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Miller Stenberg also identied the agent in the blood of a rabbit injected with human
saliva subcutaneously termed “Micrococcus pasteri” in the United States of America
(USA) [1–3]. By the end of the 1880s, it was established that this bacterium was one
of the leading causes of pneumonia, meningitis, arthritis, otitis, and endocarditis
[4]. By the 1940s, 80 distinct serotypes of pneumococci were detected, and by 2020,
the serotypes would be 100 [5].
A. Tekin Yılmaz et al.
28.2 Etiology
28.2.1 Microbiology
Streptococcus pneumoniae is a facultative anaerobic bacteria with lancet-shaped
gram-positive staining. It requires a medium containing 5% carbon dioxide and a
source of catalase enzyme, such as blood, for growing. Pneumococci lack catalase
and oxidase enzymes. One characteristic that distinguishes pneumococcus is its
sensitivity to optochin and bile salts. In the stationary phase of growth, it is capable
of deoxyribonucleic acid (DNA) exchange and autolysis. On solid media, it appears
as colorless colonies associated with alpha-hemolysis. The pneumococci are frequently found in pairs and can also be observed singly or as short-chain bacteria
under light microscopy. As of 2020, there are 100 serotypes dened based on the
capsule structure formed by complex polysaccharides [5]. Although various methods for determining serotypes exist, serotyping is classically based on the Quellung
capsule swelling reaction, not limited to pneumococci, and can be used to identify
any bacteria with a polysaccharide capsule structure [6]. Molecular methods for
serotyping are now used at the USA Centers for Disease Control and Prevention
(CDC) and some other leading reference laboratories worldwide.
The entire genetic material of S. pneumoniae serotype 4 was sequenced in 1977.
Genetic sequencing was then performed on all serotypes, and a wide range of
genetic diversity among serotypes was discovered [7]. However, some pneumococcal species cannot be typed based on their capsular structures [5]. The prevalence of
non-serotypeable pneumococcal species, which account for 15–18% of all pneumococci, gradually increased, particularly with the widespread use of pneumococcal
conjugate vaccines (PCVs) [8].
28.2.2 Virulence
The pneumococcal capsule structure has been an extensive research focus for a long
time. The capsule, composed of complex carbohydrates, is a critical structure that
inuences virulence, the host’s defense response, and serotyping. The virulence of
the pneumococci is directly proportional to the capsule thickness. The host, producing antibodies against capsule polysaccharides, develops a serotype-specic
defense. The capsule’s function begins with the entry of pneumococcus into the
host’s body. Nonencapsulated pneumococci can colonize the nasal and
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nasopharyngeal mucosa with signicantly less intensity and shorter duration than
encapsulated strains. The capsule, generally negatively charged, prevents the bacteria from being retained in the mucosa secretions, making it easier for the bacteria to
reach the epithelial surface cells [9]. As the primary effect on virulence, the capsule
prevents complement system elements and immunoglobulins (Igs) from adhering to
the bacterial surface and reduces the impact of classical and alternative complement
systems in defense. However, not the capsules of all serotypes effectively inhibit
binding to the Igs of the host [10].
Again, by preventing neutrophils from recognizing Toll-like receptor (TLR)
ligands on the bacterial surface, the capsule impairs the antimicrobial defense system mediated by myeloid differentiation factor 88 (MyD88) [11]. Although the capsular structure is thought to be the primary determinant of virulence, the later
identied nonencapsulated pneumococci and the novel features discovered through
the determination of their genetic sequences have shifted attention to the other characteristics contributing to virulence, neuraminidases, pneumolysin, hyaluronidase,
choline-binding surface proteins, IgA1 protease, phase variation characteristics, and
antibiotic tolerance [12, 13].
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28.3 Epidemiology andTransmission
Pneumococci, spread via respiratory droplets, are human pathogens frequently
found in the respiratory epithelium. In healthy individuals, pneumococcus is isolated from the nasopharynx at a rate ranging from 5% to 90%. Colonization begins
early in life, peaks around 3years, and gradually declines throughout adulthood.
Pneumococcal colonization occurs in the nasopharynx of 90% of children aged
6months to 5years at any time [12, 14]. Asymptomatic carriage occurs at a rate of
5–10% in adults and 20–60% in school-aged children [5]. Because asymptomatic
carriage does not stimulate the host’s defense system or cause an inammatory
response, an individual can be recolonized with the same serotype. Asymptomatic
carriage is more prevalent in nursing home residents, particularly during winter. The
carriage may last for a period of up to 6months. Transmissibility persists throughout the pneumococcal presence in the respiratory epithelium. Effective antibiotic
treatment resolves the transmissibility within 24h [5, 14, 15].
Streptococcus pneumoniae is one of the most prevalent agents of mucosal infectious diseases such as otitis media and sinusitis, not associated with bacteremia. It
is also one of the most prevalent agents of invasive infectious diseases associated
with bacteremia, such as pneumonia and meningitis [16]. According to data from
the CDC, approximately 150,000 people with pneumococcal pneumonia are hospitalized in the USA yearly. About 1,190,000 people worldwide are estimated to die
each year from pneumococcus-related lower respiratory tract infections. Considering
all age groups, the morbidity and mortality rates of invasive pneumococcal disease
(IPD) were 9.2 and 0.98 per 100,000 individuals in 2019, respectively. Children and
adolescents accounted for 7.1% of all cases, and children under 5years accounted
for 65.9% of all patients under the age of 18 [17]. Given that these gures reect
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only those instances in which the etiologic agents can be demonstrated, the actual
number of cases is likely to be much higher.
Despite widespread vaccination, IPDs continue to concern pediatric health. By
the end of 2021, the pneumococcal vaccines were introduced in 154 member states
of the World Health Organization (WHO) [18]. Although the causes of pneumonia
vary by age, vaccination status, and the presence of concomitant diseases, S. pneu-
moniae is the most common pathogen associated with bacterial lower respiratory
tract infections. Pneumococci, meningococci, Haemophilus inuenzae type b (Hib),
and Streptococcus agalactiae (group B streptococcus, GBS) are the most common
causes of bacterial meningitis, fatal in one out of every 10 cases and causes permanent damage in one out of every 5 cases [16, 19]. According to WHO data, pneumo-
nia is the leading cause of infection-related death in children [20]. In 2019, 740,180
children under 5years died from lower respiratory tract infections [20]. Another
reason pneumococcal infections are a serious problem is that antibiotic resistance is
increasing. Streptococcus pneumoniae is one of the top 12 antibiotic-resistant
pathogens listed by the WHO in 2017 [21].
Invasive pneumococcal diseases are more prevalent in children aged 5years and
under and have a higher mortality rate. Similarly, individuals over the age of 65years
are at risk. Compared to their peers, nursery school children have twice the rate of
IPDs [22]. The male gender is another risk factor. Also, IPDs are more prevalent
during the winter and following inuenza infection [23]. Children with human
immunodeciency virus (HIV) infection or acquired immunodeciency syndrome
(AIDS), chronic kidney failure and nephrotic syndrome, chronic liver disease,
malignancy, leukemia, lymphoma, and diseases requiring immunosuppressive drug
therapy, such as Hodgkin’s disease, immunosuppressive diseases requiring stem
cell or solid organ transplantation, or congenital immunodeciency, are at risk of
developing IPD.The risk is increased in individuals with congenital immune system
deciencies, particularly B- and T-cell deciencies, C1–4 complement deciencies,
and disorders of phagocytosis other than chronic granulomatous disease [12, 15].
Invasive pneumococcal diseases are more likely to occur in patients with sickle
cell anemia and other hemoglobinopathies resulting in the spleen’s functional or
anatomical absence [14]. Children with a normally functioning immune system but
have cyanotic heart disease or heart failure, chronic lung disease, asthma that
requires long-term high-dose steroid therapy, diabetes, cerebrospinal uid (CSF)
leakage, or cochlear implants are also at an increased risk of developing IPDs. Older
implants with cochlear electrodes pose a greater risk of IPD [12, 15]. In some ethnic
groups, such as Alaska natives and native American communities, IPDs were more
prevalent, but these racial disparities vanished after pneumococcal vaccination [15].
A. Tekin Yılmaz et al.
28.4 Pathogenesis
Colonization is the adhesion and proliferation of bacteria to the nasopharyngeal
epithelium without causing inammation or disease. While colonization does not
always result in disease, it is a necessary precursor to developing IPD.Additionally,
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colonization is the source of human-to-human transmission [24]. Pneumococci
adhere to the nasopharyngeal epithelium via pili, brillar structures, and attachment
proteins. Pneumococcus attaches to tissues via various structures; sialic acid in the
nasopharynx; and the disaccharide N-acetylgalactosamine b1–4 galactose in the
lower respiratory tract epithelium function as receptors. After attachment, if intracellular signaling pathways are activated, bacteria are taken into the cell, and the
inammatory response is triggered. Cell invasion is also inuenced by pneumolysin, a cellular toxin.
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28.5 Pneumococcal Vaccines
Certain serotypes are responsible for most IPDs, and current vaccines have been
designed to protect against these serotypes. The pneumococcal vaccines currently in
use are summarized in Table28.1 [25, 26].
In the late 1940s, the hexavalent, in the 1970s, the 14-valent, and in the early
1980s, the 23-valent pneumococcal polysaccharide vaccines (PPVs) were introduced [25]. Polysaccharide capsule vaccines induce IgM, IgG2, and very low levels
of IgG1 antibody production. The pneumococcal polysaccharide vaccine is also
expected to be effective against bacterial colonization via the production of IgA by
stimulated B lymphocytes stored in the mucosa [13]. However, the response induced
by the polysaccharide antigens is transient and requires repeated doses because of
the inability to stimulate the T-cell immune response. Also, PPV does not evoke an
amnestic response.
So, polysaccharide vaccines cannot provide an adequate protective response in
children younger than 2years, as their immune systems are not mature enough, or
in the elderly, as their immune response weakens with age. The pneumococcal polysaccharide vaccine’s inability to elicit an adequate immune response in the most
at-risk age groups for IPD, provide herd immunity, and provide sufcient protection
against non-invasive infections such as otitis and conjunctivitis limits its use. These
issues underscore the importance of developing PCVs.
In 2000, the rst pneumococcal conjugate vaccine (PCV-7) was approved in
the USA following studies demonstrating greatly improved immunogenicity in
children less than 2years of age and efcacy for preventing IPD due to the seven
serotypes contained in PCV-7. In 2010, the 13-valent PCV (PCV-13) was
approved in the USA.Some countries in Europe have begun using the 10-valent
PCV (PVC-10). Many countries use PCV-13, some because it is part of the
Global Alliance for Vaccines and Immunisation (GAVI) initiative, an international organization created in 2000 to improve access to new and underused vaccines for children living in the world’s poorest countries. Finally, in 2021,
15-valent and 20-valent PCVs (PCV-15 and PCV-20) were licensed by the Food
and Drug Administration (FDA) for adults aged ≥18 years but not for children
[25, 27]. Recently, PCV-15 has been licensed for use in infants starting at
2months of age in the USA, and PCV-20 will probably be licensed for use in
infants starting at 2months of age in 2023.
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A. Tekin Yılmaz et al.
Table 28.1 Commonly used pneumococcal vaccines and their characteristics
Type Unconjugated
capsular
Conjugated capsular polysaccharide vaccines
(pneumococcal conjugate vaccines, PCVs)
a
polysaccharide
vaccines
(pneumococcal
polysaccharide
vaccines, PPVs)
(PPV-23) PCV-7 PCV-10 PCV-13
Pneumococcal
polysaccharides
1, 2, 3, 4, 5, 6B, 7F,
8, 9N, 9F, 10A, 11A,
12F, 14, 15B, 17F,
4, 6B, 9V,
14, 18C,
19F, 23F
1, 4, 5, 6B, 7F, 9V,
14, 18C, 19F, 23F
18C, 19A, 19F, 20,
22F, 23F, 33F
Carrier protein CRM197 Conjugated to protein
b
1, 3, 4, 5,
6A, 6B, 7F,
9B, 14,
18C, 19A,
19F, 23F
CRM197
D from non-typeable
Haemophilus
inuenzae except
18C (tetanus toxoid)
and 23F (diphtheria
toxoid)
Age of use
≥2years of age
Mechanism B-cell-dependent
immune response
It is recommended
for high-risk patients
>6weeks of age
T-cell-dependent immune response—memory
T-cell activation
Included in several national immunization
programs
with pneumococcal
diseases.
Vaccination
schedules
2+1 First 2 doses in the rst year of life, then a
booster dose in the second year of life
3+1 First 3 doses in the rst year of life, then a
booster dose in the second year of life
PCV-20 (adds 22F, 33F, 8, 10A, 11A, 12F, 15B to PCV-13) is recommended for adults ≥65years
old and those 19–64years old with certain underlying conditions in the USA
In 2023, PCV-20 is expected to be approved by the FDA and then recommended by the CDC ACIP
for routine administration to infants starting at 2months of age
a
Adapted and modied from Refs. [25, 26]
b
PCV-15 (adds 22F and 33F to PCV-13) is FDA-approved and is an option for administration to
infants starting at 2months of age and children
The most effective strategy for eradicating meningitis as a public health problem,
one of the WHO’s 2030 targets, is increasing vaccine coverage. The global population, the low coverage of the vaccines worldwide, the fact that the vaccines cover
only a small subset of serotypes, and the serotype change decreased the expected
benet from the vaccines are the issues faced at the current stage of pneumococcal
vaccine development.
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28.6 Pneumococcal Meningitis inChildren
Meningitis is caused by inammation of the membranes that surround the brain and
spinal cord. Typically, the causative agent is a virus or bacteria. Meningitis is a lifethreatening medical emergency with a high rate of mortality and morbidity that
should be recognized and treated promptly.
28.6.1 Vaccination andChanging Epidemiology
One of the most signicant reasons for the global change in the epidemiology of
bacterial meningitis over the last 25years is the introduction of conjugate vaccines
into childhood immunization practices. The etiology of bacterial meningitis is
dynamic and has changed over time in response to the development of vaccines
against Hib, and after 2000 with the widespread use of 7-valent, then 10- and
13-valent PCVs, the frequency of IPDs decreased signicantly. However, over time,
the distribution of the predominant pneumococcal serotypes circulating in the community changed, and while the serotypes covered by vaccines decreased, the nonvaccine serotypes increased. The serotype change resulted in regional differences in
the prevalence of pneumococcal meningitis (PM) but did not result in the desired
reduction [28–34]. One reason is that pneumococcal pneumonia is primarily caused
by a few serotypes, such as 1, 3, 5, 7F, 14, and 19A, whereas meningitis is caused
by a much larger number of pneumococcal serotypes [35].
The changing epidemiology may be clearly shown through the example of
England and Wales: In November 2006, the PCV-7 was added to the routine childhood immunization program. In the second year following vaccination, a 93%
reduction in the frequency of IPDs caused by the vaccine’s serotypes was observed.
However, in the fourth year, the frequency of IPDs caused by non-vaccine serotypes
increased by 19%. In April 2010, PCV-13 began to be used in place of PCV-7. In
addition, PPV-23 was recommended for adults aged 65years and older and adults
and children over the age of 2years at risk. Over 90% of the target population
received vaccinations. Although the frequency of IPDs caused by the vaccine serotypes decreased by up to 95% in the second year of application, the frequency of
IPDs caused by non-vaccine serotypes increased by 25%, similar to PCV-7.
Additionally, following the start of the PCV-13 vaccination program, the frequency
of IPDs increased for the rst time between 2013 and 2014, indicating that the
maximum benet point for PCV-13 administration was reached [36].
In a 2020 study based on European data, a 35.3% decrease in the frequency of
IPDs was observed, attributed to the decline in the incidence of pneumonia associated with bacteremia. Throughout the study period, the prevalence of PM remained
constant while the prevalence of bacteremia increased. As expected, vaccinecovered serotypes decreased in frequency while non-vaccine serotypes increased.
While the most frequently observed non-vaccine serotypes were 24F, 12F, 15BC,
and 10A, the prevalence of serotype 24F in PM cases increased from 2.9% to 25%.
The most common vaccine serotypes were serotypes 3 and 19A.In addition, the
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prevalence of penicillin-resistant strains increased from 28 to 44.8% [31]. Meningitis
was more prevalent, particularly among children in the risk groups. There was no
signicant change in the prevalence of PM in the Cameroon data, but the serotype
distribution changed [37].
Pneumococcal meningitis remains a problem for children and adults for various
reasons, including serotype change following vaccination and the inability to stimulate an adequate immune response against some serotypes covered by vaccines,
such as serotypes 3 and serogroup 19. The rise in antibiotic-resistant pneumococcal
serotypes exacerbates this problem [38].
Between 2014 and 2019, there was no signicant change in the frequency of
IPDs across all European countries. Despite similar vaccination practices, epidemiology varies signicantly across European countries, and the primary reason for this
is thought to be serotype diversity [38, 39]. In 2018, the most frequently detected
serotypes in IPD and meningitis in Swedish children aged 1–4years were 8, 10A,
3, 19A, 24F, and 19A, and only 19A was covered by the vaccine [40]. The 24F
serotype caused an increase in meningitis cases in France [41]. Another issue is that
nearly half of infants worldwide lack access to vaccines [26].
Despite a relative decline in the number of cases, pneumococci and meningococci continue to be the most common causes of bacterial meningitis in children and
adults after the neonatal period in low-, middle-, and high-income countries [38,
39]. Although the disease is more prevalent in children under the age of 5years, the
average age has increased due to childhood vaccinations. Despite herd immunity,
pneumococcal infections continue to be a problem in adults. This situation demonstrates the critical need for vaccination programs covering children under 2years,
at-risk populations, and older children and adults [26].
Pneumococcal meningitis is associated with a high mortality rate and a high
likelihood of causing permanent neurological problems. While mortality rates in
high-income countries range between 20% and 37%, they can reach up to 51% in
other countries [42]. Permanent neurological problems such as hearing loss (HL),
cognitive dysfunction, and epilepsy can affect up to 50% of survivors [43–45].
Pneumococcal meningitis has a higher mortality rate than meningococcal and Hib
meningitis, and survivors have a higher prevalence of neurological problems [26,
42, 46, 47].
A. Tekin Yılmaz et al.
28.6.2 Pathogenesis
Despite appropriate antibiotic therapy and advanced supportive care, the high prevalence of persistent complications in PM requires the development of novel treatments and protective strategies for the central nervous system (CNS), which might
be possible if the pathogenesis of PM is understood at the cellular molecular level.
The main PM stages are colonization of the nasopharyngeal epithelium by the pneumococci, development of bloodstream infection, bacteria entry into the subarachnoid space via barrier structures, and destruction caused by rapidly multiplying
pneumococci and increasing proinammatory cytokines. The pneumococci may
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also reach the subarachnoid space via direct transport caused by breaking the bone
structure following trauma leading to a CSF leak or neighborhood spread following
infection of adjacent anatomical structures, such as mastoiditis, otitis, and frontal
sinusitis [48].
The bone skull, meninges, blood–brain, and blood–CSF barriers isolate the brain
from the rest of the body. The most challenging aspect of the pathogenesis of meningitis is how bacteria enter this specially protected structure. Molecules such as the
platelet-activating factor receptor (PAFR), laminin receptor (LR), polymeric immunoglobulin receptor (pIgR), and CD31, the platelet endothelial cell adhesion molecule- 1 (PECAM-1) have been implicated in various studies, either directly or
indirectly. It is supported by evidence that bacterium enters brain tissue via mediated intercellular transfer [49, 50]. It is also possible for the bacterium to reach the
CNS via the olfactory nerve [48, 51].
Toll-like receptors 2, 4, and 9, the primary receptors in the CNS involved in PM
pathogenesis, activate nuclear factor kappa B (NF-kB), or mitogen-activated protein
kinase (MAPK) signaling pathways and proinammatory caspase enzymes. The
MyD88 protein serves as an intracellular adapter molecule for TLR-2 and TLR-4.
The MyD88-induced NF-kB activation increases proinammatory cytokines such
as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-10, and transforming
growth factor-beta (TGF-β), all involved in PM pathogenesis. On the other hand,
bacteria that enter the CNS, an immune-privileged area, multiply exponentially in a
short period. The bacterial products that emerge during this period result in the
release of cytokines. Increased cytokines cause neutrophils to release large amounts
of oxygen and nitrogen radicals, which cause nerve tissue damage [50, 52, 53].
Increased cytokine release and oxidative stress are the primary causes of tissue
damage in meningitis. In summary, the rst stage of cell destruction is caused by
bacterial toxins such as pneumolysin; the second stage is by an increase in the
release of proinammatory cytokines, which occurs as the bacterial cell wall disintegrates, resulting in cell damage, destruction, and death [54].
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28.6.3 Clinical Evaluation
The classic clinical manifestations of bacterial meningitis include fever, headache,
vomiting, nuchal rigidity, and meningeal irritation, but not all are present in every
case. Non-specic ndings like fever, restlessness, drowsiness, vomiting, diarrhea,
and breathing difculties are common in newborns and infants. Unsurprisingly,
viral upper respiratory tract infection symptoms and signs are observed a few days
prior to the clinical manifestations of bacterial meningitis. Occasionally, symptoms
manifest abruptly, and the clinical picture deteriorates within hours. Increased intracranial pressure typically results in symptoms such as headache, vomiting, and
paralysis of the third, fourth, and/or sixth cranial nerves. In infants, it can manifest
as fontanelle bulging or expansions of suture lines.
Papilledema may be observed, but it is not a typical nding because of the disease’s acute onset. When papilledema is present, it is vital to consider possible
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A. Tekin Yılmaz et al.
causes such as subdural empyema, abscess, or venous sinus occlusion. Seizures
may occur throughout the disease. Early seizures are typically generalized; lateonset focal seizures are commonly due to intracranial complications. Petechiae and
purpura are most frequently associated with meningococcal infections but can also
occur in pneumococcal bacteremia or meningitis. In a study involving numerous
pediatric cases, petechiae and/or purpura prevalence was 61% in meningococcal
meningitis and 9% in PM [55]. Based on the clinical ndings observed during acute
meningitis, the causative agent cannot be predicted [56].
28.6.4 Complications andLong-Term Sequelae
Generally, PM has a higher mortality rate in adults; however, pediatric cases have a
higher rate of permanent neurological problems [57]. Table 28.2 summarizes several PM clinical and laboratory ndings associated with poor prognoses [12, 57–
60]. Along with the acute complications of bacterial meningitis, a signicant
proportion of survivors develop permanent neurological problems. Long-term follow- up can reveal HL, cognitive function problems, spasticity, paresis, epilepsy, and
behavioral issues. A study of pediatric acute bacterial meningitis cases reported that
50% of survivors experienced at least one meningitis-related problem during longterm follow-up (5years or more) after the acute period [61]. Permanent neurological problems occur at rates that vary according to the patient’s age, comorbidities,
effective treatment timing, and clinical ndings. Pneumococci, the leading cause of
acute bacterial meningitis in children worldwide, are also the most common cause
of permanent problems [62, 63].
Table 28.2 Factors associated with a poor outcome in pneumococcal meningitis
Age<12months old
Cerebrospinal uid ndings
High protein concentration
Low glucose concentration
Low cell count
Initial evaluation
Clinical ndings
Unconsciousness
Septic shock
Hypotension
Need for mechanical ventilation
Focal neurological ndings
Laboratory
Hyponatremia
Low serum white blood cell and neutrophil count
In hospital follow-up, the development of focal neurological signs or seizures
Delay in sterilization of cerebrospinal uid
Presence of cochlear implant
a
Adapted and modied from Refs. [12, 57–60]
a
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28.6.5 Treatment
The rst antibiotics used to treat pneumococcal infections were sulfonamides.
However, the sulfonamide usage in treatment was brief due to the development of
resistance and the demonstration of the efcacy of penicillin group antibiotics [64].
Penicillin was the favorite antibiotic in the 1940s; it was only in the 1960s that penicillin and multi-drug resistance began to occur. Pneumococcal infections resistant
to antibiotics continue to be frightening [21].
Recommendations for treating meningitis, less common among pneumococcal
infections but whose mortality and morbidity cannot be reduced to the desired level
despite effective treatment and widespread vaccination, are also made considering
the resistance problem. Ceftriaxone and cefotaxime, third-generation cephalosporins, are effective against pneumococcal infections, have a reasonable penetration
rate into the CSF, and are used in empirical PM treatment. Minimal inhibitory concentrations interpretive breakpoints for pneumococcus are different for meningitis
and non-meningitis infections due to the higher concentrations of penicillin or ceftriaxone/cefotaxime that can be achieved in serum, pleural, or synovial uid compared to concentrations in the CSF [15]. Cephalosporin resistance may also be
present in penicillin-resistant pneumococci. Thus, ceftriaxone and cefotaxime are
not used alone empirically to treat PM; cephalosporin-resistant S. pneumoniae
strains can be effectively treated with vancomycin. However, vancomycin is used in
combination with third-generation cephalosporins in empirical treatment because it
is difcult to maintain adequate CSF concentrations of vancomycin, and sufcient
experience does not exist with its use as monotherapy. Even if the causative pneumococci are determined to be resistant to cephalosporins, it is recommended that
vancomycin be used in combination with third-generation cephalosporins due to
their synergistic effect [12].
Vancomycin is thought by some experts to be no longer needed for empiric therapy of possible penicillin-resistant pneumococci in North America, given the current exceedingly high third-generation cephalosporin susceptibility [65]. Some
pneumococci strains may be resistant to penicillin but susceptible to third- generation
cephalosporins and may be treated with the cephalosporin alone. If the prevalence
of invasive penicillin-resistant pneumococci strains is more than 5%, the standard
empirical treatment for suspected pneumococcal meningitis is concurrent administration of ceftriaxone and vancomycin [65]. The treatment dosages are listed in
Table28.3 [15, 65].
While vancomycin resistance has not been demonstrated in pneumococci,
vancomycin- tolerant pneumococci exist. The increased prevalence of vancomycintolerant pneumococci may pose a new difculty in treating PM.Rifampin is another
effective antibiotic that may be used to treat meningitis caused by pneumococciresistant to third-generation cephalosporins or in cases of signicant allergies to
beta-lactam antibiotics in combination with vancomycin. The use of rifampin alone
is not recommended because resistance will rapidly develop. Carbapenems are also
effective in treating PM but should not be used as rst-line therapy.
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