and may possibly be associated with severity of OPSI observed in this case. Chromosome 22q11.2 deletion syndrome is associated with certain immunodeficiency, especially susceptible to S. pneumoniae infections; however, fatal OPSI has not been reported. In addition to vaccination, prophylactic antibiotics may be necessary for these patients who are at risk of immunodeficiency.     

Antibiotic susceptibility in relation to penicillin-binding protein genes and serotype distribution of Streptococcus pneumoniae strains responsible for meningitis in Japan, 1999 to 2002

The antibiotic susceptibilities, genotypes of penicillin (PEN)-binding protein genes (pbp), and serotype distributions of Streptococcus pneumoniae isolates from meningitis patients were investigated by a nationwide surveillance group in Japan between 1999 and 2002. We analyzed 146 isolates from children (/=18 years old). Isolates with or without abnormal pbp1a, pbp2x, or pbp2b genes identified by PCR were classified into six genotype patterns and 90% MIC (MIC(90)) values for PEN: (i) strains with three normal genes (17.2% of isolates; MIC(90), 0.031 micro g/ml); (ii) strains with abnormal pbp2x (22.1%, 0.063 micro g/ml); (iii) strains with abnormal pbp2b (1.0%, 0.125 micro g/ml); (iv) strains with abnormal pbp2x and pbp2b (7.4%, 0.25 micro g/ml); (v) strains with abnormal pbp1a and pbp2x (12.7%, 0.25 micro g/ml); and (vi) strains with three abnormal PBP genes (39.7%, 4 micro g/ml), which are termed genotypic PEN-resistant S. pneumoniae (gPRSP). Panipenem, a carbapenem, showed an excellent MIC(90) (0.125 micro g/ml) against gPRSP, followed by meropenem and vancomycin (0.5 micro g/ml), cefotaxime and ceftriaxone (1 micro g/ml), and ampicillin (4 micro g/ml). Strains of gPRSP were significantly more prevalent in children (45.2%) than in adults (27.4%). The most frequent serotypes were 6B, 19F, 23F, 6A, and 14 in children and 23F, 22, 3, 10, 6B, and 19F in adults. Serotypes 6B, 6A, 19F, 23F, and 14 predominated among gPRSP. In children, 7- and 11-valent pneumococcal conjugate vaccines would cover 76.2 and 81.3% of isolates, respectively, although coverage would be lower in adults (43.9 and 56.0%, respectively). These findings suggest the need for early introduction of pneumococcal conjugate vaccines and continuous bacteriological surveillance for meningitis.     

Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center

Our objective was to analyze the presentation, time to antibiotics, treatment, and mortality of patients with bacterial meningitis at a large urban county hospital over a 10-year period. A retrospective chart review of all patients with the diagnosis of bacterial meningitis was done. Information concerning presentation, etiologic organisms, treatment (including time to antibiotics), and outcomes were collected and analyzed. There were 165 charts reviewed with 171 total cases of bacterial meningitis. For adults with community-acquired meningitis, the mortality rate was 14%, for children it was 1.6%. Seventy-six percent of patients received antibiotics in the Emergency Department (ED) with a mean time to antibiotics of 1:08 h ± 13 min. The rest received them as inpatients with a mean time to antibiotics of 6 ± 9 h. The mortality rate for patients with community-acquired disease who received an Emergency Department antibiotic was 7.9%; for patients who received their antibiotics as inpatients the mortality rate was 29%. Our results indicate that the mortality rates from bacterial meningitis at our institution are lower than previously published results. Furthermore, our study supports the concept that the early administration of antibiotics in the ED may reduce mortality and may be an explanation of the lower mortality rates seen here.     

Two sporadic cases of infections due to Klebsiella pneumoniae resistant to expanded-spectrum cephalosporins in Japan

TEM- or SHV-type extended-spectrum β-lactamases (ESBLs) are of clinical concern in Europe and the United States, whereas bacterial strains producing such types of ESBLs have not been reported in Japan. We report here two cases of infection due to Klebsiella pneumoniae resistant to extended-spectrum cephalosporins in Japan. A ceftadizime-resistant K. pneumoniae strain (minimum inhibitory concentration; 32 μg/ml) was isolated transiently from the sputum of an 87-year-old woman with acute myocardial infarction and pneumonia (patient 1). Ceftadizime-susceptible and -resistant (minimum inhibitory concentration; ≥8 μg/ml) K. pneumoniae strains were isolated over a month from the blood, ascites, and feces of a 44-year-old man after bone marrow transplantation for acute lymphoblastic leukemia (patient 2); this patient died of K. pneumoniae sepsis and peritonitis followed by multiple organ failure. These isolates produced penicillinase, which was inhibited by clavulanic acid. A polymerase chain reaction (PCR) study showed that both isolates carried the SHV or LEN genes, but not the TEM, Toho-1, and IMP-1 genes. The pulsed-field gel electrophoresis profile of the strain isolated from patient 1 was genetically distinguishable from the profiles of the strains isolated from patient 2. It appeared that mutation of the β-lactamase gene may have occurred in the body of patient 2, since the genotypes of the ceftadizime-susceptible and -resistant isolates from this patient were identical. Another 12 strains of K. pneumoniae, isolated from other patients in the same wards during the period in which the K. pneumoniae strains were isolated from patients 1 and 2, did not produce ESBLs and showed different genotypes. The results suggest that these isolates of resistant K. pneumoniae did not spread by cross transmission in the hospital and that the two cases were sporadic. Surveillance of these types of resistant bacteria is necessary, since they may well be present in other hospitals in Japan. Although the organisms are suspected to produce SHV-type ESBLs or LEN-1 variant β-lactamases, further studies are necessary to specify the resistance genes. Received: July 6, 1998 / Accepted: December 17, 1998     

2005-2007年儿科分离的流感嗜血杆菌、肺炎链球菌(包括血清型19A)和卡他莫拉菌对常用抗菌药物的敏感性

儿科上呼吸道感染最常见的3种病原菌为未分型流感嗜血杆菌、肺炎链球菌和卡他莫拉菌。其中,19A血清型肺炎链球菌越来越多,且对多种药物呈高水平耐药,包括青霉素、阿莫西林、口服头孢菌素、大环内酯类、克林霉素和磺胺甲嗯唑一甲氧苄啶等。另外,未分型流感嗜血杆菌产β内酰胺酶,也导致对阿莫西林和部分口服头孢菌素耐药。     

Evolution of clonal and susceptibility profiles of serotype 19A Streptococcus pneumoniae among invasive isolates from children in Spain, 1990 to 2008

The genetic structure and antibiotic nonsusceptibility of all serotype 19A Streptococcus pneumoniae pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n=471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2=0.872; P=0.001). Decreasing trends (P<0.03) were found for ST202 (R2=0.774) and ST81 (R2=0.559), and increasing trends (P<0.03) for ST878 (R2=0.544) and ST320 (R2=0.530), both belonging to the clonal complex (CC) Denmark(14)-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2=0.704) and ST4461 (R2=0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90=8/8 μg/ml) and 43.5% cefotaxime (MIC50/MIC90=1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P<0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008; R2=0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008; R2=0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.     

Emergence of Streptococcus pneumoniae of serotype 19A in France: molecular capsular serotyping, antimicrobial susceptibilities, and epidemiology

We have studied 457 Streptococcus pneumoniae isolated in 2007 from adults and children. For all isolates, both latex agglutination and molecular capsular typing were performed. Antibiotic resistance patterns were determined. S. pneumoniae 19A was the most frequently isolated serotype (34.7%) both in children and adults. It represented 12.8% of the strains isolated from invasive infections in adults and 27.0% in children and 63.6% (110/173) of strains isolated from acute otitis media. Between children and adults, no difference concerning antibiotic susceptibility was observed for penicillin, amoxicillin, cefotaxime, and erythromycin in strains isolated from invasive diseases. Comparing antibiotic susceptibilities according to the serotype, the 19A isolates appeared to be the least susceptible to penicillin (3.2%) and erythromycin (4.5%), followed by serotypes 19F and 14. We confirm the predominance of serotype 19A among S. pneumoniae responsible for invasive and noninvasive diseases either in children or adults in France.