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1.  Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana 
PLoS Medicine  2007;4(3):e101.
The Kassena-Nankana District of northern Ghana lies in the African “meningitis belt” where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes.
Methods and Findings
Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics.
The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines.
An analysis of pharyngeal carriage of meningococci in one district of Ghana examined the features of the isolates that might contribute to the susceptibility to meningococcal epidemics in the African meningitis belt.
Editors' Summary
Bacterial meningitis is a rare but often fatal infection of the meninges—the thin membrane around the brain and the spinal cord. It can be caused by several types of bacteria, but meningococcal meningitis, which is caused by Neisseria meningitidis, is the most common form of bacterial meningitis in children and the second most common form in adults. About 10% of healthy people have N. meningitidis growing in their nose and throat; the bacteria are spread by exposure to infected respiratory secretions. In these “carriers,” the immune system keeps the bug in check but sometimes this surveillance fails, N. meningitidis enters the bloodstream and travels to the brain, where it infects the meninges and causes inflammation. The symptoms of meningococcal meningitis are sudden fever, headache, and a stiff neck and, even if strong antibiotics are given quickly, 10%–15% of patients die.
Why Was This Study Done?
Outbreaks of meningococcal meningitis occur all over the world, but the highest burden of disease is in the African meningitis belt, which stretches across sub-Saharan Africa from Senegal to Ethiopia. Here, localized epidemics of meningococcal meningitis occur every eight to 12 years during the dry season. Control of these epidemics relies on their early detection followed by mass immunization. This approach can be hard to implement in countries with limited resources, but the introduction of other control measures (for example, routine childhood immunization) requires an understanding of how the spread of different strains of N. meningitides through the community causes periodic epidemics. In this study, the researchers have studied the long-term dynamics of colonization by N. meningitidis and the occurrence of meningococcal meningitis in one region of the African meningitis belt.
What Did the Researchers Do and Find?
The researchers took throat swabs twice a year from people living in rural northern Ghana for eight years. They tested each swab for N. meningitidis and determined the serogroup of the bacteria they found. Bacterial serogroups differ only in terms of the antigens (molecules recognized by the immune system) that they express; N. meningitidis is classified into 13 serogroups based on the sugars that coat its surface. The researchers also used DNA sequencing to group the bacterial isolates into genoclouds—genetically closely related groups of meningococci represented by a sequence type (ST) number. Finally, they monitored meningococcal disease throughout the study and determined the serogroup and genocloud of patient isolates. Their results show colonization of 6% of the study population by N. meningitidis and reveal three consecutive waves of colonization and disease characterized by the presence of a serogroup A ST5 genocloud, a serogroup X ST751 genocloud, and finally a serogroup A ST7 genocloud. Colonizing bacteria isolated in this study in Ghana, the researchers report, changed their genotype more frequently but were less genetically diverse than those isolated in industrialized countries. In addition, the commonest serogroups of N. meningitidis in carriers in Ghana were disease-causing serogroups, whereas in industrialized countries these serogroups are rarely seen in carriers. However, non-groupable bacteria (bacteria that lack surface sugars), although common in industrialized countries, were rare in Ghana.
What Do These Findings Mean?
These findings begin to explain why epidemics of meningococcal meningitis are common in the African meningitis belt. Because there isn't a stable, genetically diverse population of N. meningitidis in carriers, the immune systems of people living here may not be optimally prepared to deal with new bacterial clones that arrive in the region, and this lack of immunity could result in frequent epidemics. However, because the researchers took relatively few samples every six months from one small area of the meningitis belt, the genetic diversity of N. meningitidis over the whole region might be considerably greater than that colonizing the study population. Nevertheless, the description of successive waves of meningococci colonization in Ghana has important implications for the proposed introduction of childhood vaccination against meninogococcal disease in the African meningitis belt. If this vaccination program goes ahead, warn the researchers, it will be essential to monitor which strains of N. meningitidis are colonizing the population and to have emergency plans ready to deal with any emerging disease-causing serogroups that are not covered by the vaccine.
Additional Information.
Please access these Web sites via the online version of this summary at
The Web sites of the institutions at which this research was performed, the Swiss Tropical Institute and the Navrongo Health Research Centre, provide more information about the programs
The World Health Organization provides information on meningococcal disease, including the African meningitis belt (in English, Spanish, Chinese, Russian, and Arabic)
Information on meningitis and vaccines and their potential use in Africa is available from the Meningitis Vaccine Project (in English and French)
Medline Plus has encyclopedia pages on meningococcal meningitis
The US Centers for Disease Control and Prevention provides information on meningococcal disease (in English and Spanish)
PMCID: PMC1831736  PMID: 17388665
2.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
PMCID: PMC1563501  PMID: 16953658
3.  Etiology and Antimicrobial Resistance Patterns of Acute Bacterial Meningitis in Children: A 10-Year Referral Hospital-Based Study in Northwest Iran 
Bacterial meningitis is still considered as one of the most dangerous infectious diseases, which causes numerous complications and high mortality if not diagnosed and treated timely.
This study was performed to determine antimicrobial resistance patterns of bacterial pathogens isolated from acute bacterial meningitis at Tabriz Children Educational-Health Care Center in Iran.
Patients and Methods:
In a retrospective study (from 2003 through 2013), all patients with bacterial meningitis were identified by cerebrospinal fluids with positive results in culture (107 cases). Patients' necessary data was recorded in a questionnaire. Furthermore, the results of simultaneous blood culture were also examined. Ultimately, antimicrobial susceptibility of isolates was determined using the disc diffusion method.
One hundred and seven patients with bacterial meningitis were identified by cerebrospinal fluids with positive results in culture. All of patients (100%) had fever (male/female = 1.27/1). The most prevalent pathogens isolated from CSF culture were Streptococcus pneumoniae (34.5%), Haemophilus influenzae type b (23.36%), Neisseria meningitidis (6.54%), Serratia spp. (6.54%), and Klebsiella pneumoniae (5.6%), respectively. Moreover, the patients' blood culture had positive results in 36.44% of cases with H. influenzae type b (20.65%) and S. pneumoniae (6.54%) as the main bacteria isolated from blood. Meningitis occurred mostly in children under two years (P = 0.001). According to antimicrobial susceptibility test, a relatively high resistance was reported against some conventional cephalosporins and other antibiotics.
S. pneumoniae and H. influenzae type b were the main pathogens of bacterial meningitis in children in the area under study. Most species had relatively high resistance to conventional antibiotics as compared to the past.
PMCID: PMC4166102  PMID: 25237583
Bacterial Meningitis; Child; Antibiotics
4.  Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and Haemophilus influenzae Type b Vaccination, 2000–2012 
Culture positive bacterial meningitis has fallen over a 12-year period in urban Malawi following Hib vaccination. Hib, NTS, and pneumococcal meningitis have fallen significantly in children. Pneumococcal meningitis has not fallen in adults; NTS and pneumococcal meningitis are seasonal.
Background. We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of Haemophilus influenzae type b (Hib) vaccination and the rollout of antiretroviral therapy (ART).
Methods. We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012.
Results. There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92–.94; P < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85–.88; P < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97–1.0; P = .135) despite rapid scale-up of ART provision. In children aged <5 years, Streptococcus pneumoniae, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. Streptococcus pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100 000 cases in children aged <14 years, 6 per 100 000 adolescents, and 10 per 100 000 adults.
Conclusions. Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic “meningitis belt” in Africa is essential.
PMCID: PMC4001285  PMID: 24496208
meningitis; Africa; HIV; vaccination; antiretroviral therapy
5.  African meningitis belt pneumococcal disease epidemiology indicates a need for an effective serotype 1 containing vaccine, including for older children and adults 
Pneumococcal conjugate vaccine strategies in GAVI-eligible countries are focusing on infant immunization but this strategy may not be optimal in all settings. We aimed to collect all available population based data on pneumococcal meningitis throughout life in the African meningitis belt and then to model overall meningitis risk to help inform vaccine policy.
After a systematic review of literature published from 1970 through the present, we found robust population-based Streptococcus pneumoniae (Sp) meningitis data across age strata for four African meningitis belt countries that included 35 surveillance years spanning from 1970 to 2005. Using these data we modeled disease risk for a hypothetical cohort of 100,000 persons followed throughout life.
Similar to meningococcal meningitis, laboratory-confirmed pneumococcal meningitis was seasonal, occurring primarily in the dry season. The mean annual Sp meningitis incidence rates were 98, 7.8 to 14, and 5.8 to 12 per 100,000 among persons <1, 1 through 19, and 20 to 99 years of age, respectively, which (in the absence of major epidemics) were higher than meningococcal meningitis incidences for persons less than 1 and over 20 years of age. Mean Sp meningitis case fatality ratios (CFR) among hospitalized patients ranged from 36-66% depending on the age group, with CFR exceeding 60% for all age groups beyond 40 years; depending on the age group, Sp meningitis mortality incidences were 2 to 12-fold greater than those for meningococcal meningitis. The lifetime risks of pneumococcal meningitis disease and death were 0.6% (1 in 170) and 0.3% (1 in 304), respectively. The incidences of these outcomes were highest among children age <1 year. However, the cumulative risk was highest among persons age 5 to 59 years who experienced 59% of pneumococcal meningitis outcomes. After age 5 years and depending on the country, 59-79% of meningitis cases were caused by serotype 1.
In the African meningitis belt, Sp is as important a cause of meningitis as Neisseria meningitidis, particularly among older children and working age adults. The meningitis belt population needs an effective serotype 1 containing vaccine and policy discussions should consider vaccine use outside of early childhood.
PMCID: PMC2838886  PMID: 20146815
6.  Chloramphenicol or ceftriaxone, or both, as treatment for meningitis in developing countries? 
Archives of Disease in Childhood  2003;88(6):536-539.
Aims: To determine in children with meningitis whether there is any difference in mortality and neurological sequelae using chloramphenicol as first line treatment, with a change to ceftriaxone if chloramphenicol resistance is shown in vitro, compared to using ceftriaxone as first line treatment, with a change to chloramphenicol if there is no evidence of in vitro resistance.
Methods: An observational study with a retrospective control group nested within a randomised trial of fluid management for bacterial meningitis where clinical care was standardised. Chloramphenicol is standard treatment for bacterial meningitis in Papua New Guinea. In the first 150 cases we used chloramphenicol and only changed treatment to ceftriaxone if chloramphenicol resistance for cerebrospinal fluid isolates was proved. After finding 20% of Haemophilus influenzae were resistant to chloramphenicol, and that most affected children had poor outcomes, we changed to an alternative strategy. In the next 196 cases first line treatment was ceftriaxone and treatment was changed to chloramphenicol if the isolated bacteria were found to be susceptible.
Results: When chloramphenicol was used as first line treatment for meningitis followed by ceftriaxone when in vitro resistance was shown, there was invariably a very poor outcome in chloramphenicol resistant disease (71% of children died or had severe neurological complications). Using ceftriaxone as first line treatment was effective in reducing mortality and neurological sequelae from chloramphenicol resistant Haemophilus influenzae type (71% v 9%, relative risk 0.13; 95% CI 0.02 to 0.87; p = 0.013). Changing to chloramphenicol if there was no evidence of in vitro resistance was less than half the cost of empirical use of ceftriaxone for a full course for all children with meningitis.
Conclusions: Using a third generation cephalosporin as first line treatment is effective in dealing with the problem of poor outcomes from meningitis due to Haemophilus influenzae that is resistant to chloramphenicol, and a strategy of changing to chloramphenicol if in vitro susceptibility is shown will reduce the use of expensive third generation cephalosporins without comprising on clinical outcomes. This highlights the urgent need to reduce the costs of third generation cephalosporins, to improve bacteriological services in developing countries, and to introduce effective and affordable vaccines against H influenzae and Streptococcus pneumoniae.
PMCID: PMC1763115  PMID: 12765927
7.  Bacterial Meningitis in Malawian Infants <2 Months of Age 
Supplemental Digital Content is available in the text.
Neonatal meningitis is an important cause of morbidity in sub-Saharan Africa and requires urgent empiric treatment with parenteral administered antibiotics. Here we describe the etiology, antimicrobial susceptibility and suitability of the World Health Organization first-line recommended antibiotics (penicillin and gentamicin) for bacterial meningitis in young infants in Malawi.
We reviewed all cerebrospinal fluid samples received from infants ≤2 months of age with clinically suspected meningitis between January 1, 2002, and December 31, 2008, at the Queen Elizabeth Central Hospital in Blantyre, Malawi.
We identified 259 culture-positive isolates from 259 infants ≤2 months of age. Sixty isolates were from neonates ≤7 days old, in whom the most common pathogens were Group B Streptococcus (27/60; 45.0%), Streptococcus pneumoniae (13/60; 21.7%) and nontyphoidal Salmonella enterica (7/60; 11.7%). One hundred and ninety one isolates were from young infants who were >7 days and ≤2 months of age. In this group, the most common isolates were S. pneumoniae (80/191; 41.9%), Group B Streptococcus (38/191; 19.9%) and nontyphoidal Salmonella enterica (34/191; 17.8%). More isolates were susceptible to ceftriaxone than to the combination of penicillin and gentamicin (218/220; 99.1% vs. 202/220; 91.8%, Fisher’s exact test P = 0.006). In particular, Gram-negative isolates were significantly more susceptible to ceftriaxone than to gentamicin (72/74; 97.3% vs. 63/74; 85.1%, Fisher’s exact test P = 0.020). Penicillin and gentamicin provided less coverage for Gram-negative than Gram-positive isolates (74/86; 86.0% vs. 155/163; 95.1%, χ2 = 6.24, P = 0.012).
In view of these results, the World Health Organization recommendations for empiric penicillin and gentamicin for suspected neonatal meningitis should be reevaluated.
PMCID: PMC4025590  PMID: 24378940
newborn; infant; meningitis; drug resistance; microbial; Africa
8.  Diagnostic Accuracy of Quantitative PCR (Xpert MTB/RIF) for Tuberculous Meningitis in a High Burden Setting: A Prospective Study 
PLoS Medicine  2013;10(10):e1001536.
Vinod Patel and colleagues evaluate the sensitivity and specificity of quantitative PCR using Xpert MTB/RIF for diagnosis of TB meningitis in the high-burden setting of South Africa.
Please see later in the article for the Editors' Summary
Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.
Methods and Findings
235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information.
Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%–75%) and 95% (87%–99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%–92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%–94%] versus 47% [31%–61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.
Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, tuberculosis (TB) is the leading cause of death among people living with HIV. The risk of developing TB is estimated to be 12–20 times greater in people with HIV than in people without HIV. The World Health Organization reported that, in 2011, there were 8.7 million new cases of TB, of which 1.1 million were among people living with HIV. TB infection in people living with HIV is a major problem in sub-Saharan Africa, where up to 80% of individuals infected with TB are also infected with HIV.
TB is caused by a bacterial infection spread through the air from one person to another when the infected person coughs or sneezes, for example. It usually affects the lungs, but it can also affect other parts of the body including the brain, where it leads to meningitis. People with meningitis caused by TB are often seriously ill. Many may develop brain damage, and 30% will die, particularly if they aren't diagnosed quickly and treatment is delayed. TB meningitis is therefore a serious health concern in countries with high rates of HIV and TB co-infection.
Why Was This Study Done?
There is currently no simple test to diagnose TB meningitis. The tests that are available detect only about 50% of cases. They are expensive and practical to use only in a high-tech environment, and are therefore unsuitable for low-income countries.
Recently, a new test has become available to detect TB, known as Xpert MTB/RIF. The test is used to detect the DNA (the molecular biological instructions for each organism) of the bacteria that causes TB. It is accurate at detecting TB lung infection, requires minimal training to operate, and is relatively inexpensive. It is now being used to diagnose TB in countries with high rates of the disease, including South Africa. However, thus far its use has been limited to detecting the TB bacterium in sputum samples (a mixture of saliva and phlegm) from people with a lung infection. The few studies that have assessed whether the test can be used to detect TB meningitis have been small and inconclusive.
This study was carried out to determine whether Xpert MTB/RIF could be used to detect TB bacteria in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) in people with TB meningitis. The researchers wanted to find out whether the test would be sensitive (correctly identifying patients with TB meningitis) and specific (correctly identifying patients without TB meningitis). They also wanted to address more practical questions such as how much cerebrospinal fluid needs to be collected and how the sample needs to be processed to ensure accurate results.
What Did the Researchers Do and Find?
The researchers used the Xpert MTB/RIF test to analyze cerebrospinal fluid samples from 204 patients with suspected TB meningitis. These patients were recruited from hospitals in South Africa between January 2008 and December 2011.
Standard diagnostic tests were used to categorize these patients as either definitely having TB meningitis, possibly having TB meningitis, or not having TB meningitis. Among patients infected with HIV, the Xpert MTB/RIF correctly identified 62% of those with TB meningitis and 95% of those without TB meningitis.
The researchers also assessed whether it would be more cost-effective to use the test only for cases where the standard diagnostic procedure was uncertain, i.e., to avoid testing in cases where TB meningitis was very likely following the normal clinical assessment. Based on the researchers' theoretical analysis, this would reduce test use by only about 10%.
What Do These Findings Mean?
This study suggests that Xpert MTB/RIF is a useful diagnostic test for TB meningitis in patients infected with HIV living in areas where there are high levels of TB infection. It is not known how well the test would perform in places where TB levels are low, and the test did not perform well in individuals without HIV, although there were very few of these patients. The Xpert MTB/RIF test correctly identified more positive cases than the other tests used to diagnose TB meningitis, within 24 hours of first seeing a patient. However, the test accuracy was best when the cerebrospinal fluid sample was centrifuged (spinning the sample very fast to concentrate the test material) to achieve the best results. This means additional apparatus would be required, resulting in higher cost and requiring more training. The researchers conclude that this test could still be useful in settings where resources are limited.
There are also important questions that remain unanswered. This study shows only that the Xpert MTB/RIF test is useful in determining that a patient has TB meningitis. It is not useful in determining that a patient does not have TB meningitis. Further research is needed to determine whether the test will be effective in areas with lower rates of TB, as well as whether its use will improve clinical practice and ultimately lead to better outcomes for patients. The hope is that the test will result in more rapid diagnosis and faster treatment, reducing the number of avoidable deaths from TB meningitis.
Additional Information
Please access these websites via the online version of this summary at
• This study is further discussed in a PLOS Medicine Perspective by David Boulware
• The US National Institutes of Health provides information on TB meningitis
• The World Health Organization provides information on tuberculosis and HIV
• The US Centers for Disease Control and Prevention has a factsheet on HIV and TB
• also provides information about HIV and TB
PMCID: PMC3805498  PMID: 24167451
9.  Antimicrobial sensitivity patterns of cerebrospinal fluid (CSF) isolates in Namibia: implications for empirical antibiotic treatment of meningitis 
Bacterial meningitis is a medical emergency associated with high mortality rates. Cerebrospinal fluid (CSF) culture is the “gold standard” for diagnosis of meningitis and it is important to establish the susceptibility of the causative microorganism to rationalize treatment. The Namibia Standard Treatment Guidelines (STGs) recommends initiation of empirical antibiotic treatment in patients with signs and symptoms of meningitis after taking a CSF sample for culture and sensitivity. The objective of this study was to assess the antimicrobial sensitivity patterns of microorganisms isolated from CSF to antibiotics commonly used in the empirical treatment of suspected bacterial meningitis in Namibia.
This was a cross-sectional descriptive study of routinely collected antibiotic susceptibility data from the Namibia Institute of Pathology (NIP) database. Results of CSF culture and sensitivity from January 1, 2009 to May 31, 2012, from 33 state hospitals throughout Namibia were analysed.
The most common pathogens isolated were Streptococcus species, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and Escherichia coli. The common isolates from CSF showed high resistance (34.3% –73.5%) to penicillin. Over one third (34.3%) of Streptococcus were resistance to penicillin which was higher than 24.8% resistance in the United States. Meningococci were susceptible to several antimicrobial agents including penicillin. The sensitivity to cephalosporins remained high for Streptococcus, Neisseria, E. coli and Haemophilus. The highest percentage of resistance to cephalosporins was seen among ESBL K. pneumoniae (n = 7, 71%–100%), other Klebsiella species (n = 7, 28%–80%), and Staphylococcus (n = 36, 25%–40%).
The common organisms isolated from CSF were Streptococcus Pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and E. coli. All common organisms isolated from CSF showed high sensitivity to cephalosporins used in the empirical treatment of meningitis. The resistance of the common isolates to penicillin is high. Most ESBL K. pneumoniae were isolated from CSF samples drawn from neonates and were found to be resistant to the antibiotics recommended in the Namibia STGs. Based on the above findings, it is recommended to use a combination of aminoglycoside and third-generation cephalosporin to treat non–ESBL Klebsiella isolates. Carbapenems (e.g., meropenem) and piperacillin/tazobactam should be considered for treating severely ill patients with suspected ESBL Klebsiella infection. Namibia should have a national antimicrobial resistance surveillance system for early detection of antibiotics that may no longer be effective in treating meningitis and other life-threatening infections due to resistance.
PMCID: PMC3987067  PMID: 24764539
Celebrospinal fluid; Antimicrobial resistance; Culture and sensitivity; Empiric therapy; Meningitis; Namibia
10.  Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study 
A low cerebrospinal fluid (CSF) white-blood cell count (WBC) has been identified as an independent risk factor for adverse outcome in adults with bacterial meningitis. Whereas a low CSF WBC indicates the presence of sepsis with early meningitis in patients with meningococcal infections, the relation between CSF WBC and outcome in patients with pneumococcal meningitis is not understood.
We examined the relation between CSF WBC, bacteraemia and sepsis in a prospective cohort study that included 352 episodes of pneumococcal meningitis, confirmed by CSF culture, occurring in patients aged >16 years.
CSF WBC was recorded in 320 of 352 episodes (91%). Median CSF WBC was 2530 per mm3 (interquartile range 531–6983 per mm3) and 104 patients (33%) had a CSF WBC <1000/mm3. Patients with a CSF WBC <1000/mm3 were more likely to have an unfavourable outcome (defined as a Glasgow Outcome Scale score of 1–4) than those with a higher WBC (74 of 104 [71%] vs. 87 of 216 [43%]; P < 0.001). CSF WBC was significantly associated with blood WBC (Spearman's test 0.29), CSF protein level (0.20), thrombocyte count (0.21), erythrocyte sedimentation rate (-0.15), and C-reactive protein levels (-0.18). Patients with a CSF WBC <1000/mm3 more often had a positive blood culture (72 of 84 [86%] vs. 138 of 196 [70%]; P = 0.01) and more often developed systemic complications (cardiorespiratory failure, sepsis) than those with a higher WBC (53 of 104 [51%] vs. 69 of 216 [32%]; P = 0.001). In a multivariate analysis, advanced age (Odds ratio per 10-year increments 1.22, 95%CI 1.02–1.45), a positive blood culture (Odds ratio 2.46, 95%CI 1.17–5.14), and a low thrombocyte count on admission (Odds ratio per 100,000/mm3 increments 0.67, 95% CI 0.47–0.97) were associated with a CSF WBC <1000/mm3.
A low CSF WBC in adults with pneumococcal meningitis is related to the presence of signs of sepsis and systemic complications. Invasive pneumococcal infections should possibly be regarded as a continuum from meningitis to sepsis.
PMCID: PMC1618396  PMID: 17038166
11.  High Cerebrospinal Fluid (CSF) Penetration and Potent Bactericidal Activity in CSF of NZ2114, a Novel Plectasin Variant, during Experimental Pneumococcal Meningitis▿  
Plectasin is the first defensin-type antimicrobial peptide isolated from a fungus and has potent activity against gram-positive bacteria. By using an experimental meningitis model, the penetration of plectasin into the cerebrospinal fluid (CSF) of infected and uninfected rabbits and the bactericidal activities in CSF of the plectasin variant NZ2114 and ceftriaxone against a penicillin-resistant Streptococcus pneumoniae strain (NZ2114 and ceftriaxone MICs, 0.25 and 0.5 μg/ml, respectively) were studied. Pharmacokinetic analysis showed that there was a significantly higher level of CSF penetration of NZ2114 through inflamed than through noninflamed meninges (area under the concentration-time curve for CSF/area under the concentration-time curve for serum, 33% and 1.1%, respectively; P = 0.03). The peak concentrations of NZ2114 in purulent CSF were observed ∼3 h after the infusion of an intravenous bolus of either 20 or 40 mg/kg of body weight and exceeded the MIC >10-fold for a 6-h study period. Treatment with NZ2114 (40 and 20 mg/kg at 0 and 5 h, respectively; n = 11) caused a significantly higher reduction in CSF bacterial concentrations than therapy with ceftriaxone (125 mg/kg at 0 h; n = 7) at 3 h (median changes, 3.7 log10 CFU/ml [interquartile range, 2.5 to 4.6 log10 CFU/ml] and 2.1 log10 CFU/ml [interquartile range, 1.7 to 2.6 log10 CFU/ml], respectively; P = 0.001), 5 h (median changes, 5.2 log10 CFU/ml [interquartile range, 3.6 to 6.1 log10 CFU/ml] and 3.1 log10 CFU/ml [interquartile range, 2.6 to 3.7 log10 CFU/ml], respectively; P = 0.01), and 10 h (median changes, 5.6 log10 CFU/ml [interquartile range, 5.2 to 5.9 log10 CFU/ml] and 4.2 log10 CFU/ml [interquartile range, 3.6 to 5.0 log10 CFU/ml], respectively; P = 0.03) after the start of therapy as well compared to the CSF bacterial concentrations in untreated rabbits with meningitis (n = 7, P < 0.05). Also, significantly more rabbits had sterile CSF at 5 and 10 h when they were treated with NZ2114 than when they were treated with ceftriaxone (67% [six of nine rabbits] and 0% [zero of seven rabbits], respectively, at 5 h and 75% [six of eight rabbits] and 14% [one of seven rabbits], respectively, at 10 h; P < 0.05). Due to its excellent CSF penetration and potent bactericidal activity in CSF, the plectasin variant NZ2114 could be a promising new option for the treatment of CNS infections caused by gram-positive bacteria, including penicillin-resistant pneumococcal meningitis.
PMCID: PMC2663087  PMID: 19188395
12.  Enhanced diagnosis of pneumococcal meningitis using the Binax NOW® S. pneumoniae immuno-chromatographic test: a multi-site study 
Accurate etiologic diagnosis of meningitis in developing countries is needed to improve clinical care and optimize disease prevention strategies. Cerebrospinal fluid (CSF) culture and latex agglutination are the current standard diagnostic methods but lack sensitivity.
We prospectively assessed the utility of the Binax NOW® S. pneumoniae immuno-chromatographic test (ICT) compared to culture in five countries conducting bacterial meningitis surveillance in Africa and Asia. Most CSF was collected from patients 1 to 59 months old.
A total of 1173 CSF samples from suspected meningitis cases were included. The ICT was positive in 98.6% of culture-confirmed pneumococcal meningitis cases (N=69) and negative in 99.3% of culture-confirmed bacterial meningitis cases caused by other pathogens (N=125). Using culture and latex agglutination testing alone, pneumococci were detected from 7.4% of patients in Asia and 15.6% in Africa. The ICT increased pneumococcal detection, resulting in similar identification rates across sites, from 16.2% in Nigeria to 20% in Bangladesh. ICT detection in culture-negative cases varied by region (8.5% in Africa vs. 18.8% in Asia, p<0.001), prior antibiotic use (24.2% with prior antibiotics vs. 12.2% without, p<0.001) and WBC count (9.0% for WBC=10-99, 22.1% for WBC=100-999 and 25.4% for WBC≥1000; p<0.001 for trend).
The ICT provided substantial benefit over latex agglutination and culture in Asian sites, but not in African sites. With the addition of the ICT, the proportion of meningitis attributable to pneumococcus was similar in Asia and Africa. These results suggest that previous studies have underestimated the proportion of pediatric bacterial meningitis due to pneumococcus.
PMCID: PMC2863072  PMID: 19191619
13.  Antimicrobial Susceptibility of Bacteria Isolated from Cerebrospinal Fluids in an Iranian Referral Pediatric Center, 1998-2008 
Mædica  2012;7(2):131-137.
Antimicrobial susceptibility patterns of bacterial meningitis provide essential information regarding selection of antibiotic therapy for patients with bacterial meningitis. This study presents data on causes of bacterial meningitis and their susceptibility pattern among children at Children's Medical Center (CMC), a referral tertiary care center in Iran. In this comprehensive retrospective study we reviewed microbiology records of all inpatients suspected to bacterial meningitis, during 1998-2008 of period. Of 11269 CSF cultures examined in the study, 329 (2.9%) were positive for bacterial growth. Overall, coagulase negative staphylococci (CONS) were the most frequent group of organism recovered from our CSF cultures (40%), followed by gram negative enteric bacilli (19.7%). Also, high rates of oxacillin and vancomycin resistance were found among staphylococci. In our study more than 80% of gram-negative enteric bacteria were resistant to ampicillin; we also found high rates of cephalosporin resistance among these organisms. Over 55% of S. pneumoniae were resistant to penicillin. Staphylococci species and gram-negative enteric organisms were the most common pathogens isolated from CSF cultures in this study. It seems that nosocomial meningitis is the main cause of bacterial meningitis in CMC Hospital. Our report draws attention to the importance devising a national strategy to control the spread of resistance in Iran.
PMCID: PMC3557420  PMID: 23399784
bacterial meningitis; antimicrobial susceptibility; CSF
14.  Genomic pneumococcal load and CSF cytokines are not related to outcome in Malawian adults with meningitis 
The Journal of Infection  2014;69(5):440-446.
Bacterial meningitis in sub-Saharan Africa is predominantly caused by Streptococcus pneumoniae, is often associated with HIV co-infection and mortality rates are double those seen in better resourced settings.
To investigate the cause of this excessive mortality we quantified the pneumococcal DNA load and six common pro-inflammatory cytokines in the cerebrospinal fluid (CSF) of Malawian adults with culture proven pneumococcal meningitis and correlated the results to clinical parameters and outcome. There are currently no published data relating bacterial load to outcome in adults with pneumococcal meningitis.
The mean age of patients was 32 years, 82% were HIV infected and 49% had died by day 40. CSF bacterial loads were high (median 6.5 × 105 copies/ml CSF) and there was no significant variation in bacterial load between survivors and non-survivors. All pro-inflammatory CSF cytokines were elevated in the CSF, with no clinically important differences between survivors and non-survivors. HIV status did not affect the CSF bacterial load or cytokine response.
Mortality from pneumococcal meningitis in adults in sub-Saharan Africa is not related to pneumococcal bacterial load. More research is needed to understand the very high mortality from meningitis in this region.
•Pneumococcal meningitis in Malawian adults has a very high mortality rate.•Bacterial load and cytokine response may predict outcome in children.•Pneumococcal load and cytokine response were not associated with outcome in adults.•Low CSF white cell count and Glasgow coma score were associated with mortality.•Anti-cytokine therapies are unlikely to be effective in bacterial meningitis.
PMCID: PMC4209731  PMID: 24975177
Bacterial meningitis; Streptococcus pneumoniae; Bacterial load; Cerebrospinal fluid; Cytokine response; Mortality; Africa
15.  The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review 
BMC Public Health  2013;13(Suppl 3):S21.
Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST).
We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST.
We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology data to provide an estimate of the preventable fraction of childhood meningitis mortality with three doses of Hib (38-43%) and pneumococcal conjugate vaccines (28-35%) for use in LiST.
Few RCTs or vaccine effectiveness studies evaluated the dose-specific impact of Hib and PCV vaccines on childhood meningitis mortality, necessitating use of proxy measures to estimate population impact in LiST. Our analysis indicates that approximately three-quarters of meningitis deaths are preventable with existing Hib and PCV vaccines.
PMCID: PMC3847464  PMID: 24564188
16.  Method for inducing experimental pneumococcal meningitis in outbred mice 
BMC Microbiology  2004;4:36.
Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is associated with the highest mortality among bacterial meningitis and it may also lead to neurological sequelae despite the use of antibiotic therapy. Experimental animal models of pneumococcal meningitis are important to study the pathogenesis of meningitis, the host immune response induced after infection, and the efficacy of novel drugs and vaccines.
In the present work, we describe in detail a simple, reproducible and efficient method to induce pneumococcal meningitis in outbred mice by using the intracranial subarachnoidal route of infection. Bacteria were injected into the subarachnoid space through a soft point located 3.5 mm rostral from the bregma. The model was tested with several doses of pneumococci of three capsular serotypes (2, 3 and 4), and mice survival was recorded. Lethal doses killing 50 % of animals infected with type 2, 3 and 4 S. pneumoniae were 3.2 × 10, 2.9 × 10 and 1.9 × 102 colony forming units, respectively. Characterisation of the disease caused by the type 4 strain showed that in moribund mice systemic dissemination of pneumococci to blood and spleen occurred. Histological analysis of the brain of animals infected with type 4 S. pneumoniae proved the induction of meningitis closely resembling the disease in humans.
The proposed method for inducing pneumococcal meningitis in outbred mice is easy-to-perform, fast, cost-effective, and reproducible, irrespective of the serotype of pneumococci used.
PMCID: PMC524167  PMID: 15385055
17.  Prevention of Brain Injury by the Nonbacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis▿  
Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 × 104 ± 0.5 × 104 CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log10 3.6 ± 1.0 and log10 6.3 ± 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.
PMCID: PMC1891377  PMID: 17371820
18.  Serum Procalcitonin in Viral and Bacterial Meningitis 
In children with meningitis, there is a difficulty to verify the etiology as viral or bacterial. Therefore, intensive research has been carried out to find new and rapid diagnostic methods for differentiating bacterial from viral meningitis.
The aim of this work was to study the behavior of procalcitonin (PCT) and whether it can be used to differentiate children with bacterial from those with viral meningitis. We also compared PCT to C-reactive protein (CRP) and white blood cell count.
Patients and Methods:
Forty children aged from 4 months to 12 years with clinically suspected meningitis were studied. Lumbar punctures were done for all cases before starting initial antibiotic treatment. According to the results of bacterial cultures and cerebrospinal fluid (CSF) cytochemical profile, our patients were classified into two groups: bacterial meningitis group and viral meningitis group. PCT, CRP, and leukocyte count were measured at the time of admission and after 3 days.
Forty children aged from 4 months to 12 years with clinically suspected meningitis were studied. Lumbar punctures were done for all cases before starting initial antibiotic treatment. According to the results of bacterial cultures and cerebrospinal fluid (CSF) cytochemical profile, our patients were classified into two groups: bacterial meningitis group and viral meningitis group. PCT, CRP, and leukocyte count were measured at the time of admission and after 3 days.
PCT levels were significantly higher in patients with bacterial meningitis (mean, 24.8 ng/ml) compared to patients with viral meningitis (mean, 0.3 ng/ml) (P<0.001). PCT levels in bacterial meningitis group decreased after 3 days of starting treatment, but remained higher than viral meningitis group (mean, 10.5 ng/ml). All CSF parameters, blood leukocytes, and CRP showed overlapping values between the two groups. Serum PCT with cut off value >2 ng/ml showed sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 66%, 68%, and 100%, respectively, for the diagnosis of bacterial meningitis.
Serum procalcitonin level has a better diagnostic and prognostic value than CRP or leukocyte count to distinguish between bacterial and viral meningitis. It is also a good indicator of the efficacy of treatment of bacterial meningitis.
PMCID: PMC3068572  PMID: 21572603
C-reactive protein; Meningitis; Procalcitonin
19.  Factors Associated with Ceftriaxone Nonsusceptibility of Streptococcus pneumoniae: Analysis of South African National Surveillance Data, 2003 to 2010 
It is important to monitor β-lactam antimicrobial nonsusceptibility trends for Streptococcus pneumoniae to inform empirical treatment guidelines. In this study, we describe penicillin and ceftriaxone susceptibility trends using national laboratory-based pneumococcal surveillance data from 2003 to 2010. A sentinel enhanced-site patient subset (2009 to 2010) contributed to the risk factor and mortality analyses. We included 9,218 invasive pneumococcal disease (IPD) cases for trend analyses and 2,854 IPD cases for risk factor and mortality analyses. Overall, we detected no significant changes in penicillin (patients <5 years of age, P = 0.50; patients ≥5 years of age, P = 0.05) or ceftriaxone nonsusceptibility rates (patients <5 years of age, P = 0.21; patients ≥5 years of age, P = 0.60). Factors associated with ceftriaxone nonsusceptibility on multivariate analysis were an age of <5 years (<1 year of age: adjusted odds ratio [aOR], 2.87; 95% confidence interval [CI], 1.70 to 4.86; 1 to 4 years of age: aOR, 2.58; 95% CI, 1.53 to 4.35, versus 25 to 44 years of age), province (Gauteng [aOR, 2.46; 95% CI, 1.26 to 4.84], and Northern Cape [aOR, 4.52; 95% CI, 1.95 to 10.52] versus KwaZulu-Natal), β-lactam use within 24 h preceding admission (aOR, 2.52; 95% CI, 1.41 to 4.53), and 13-valent vaccine serotypes (aOR, 51.64; 95% CI, 7.18 to 371.71). Among patients ≥5 years of age with meningitis who were treated according to current guidelines, HIV-infected patients (aOR, 2.94; 95% CI, 1.32 to 6.54) and patients infected with ceftriaxone-nonsusceptible isolates (aOR, 3.17; 95% CI, 1.27 to 7.89) had increased mortality rates. Among children <5 years of age with meningitis, mortality was increased in HIV-infected patients (aOR, 3.04; 95% CI, 1.40 to 6.56) but not in those with ceftriaxone-nonsusceptible isolates. Penicillin and ceftriaxone nonsusceptibility remained stable over the study period. Ceftriaxone nonsusceptibility was associated with increased mortality among patients ≥5 years of age with meningitis. The introduction of a pneumococcal conjugate vaccine may reduce ceftriaxone-nonsusceptible meningitis.
PMCID: PMC4068496  PMID: 24687499
20.  Phenotypic Characterization and Antibiogram of CSF Isolates in Acute Bacterial Meningitis 
Context: Acute bacterial meningitis (ABM) is a medical emergency, which warrants an early diagnosis and an aggressive therapy. Despite the availability of potent newer antibiotics, the mortality rate caused by acute bacterial meningitis remains significantly high in India and in other developing countries, which ranges from 16 - 32%. There is a need of a periodic review of bacterial meningitis worldwide, since the pathogens which are responsible for the infection may vary with time, geography and the age of the patient.
Aims: Our aim was to study the bacterial profiles and antimicrobial susceptibility patterns of the CSF isolates which were obtained from patients of acute bacterial meningitis in our area.
Settings and Design: Two hundred and fifty two clinically diagnosed cases of acute bacterial meningitis, who were admitted to the wards of a tertiary medical centre in Patna, during the period from August 2011 to December 2012, were included in this study.
Material and Methods: Two hundred and fifty two CSF samples from as many patients of ABM were processed for cell counts, biochemical analysis, gram staining, culture, antigen detection by latex agglutination test (LAT) and antibiotic susceptibility tests, as per the standard techniques.
Results: In this study, 62.3% patients were males and 37.7% were females The most common age group of presentation was 12-60 years (80.2%). Gram stained smears were positive in 162 (64.3%) samples, while culture yielded positive growth in 200 (79.4%) patients. Streptococcus pneumoniae was the most common pathogen which was isolated in 120 (60%) culture positive cases. Cell counts showed the predominance of neutrophils in all cases with ABM. High protein and low sugar levels correlated well with the features of ABM. All gram positive isolates were sensitive to vancomycin. All the gram negative isolates were sensitive to imipenem. Twenty two (8.7%) patients expired during the course of study. Deaths were caused by N.meningitidis in 9 (40.9%) cases, by S.pneumoniae in 3 (13.6%) cases and by H.influenzea in 1 (4.5%) case. In the remaining 9 (40.9%) mortality cases, the organism could not be identified.
Conclusion: Simple, rapid, inexpensive tests like gram staining remain significant means for diagnosis of ABM in developing countries. LAT for pneumococcal antigen should be performed first, since Streptococcus pneumoniae remains the major aetiological agent of ABM, both in adults and children. The final diagnosis of ABM depends upon a comprehensive analysis of CSF smears, cultures, LAT, cytological, biochemical and clinical findings of the cases, and a single test or parameter cannot be used to decide the course of management in the patients. However, empirical therapy is advocated, considering the potentially high rate of mortality in these patients.
PMCID: PMC3919387  PMID: 24551618
Acute bacterial meningitis; Antimicrobial susceptibility pattern; Haemophilus influenzae; Neisseria meningitidis; Latex agglutination test; Pyogenic meningitis; Streptococcus pneumoniae
21.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at:
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at:
For more information on the economic analysis, please visit the PATH website:
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website:
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
22.  Evaluation of Moxifloxacin, a New 8-Methoxyquinolone, for Treatment of Meningitis Caused by a PenicillinResistant Pneumococcus in Rabbits 
Moxifloxacin is a new 8-methoxyquinolone with high activity against gram-positive bacteria, including penicillin-resistant pneumococci. In an experimental meningitis model, we studied the pharmacokinetics of moxifloxacin in infected and uninfected rabbits and evaluated the antibiotic efficacies of moxifloxacin, ceftriaxone, and vancomycin against a penicillin-resistant Streptococcus pneumoniae strain (penicillin, ceftriaxone, vancomycin, and moxifloxacin MICs were 1, 0.5, 0.5, and 0.125 μg/ml, respectively). Moxifloxacin entered cerebrospinal fluid (CSF) readily, with peak values within 15 to 30 min after bolus intravenous infusion and with a mean percent penetration into normal and purulent CSF of approximately 50 and 80%, respectively. The bactericidal effect of moxifloxacin was concentration dependent, and regrowth was seen only when the concentration of moxifloxacin in CSF was below the minimal bactericidal concentration. All antibiotic-treated groups (moxifloxacin given in two doses of 40 mg/kg of body weight, moxifloxacin in two 20-mg/kg doses, ceftriaxone in one 125-mg/kg dose, and vancomycin in two 20-mg/kg doses) had significantly higher reductions in CSF bacterial concentration than the untreated group (P < 0.05). Moxifloxacin was as effective as vancomycin and ceftriaxone in reducing bacterial counts at all time points tested (3, 5, 10, and 24 h). Moreover, moxifloxacin given in two 40-mg/kg doses resulted in a significantly higher reduction in CSF bacterial concentration (in log10 CFU per milliliter) than vancomycin within 3 h after the start of antibiotic treatment (3.49 [2.94 to 4.78] versus 2.50 [0.30 to 3.05]; P < 0.05). These results indicate that moxifloxacin could be useful in the treatment of meningitis, including penicillin-resistant pneumococcal meningitis.
PMCID: PMC105670  PMID: 9661008
23.  Streptococcus pneumoniae Serotype-2 Childhood Meningitis in Bangladesh: A Newly Recognized Pneumococcal Infection Threat 
PLoS ONE  2012;7(3):e32134.
Streptococcus pneumoniae is a leading cause of meningitis in countries where pneumococcal conjugate vaccines (PCV) targeting commonly occurring serotypes are not routinely used. However, effectiveness of PCV would be jeopardized by emergence of invasive pneumococcal diseases (IPD) caused by serotypes which are not included in PCV. Systematic hospital based surveillance in Bangladesh was established and progressively improved to determine the pathogens causing childhood sepsis and meningitis. This also provided the foundation for determining the spectrum of serotypes causing IPD. This article reports an unprecedented upsurge of serotype 2, an uncommon pneumococcal serotype, without any known intervention.
Methods and Findings
Cases with suspected IPD had blood or cerebrospinal fluid (CSF) collected from the beginning of 2001 till 2009. Pneumococcal serotypes were determined by capsular swelling of isolates or PCR of culture-negative CSF specimens. Multicenter national surveillance, expanded from 2004, identified 45,437 patients with suspected bacteremia who were blood cultured and 10,618 suspected meningitis cases who had a lumber puncture. Pneumococcus accounted for 230 culture positive cases of meningitis in children <5 years. Serotype-2 was the leading cause of pneumococcal meningitis, accounting for 20.4% (45/221; 95% CI 15%–26%) of cases. Ninety eight percent (45/46) of these serotype-2 strains were isolated from meningitis cases, yielding the highest serotype-specific odds ratio for meningitis (29.6; 95% CI 3.4–256.3). The serotype-2 strains had three closely related pulsed field gel electrophoresis types.
S. pneumoniae serotype-2 was found to possess an unusually high potential for causing meningitis and was the leading serotype-specific cause of childhood meningitis in Bangladesh over the past decade. Persisting disease occurrence or progressive spread would represent a major potential infection threat since serotype-2 is not included in PCVs currently licensed or under development.
PMCID: PMC3316528  PMID: 22479314
24.  Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. 
The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.
PMCID: PMC188032  PMID: 8215275
25.  Rosaramicin Versus Penicillin G in Experimental Pneumococcal Meningitis 
Rosaramicin, a new macrolide antibiotic, was compared with penicillin G in the treatment of pneumococcal meningitis in rabbits. Animals were infected intracisternally with 104 colony-forming units of Streptococcus pneumoniae type III (rosaramicin minimal inhibitory/bactericidal concentrations, 0.25/0.5 μg/ml; penicillin G minimal inhibitory/bactericidal concentrations, 0.03/0.06 μg/ml). Treatment was instituted 96 h later. Infusion of rosaramicin at 25 mg/kg per h intravenously for 8 h produced a peak cerebrospinal fluid (CSF) drug concentration of 1.54 μg/ml (range, 0.87-3.6 μg/ml). During this infusion the numbers of pneumococci in CSF decreased from 6.2 ± 0.5 to 3.36 ± 1.12 log10 colony-forming units per ml. Penicillin G, infused at 30 mg/kg per h for 8 h, reached a similar concentration in CSF but caused a greater reduction (P < 0.01) in CSF bacteria, from 6.4 ± 0.36 to 1.3 ± 0.67 log10 colony-forming units per ml. Penicillin G, at 100 mg/kg per day intramuscularly for 5 days, cured 7 of 10 rabbits with pneumococcal meningitis. A higher dose, 300 mg/kg per day for 5 days, was no more efficacious: 11 of 14 rabbits were cured. Rosaramicin at 100 mg/kg per day intramuscularly for 5 days cured only 5 of 15 rabbits with meningitis, but a higher dosage regimen of that drug (250 mg/kg per day intramuscularly) produced acute, fulminant enterocecitis and death within 48 h in seven of eight rabbits. No cytotoxin was detected in the feces of one rabbit with acute enterocecitis. Thus the efficacy of rosaramicin in experimental pneumococcal meningitis, measured by bacterial clearance from CSF and by treatment outcome, was less than that of penicillin G. In addition, high-dose parenteral rosaramicin caused acute, fulminant enterocecitis in a high proportion of treated rabbits.
PMCID: PMC352952  PMID: 43705

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