Antibiotic resistance among invasive Neisseria meningitidis isolates in England, Wales and Northern Ireland (2010/11 to 2018/19).

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, can have a fatality rate as high as 10%, even with appropriate treatment. In the UK, penicillin is administered to patients in primary care whilst third generation cephalosporins, cefotaxime and ceftriaxone, are administered in secondary care. The first-choice antibiotic for chemoprophylaxis of close contacts is ciprofloxacin, followed by rifampicin. Immunocompromised individuals are often recommended antibiotic chemoprophylaxis and vaccination due to a greater risk of IMD. Resistance to antibiotics among meningococci is relatively rare, however reduced susceptibility and resistance to penicillin are increasing globally. Resistance to third generation cephalosporins is seldom reported, however reduced susceptibility to both cefotaxime and ceftriaxone has been observed. Rifampicin resistance has been reported among meningococci, mainly following prophylaxis, and ciprofloxacin resistance, whilst uncommon, has also been reported across the globe. The Public Health England Meningococcal Reference Unit receives and characterises the majority of isolates from IMD cases in England, Wales and Northern Ireland. This study assessed the distribution of antibiotic resistance to penicillin, rifampicin, ciprofloxacin and cefotaxime among IMD isolates received at the MRU from 2010/11 to 2018/19 (n = 4,122). Out of the 4,122 IMD isolates, 113 were penicillin-resistant, five were ciprofloxacin-resistant, two were rifampicin-resistant, and one was cefotaxime-resistant. Penicillin resistance was due to altered penA alleles whilst rifampicin and ciprofloxacin resistance was due to altered rpoB and gyrA alleles, respectively. Cefotaxime resistance was observed in one isolate which had an altered penA allele containing additional mutations to those harboured by the penicillin-resistant isolates. This study identified several isolates with resistance to antibiotics used for current treatment and prophylaxis of IMD and highlights the need for continued surveillance of resistance among meningococci to ensure continued effective use.

Combined therapy with ceftriaxone and doxycycline does not improve the outcome of meningococcal meningitis in mice compared to ceftriaxone monotherapy.

BACKGROUND: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM. METHODS: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi. RESULTS: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX. CONCLUSIONS: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Surveillance of penicillin resistance of Neisseria meningitidis strains from invasive infections between 2013 and 2018 in Turkey.

Neisseria meningitidis (N. meningitidis) is regarded as the leading cause of bacterial meningitis in many regions of the world. The empiric antimicrobial treatment is mainly based on antimicrobial resistance and patient characteristics. We aimed to analyze susceptibility patterns of N. meningitidis strains isolated in Turkey. Invasive meningococci collected in a multicenter, hospital-based, epidemiological surveillance study of pediatric (0-18 years of age) bacterial meningitis cases between 2013 and 2018 were studied. Five isolates (8.7%) displayed resistance to penicillin-G, while 13 isolates (22.8%) had intermediate susceptibility. All isolates were cefotaxime and rifampin susceptible. The data shows appropriateness of third-generation cephalosporins in empirical use for meningococcal infections in children. Since Turkey is located in a transition zone geographically, surveillance reports are very crucial.

Single-dose oral ciprofloxacin prophylaxis as a response to a meningococcal meningitis epidemic in the African meningitis belt: A 3-arm, open-label, cluster-randomized trial.

BACKGROUND: Antibiotic prophylaxis for contacts of meningitis cases is not recommended during outbreaks in the African meningitis belt. We assessed the effectiveness of single-dose oral ciprofloxacin administered to household contacts and in village-wide distributions on the overall attack rate (AR) in an outbreak of meningococcal meningitis. METHODS AND FINDINGS: In this 3-arm, open-label, cluster-randomized trial during a meningococcal meningitis outbreak in Madarounfa District, Niger, villages notifying a suspected case were randomly assigned (1:1:1) to standard care (the control arm), single-dose oral ciprofloxacin for household contacts within 24 hours of case notification, or village-wide distribution of ciprofloxacin within 72 hours of first case notification. The primary outcome was the overall AR of suspected meningitis after inclusion. A random sample of 20 participating villages was enrolled to document any changes in fecal carriage prevalence of ciprofloxacin-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae before and after the intervention. Between April 22 and May 18, 2017, 49 villages were included: 17 to the control arm, 17 to household prophylaxis, and 15 to village-wide prophylaxis. A total of 248 cases were notified in the study after the index cases. The AR was 451 per 100,000 persons in the control arm, 386 per 100,000 persons in the household prophylaxis arm (t test versus control p = 0.68), and 190 per 100,000 persons in the village-wide prophylaxis arm (t test versus control p = 0.032). The adjusted AR ratio between the household prophylaxis arm and the control arm was 0.94 (95% CI 0.52-1.73, p = 0.85), and the adjusted AR ratio between the village-wide prophylaxis arm and the control arm was 0.40 (95% CI 0.19‒0.87, p = 0.022). No adverse events were notified. Baseline carriage prevalence of ciprofloxacin-resistant Enterobacteriaceae was 95% and of ESBL-producing Enterobacteriaceae was >90%, and did not change post-intervention. One limitation of the study was the small number of cerebrospinal fluid samples sent for confirmatory testing. CONCLUSIONS: Village-wide distribution of single-dose oral ciprofloxacin within 72 hours of case notification reduced overall meningitis AR. Distributions of ciprofloxacin could be an effective tool in future meningitis outbreak responses, but further studies investigating length of protection, effectiveness in urban settings, and potential impact on antimicrobial resistance patterns should be carried out. TRIAL REGISTRATION: ClinicalTrials.gov NCT02724046.

Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras.

BACKGROUND: Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis. METHODS AND FINDINGS: A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965-1973 to serogroup A CC1 (58%) in 1974-1985, then to serogroup C or B CC4821 (62%) in 2005-2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965-1985 to 84% (31/37) in 2005-2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986-2004 were not available and that only a small sample of convenience isolates from 1965-1985 were available. CONCLUSIONS: The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China.

Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis.

BACKGROUND: Approximately 7% of survivors from meningococcal meningitis (MM) suffer from neurological sequelae due to brain damage in the course of meningitis. The present study focuses on the role of matrix metalloproteinases (MMPs) in a novel mouse model of MM-induced brain damage. METHODS: The model is based on intracisternal infection of BALB/c mice with a serogroup C Neisseria meningitidis strain. Mice were infected with meningococci and randomised for treatment with the MMP inhibitor batimastat (BB-94) or vehicle. Animal survival, brain injury and host-response biomarkers were assessed 48 h after meningococcal challenge. RESULTS: Mice that received BB-94 presented significantly diminished MMP-9 levels (p < 0.01), intracerebral bleeding (p < 0.01), and blood-brain barrier (BBB) breakdown (p < 0.05) in comparison with untreated animals. In mice suffering from MM, the amount of MMP-9 measured by zymography significantly correlated with both intracerebral haemorrhage (p < 0.01) and BBB disruption (p < 0.05). CONCLUSIONS: MMPs significantly contribute to brain damage associated with experimental MM. Inhibition of MMPs reduces intracranial complications in mice suffering from MM, representing a potential adjuvant strategy in MM post-infection sequelae.

Management of a rifampicin-resistant meningococcal infection in a teenager.

We report a secondary case of rifampicin-resistant meningococcal disease and our experience in managing contact cases. Rifampicin resistance resulting from rpoB gene mutations is still uncommon enough that changing the current recommendations for chemoprophylaxis is unwarranted. However, ensuring limited but appropriate chemoprophylaxis may prevent the development of antimicrobial resistance. Thus, the definition of contact cases should be strictly respected. In the case of culture-positive Neisseria meningitidis, in vitro susceptibility testing to rifampicin must be systematically performed in order to detect rifampicin-resistant strains and, thus, institute appropriate prophylaxis in order to prevent secondary transmission.

[Presumptive bacterial meningitis in adults: initial antimicrobial therapy]. / Méningites présumées bactériennes communautaires de l'adulte : antibiothérapie initiale.

CSF sterilization should be obtained very rapidly to reduce both mortality and morbidity due to bacterial meningitis. Thus, antibiotic treatment should be adapted to the suspected bacterium and administered as early as possible at high dosage with - if necessary - a loading dose and continuous perfusion. The rates of abnormal susceptibility to penicillin of Streptococcus pneumoniae, Neisseria meningitis and Haemophilus influenzae are 37%, 30% and 12% respectively. Thus, ceftriaxone or cefotaxim must be used as empirical treatment. Listeria monocytogenes remains fully susceptible to aminopenicillin, so, the combination aminopenicillin and aminoglycoside is the first-line treatment. Antibiotic resistance, allergy or contra-indications, are in fact rare but in these cases, antibiotic combinations are often needed. The latter are more or less complex and clinically validated; they include molecules such as vancomycine, fosfomycin, fluoroquinolone or linezolid.

[First and second line antibiotic therapy for bacterial meningitis in infants and children]. / Modalités de l'antibiothérapie (initiale et ultérieure) chez l'enfant d'un à trois mois et de plus de trois mois (examen direct positif et examen direct négatif).

The potential severity of meningitis in infants and children requires an optimized initial empirical therapy, mainly based on direct cerebro spinal fluid (CSF) examination, and rapid therapeutic adaptation according to bacterial identification and susceptibility. Combination treatment including cefotaxim (300 mg/kg per day) or ceftriaxone (100mg/kg per day) and vancomycine (60 mg/kg per day) remains the standard first line if pneumococcal meningitis cannot be ruled out. A simple treatment with third generation cephalosporin can be used for Neisseria meningitidis or Haemophilus influenzae meningitis, aminoglycosides must be added in case of Enterobacteriacae, mainly before 3 months of age. Second line antibiotic therapy is adapted according to the clinical and bacteriological response on Day 2. When the minimal inhibitory concentration (MIC) of pneumococcal strain is less than 0.5mg/L, third generation cephalosporin should be continued alone for a total of 10 days. In other cases, a second lumbar puncture is necessary and the initial regimen, with or without rifampicin combination, should be used for 14 days. Amoxicillin during 3 weeks, associated with gentamycin or cotrimoxazole is recommended for listeriosis.

[Antibiotic management of presumptive bacterial meningitis in adults (rational, methods, course, and follow-up)]. / Antibiothérapie d'une méningite présumée bactérienne adulte (rationnel, modalités, durée, suivi).

The annual incidence of community acquired meningitis ranges between 0.6 and four per 100,000 adults in industrialized countries. The most common causative bacteria are Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes. The emergence of resistance to antibiotics, especially for S. pneumoniae, could explain the clinical failure of third generation cephalosporins used to treat adults with S. pneumoniae meningitis. The present therapeutic suggestions are more based on the extrapolation of an experimental model than on relevant clinical trials.

Rescue treatment with terlipressin in children with refractory septic shock: a clinical study.

INTRODUCTION: Refractory septic shock has dismal prognosis despite aggressive therapy. The purpose of the present study is to report the effects of terlipressin (TP) as a rescue treatment in children with catecholamine refractory hypotensive septic shock. METHODS: We prospectively registered the children with severe septic shock and hypotension resistant to standard intensive care, including a high dose of catecholamines, who received compassionate therapy with TP in nine pediatric intensive care units in Spain, over a 12-month period. The TP dose was 0.02 mg/kg every four hours. RESULTS: Sixteen children (age range, 1 month-13 years) were included. The cause of sepsis was meningococcal in eight cases, Staphylococcus aureus in two cases, and unknown in six cases. At inclusion the median (range) Pediatric Logistic Organ Dysfunction score was 23.5 (12-52) and the median (range) Pediatric Risk of Mortality score was 24.5 (16-43). All children had been treated with a combination of at least two catecholamines at high dose rates. TP treatment induced a rapid and sustained improvement in the mean arterial blood pressure that allowed reduction of the catecholamine infusion rate after one hour in 14 out of 16 patients. The mean (range) arterial blood pressure 30 minutes after TP administration increased from 50.5 (37-93) to 77 (42-100) mmHg (P < 0.05). The noradrenaline infusion rate 24 hours after TP treatment decreased from 2 (1-4) to 1 (0-2.5) microg/kg/min (P < 0.05). Seven patients survived to the sepsis episode. The causes of death were refractory shock in three cases, withdrawal of therapy in two cases, refractory arrhythmia in three cases, and multiorgan failure in one case. Four of the survivors had sequelae: major amputations (lower limbs and hands) in one case, minor amputations (finger) in two cases, and minor neurological deficit in one case. CONCLUSION: TP is an effective vasopressor agent that could be an alternative or complementary therapy in children with refractory vasodilatory septic shock. The addition of TP to high doses of catecholamines, however, can induce excessive vasoconstriction. Additional studies are needed to define the safety profile and the clinical effectiveness of TP in children with septic shock.

Acute bacterial meningitis in a patient receiving ibuprofen.

We report an atypical presentation of meningitis due to Neisseria meningitidis in a patient who received large doses of ibuprofen. Anti-inflammatory therapy such as NSAIDs could reduce CSF inflammation and modify the clinical outcome in patients with bacterial meningitis. However, the use of NSAIDs is not recommended in bacterial meningitis due to a lack of studies.

Long-term outcome for children with bacterial meningitis in rural Papua New Guinea.

This study was undertaken to evaluate the long-term neurological outcome for survivors of bacterial meningitis in rural Papua New Guinea. Children who were discharged from Nonga Base Hospital in Rabaul with a diagnosis of bacterial meningitis between 1992 and 2000 were evaluated in their home villages or on review at hospital. Neurological and developmental complications were documented. The outcomes for 80 of 121 eligible children were determined; eight had died following hospital discharge and 41 were lost to follow-up. Major neurological sequalae were found in 50 (63 per cent) of surviving children, and 27 (34 percent) had multiple severe complications. In rural Papua New Guinea meningitis causes high rates of mortality and severe long-term disability in a high proportion of survivors. High-level resistance to chloramphenicol is likely to be part of the reason for this, but widespread availability of third-generation cephalosporins for the treatment of meningitis, although urgently required, will not overcome the other problems of delayed presentation with established complications. There is a need for the introduction of conjugate Haemophilus influenzae vaccine, and affordable vaccination strategies against Streptococcus pneumoniae. Richer countries could sponsor these vaccines in developing countries, and apply pressure on vaccine producers to lower the costs.

Meningitis due to penicillin-resistant Neisseria meningitidis in a 20-year-old man.

The emergence of meningococcal strains with reduced susceptibility to penicillin has been reported in several countries during the past two decades, but not in Taiwan. We report a case of meningococcal meningitis with intermediate resistance to penicillin. A 20-year-old male soldier complained of chills, fever, and headache for 2 days, followed by drowsiness. Physical examination revealed erythema of the pharynx, stiff neck, erythematous maculopapules, and petechiae over the trunk and four limbs including palms and soles. Analysis of the cerebrospinal fluid (CSF) showed a white blood cell count of 9.06 x 10(6)/L, a glucose concentration of 0.165 mmol/L, and a protein concentration of 7.85 g/L. CSF culture yielded Neisseria meningitidis, serogroup B. The minimum inhibitory concentration of penicillin was determined using an E-test (0.125 microgram/mL); there was no beta-lactamase production. He recovered after high-dose penicillin G treatment with six doses of 24 million units per day for 11 days. The emergence of penicillin resistance in N. meningitidis in Taiwan requires surveillance. High-dose penicillin may be successful in treating penicillin-insensitive meningococcal meningitis. Alternative treatment with third-generation cephalosporins should be considered if poor response to penicillin is encountered.

Neisseria meningitidis: evolution of penicillin resistance and phenotype in a children's hospital in Barcelona, Spain.

UNLABELLED: Neisseria meningitidis is the most prevalent micro-organism involved in paediatric bacterial meningitis in the Barcelona area in children over 3 mo of age and it is an important cause of morbidity and mortality in Spain. A total of 498 strains of N. meningitidis, obtained between the years 1986 and 1997 from children with sepsis and/or meningitis, were characterized according to their serogroup and penicillin resistance; their distribution in serotypes and subtypes was studied from 1990. A decreasing tendency in the number of annual isolates was observed in this period. Most isolates belonged to serogroups B (403 strains) and C (77 strains). Serogroup C accounted for 1.8% of the strains in 1986 and 57.1% in 1997. The most prevalent phenotype between 1990 and 1996 was B:4:P1.15. but C:2b:P1.2,5 was the most prevalent in 1997. Overall penicillin-resistance rates ranged from 9.1% in 1986 (when a non-susceptible strain was isolated for the first time in the Hospital Sant Joan de Déu, Barcelona, Spain) to 71.4% in 1997, and it was more common among strains belonging to serogroup C (52% of resistant strains) than to serogroup B (22.1 % of resistant strains). The penicillin-resistance level was low, MIC always < or = 0.5 microg/ml. The present increase in N. meningitidis group C isolates, mainly C:2b:P1.2,5, and the availability of preventive measures for this highly pathological and resistant phenotype, argues strongly for the establishment of an epidemiological monitoring system. Detection of penicillin resistance should be standardized worldwide in order to unify data from all laboratories. CONCLUSION: A shift between serogroups B and C is observed in Barcelona from 1986 to 1997, as well as a rapid distribution of decreased penicillin susceptibility.