PAEDIATRIC RESPIRATORY REVIEWS (2006) 7, 209–214
Review
Penicillin resistance and serotyping of
Streptococcus pneumoniae in Latin America
Paulo Camargos1,*, Gilberto Bueno Fischer2,
Helena Mocelin3, Cı́cero Dias4 and Raúl Ruvinsky5
1
Department of Paediatrics, Medical School, Federal University of Minas Geraias, Avenida Alfredo Balena,
190/Room 4061, 30130-100 Belo Horizonte, Brazil; 2Fundação Faculdade Federal de Ciências Médicas de Porto
Alegre, Porto Alegre, Brazil; 3Respiratory Department, Hospital da Criança Santo Antonio, Porto Alegre, Brazil;
4
Fundação Faculdade Federal de Ciências Médicas de Porto Alegre, Brazil; 5Buenos Aires National University, Buenos
Aires, Argentina
KEYWORDS
penicillin resistance;
pneumococcal
conjugated vaccine;
serotypes;
Streptococcus
pneumoniae
Summary Streptococcus pneumoniae (Strep. pneumoniae) is the main cause of bacterial
pneumonia in children less than 5 years of age, with high mortality rates in developing
countries. In 1993, the Regional System for Vaccines Group (SIREVA) of the panAmerican Health Organisation (PAHO) began a study involving six Latin American
countries to identify serotypes and their representativity in the new conjugated vaccines,
and to determine the degree of resistance to penicillin. Serotypes 14 (highest resistance
level), 5, 1, 6A/B, 23F, 7F, 9V, 19F, 18C, 19A, 9N, were prevalent in the region, with some
differences among countries. Although resistance to penicillin ranged from 2% (Brazil) to
21.1% (Mexico), studies have shown that pneumonia caused by Strep. pneumoniae with
diminished sensitivity to penillin can be treated with this antibiotic. Only 58% of the
serotypes isolated in the region studied were represented in the seven-valent vaccine.
Continual surveillance is essential to determine which formulation of conjugated vaccine
will be suitable for use in Latin America.
ß 2006 Elsevier Ltd. All rights reserved.
INTRODUCTION
Streptococcus pneumoniae (Strep. pneumoniae) remains as
an important aetiological agent of pneumonia worldwide.
Children under the age of two, and those with predisposing
conditions (such as malnutrition), are most prone to be
infected. Penicillin is important in the treatment of pneumonia and its low cost favours its use in the developing
world. Unfortunately, the efficacy of penicillin is threatened
by the emergence of resistant strains. The rate of severe
infections is much higher in developing than in developed
* Corresponding author. Tel.: +55 31 3248 9773;
Fax: +55 31 3248 9664.
E-mail address: [email protected] (P. Camargos).
1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2006.04.004
countries and more than 50% of children in developing
countries are colonised before they are 6 months old.1
Pneumococci are not intrinsically resistant to penicillin
but, once resistance is acquired by a virulent clone, it can
spread to other countries and continents in a relatively
short time.2 Penicillin-resistant strains were first discovered
in 1965, when two strains were identified in Boston.
Further resistant strains were reported in Australia in
1967 and New Guinea in 1971. By the late 1980s, penicillin-resistant pneumococci had spread throughout the
world. In Latin America, resistance to penicillin was first
verified in Mexico in 1981.3 Since then, other authors have
reported occurrences in other countries, mostly in the late
1980s and early 1990s.
210
P. CAMARGOS ET AL.
ASSESSING RESISTANCE
Argentina
Penicillin resistance in Strep. pneumoniae is quantitative, i.e.
the level of resistance is determined using the minimum
inhibitory concentration (MIC). The dilution test and the Etest, which are used to determine the MIC in developed
countries, are not widely available in Latin America. However, the recommended two-step strategy allows relatively
unsophisticated laboratories to perform a screening test
(agar diffusion with oxacillin discs) and this is complemented by the determination of MIC in laboratories that are
able to do so. It is known that resistance of Strep. pneumoniae to beta-lactam antibiotics is the result of changes in
penicillin-binding proteins (PBP), and is not related to betalactamase production.
With a break-point for the MIC 2.0 mg/mL, the proportion of penicillin-resistant strains verified in studies conducted from 1993 to 2005 ranged from 9.9% to
21.5%.6,8,9 Since the break-point for highly penicillin-resistant pneumococci 4.0 mg/mL was recently proposed,10
few invasive isolated strains were classified as having that
penicillin MIC.11
In descending order, serotypes 14, 5, 1, 6A/6B, 7F, 9V,
19F, 16F, and 23F were responsible for 89.3% of 505
isolates from invasive infections in children younger than
5 years from 1994 to 1996.8 In 2002 there were few
changes in the serotype prevalence, with serotype 14
representing 34.4% of the total sample, followed by 5
(13.9%), 1 (9.4%), 6A/B (9.1%), 7F (4.4%), 9V (3.1%),
23F (2.9%), 18C (2.7%) 19A (2.7%), 19F (2.5%), 9N
(1.8%); the last nine serotypes represented 82.6% of
1650 Strep. pneumoniae isolates from invasive diseases.12
The proportion of serotypes 5 and 1 was significantly
smaller (11.1% vs 20.1%; P < 0.001) in the <2 years group.
In 2004 continual surveillance showed a similar pattern;
only 23F and 18C increased moderately.11
PENICILLIN RESISTANCE AND
SEROTYPING: A BRIEF REVIEW
Several studies on susceptibility to penicillin and prevalence
of serotypes have been carried out in Latin America.
However, prevailing conditions, such as a large geographic
area and population, along with peculiar risk factors arising
from the fact that two-thirds of children and adolescents
live in poverty, allow for only partial knowledge of the
current situation.
Due to limited resources, it is difficult to implement an
efficient continuous surveillance system of susceptibility to
penicillin and the prevalence of serotypes. For instance, in
Brazil, which has a surface area close to that of Europe, only
one reference laboratory can perform routine serotyping.
As relatively few data are available, it is difficult for health
authorities to recommend an appropriate empirical antibiotherapy for a specific region, or even to estimate the
efficacy or the impact of the current heptavalent conjugate
vaccine on the community.
Penicillin resistance is increasing in Latin America. A
comparison of data obtained in the years 1994 and
1998 showed a statistically significant distribution of highly
resistant pneumococci in five out of six countries analysed.4
In 1993, the Regional System for Vaccines (SIREVA-Vigı́a)
of the pan-American Health Organization (PAHO)
designed a study to identify the Strep. pneumoniae capsular
types that cause invasive diseases in Latin American children
under the age of five. The aim of the project was to
determine the relative prevalence of capsular types and
antimicrobial susceptibility of Strep. pneumoniae that cause
invasive diseases, especially pneumonia, in children in
Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay.
This information should provide reliable data for the formulation of an adequate vaccine for use in Latin America.
As pneumonia due to Strep. pneumoniae with diminished susceptibility to penicillin (DSP) can be treated with
penicillin,5–7 we will focus our review on the prevalence
rate of high-level resistant strains recovered from invasive
diseases.
Brazil
In Brazil, the first report of an intermediate penicillinresistant strain of Strep. pneumoniae was documented in
the city of São Paulo in 1988.13 During the 1990s, the
prevalence of resistance (MIC 2.0 mg/mL) – according
to many different well-standardised surveillance studies
(predominantly from the south-east region of the country) – was under 5%,14,15 as were the results from two
regional studies of invasive isolates from children and
adolescents.16,17 However, on average, resistance among
invasive pneumococcal isolates in 1998 was 1.9%,
whereas in 2003 it was 7.2% and the risk of having a
resistant isolate in 2003 was almost four-times the risk in
1998.18 According to the surveillance studies, penicillinresistant isolates with serotypes 6B, 14 and 23F predominate in Brazil.19
However, data collected nationally might not reflect the
epidemiology of a region of the country. For instance, in
Minas Gerais, one of the largest states in the Brazilian
federation, a survey that analysed 502 strains of Strep.
pneumoniae found a susceptibility rate of 88.2%, using
the disc diffusion method.20
According to a study in 1993 that investigated strains
isolated in Brazil, serotypes 1, 5, 6A, 6B, 9V, 14, 19A, 19F,
and 23F were responsible for 77.7% of 360 strains isolated
from children with invasive infections in three different
cities.15 In the period 1993–1999, serotypes more frequently involved in invasive infections in Brazilian children
were 14 (24.9%), 6A/6B (15.3%), 1 (9.8%), 18C (7.4%), 5
(6.7), 23F (5.2%), 19F (4.5%), and 9V (4.4%).4 It is noteworthy that the prevalence of serotype 14 increased from
18.7% in 1994 to 29.3% in 1999.
PENICILLIN RESISTANCE AND SEROTYPING OF STREPT. PNEUMONIAE IN LATIN AMERICA
Chile
The first occurrence of pneumococcal resistance in Chile
was reported in 1987.21 From 1994 to 2003, the rate of
high-level resistant pneumococci varied between 5% and
18.8%.9,22,23 No differentiation was performed between
intermediate and highly resistant isolates in another study in
which these two categories accounted for 31.3% of all 99
strains.24
A study conducted from 1989 to 1993 showed that
serotypes 1 and 5 were identified in approximately 30% of
hospitalised patients.25 However, in a study by Gherardi
et al, the 68 multidrug-resistant isolates analysed from 1994
to 1999 were represented by serotypes 19F, 14, 23F, and
6B/6A (1 isolate).26 More recently, serotypes 1, 3, 5, 7F, and
18C were added to them. In another study serotypes 1 and
5 were responsible for only 10% of the studied cases.22 This
changing pattern probably reflects Chile’s transformation
from a developing to a developed country.22
Colombia
In three studies conducted separately – the first one of 324
isolates from 1994 to 1996, the second one of 623 isolates
from 1994 to 1998, and the last one from 1997 to 2001 –
high resistance ranged from 3.1% to 25%.4,9,27
The nine most frequent types (81.0% of the total
sample) identified among 324 isolates included serotypes
14 (21.9%), 5 (10.5%), 23F (9.6%), 1 (9%), 6B (9%), 19F
(7.1%), 6A (6.2%), 18C (4.9%), and 7F (2.8%).27
Mexico
Penicillin-resistant pneumococci were first reported in
Mexico in 1981, when nine out of 117 strains (7.7%)
recovered from healthy children showed MICs >
1.25 mg/mL.3
From August 1993 to April 1995, 49 out of 220 isolates
(22.2%) obtained from blood; cerebrospinal fluid; bronchial
aspirate; or middle ear, peritoneal or joint fluids revealed an
MIC of 2 mg/mL.28 A similar resistance rate (23.2%) was
observed by others in the period 1995–2001.4,9,29
Table 1
211
Capsular typing showed that serotypes 23F, 14, 6B, 19F,
6A, 19A, 4, 11A, 5, 18C, and 19A were the prevalent
serotypes from 1993 to 1999.4,28
Uruguay
An analysis carried out from 1994 to 1998 on 322 invasive
isolates showed a resistance rate ranging from 5.6% to 20%.4
Capsular types 14, 6A/6B, 5, 1, 23F, 19F, 18C, 19A, and 9V
represented 82.2% of the isolates.4 In another paper, the
same serotypes were responsible for 80.6% of the 506
invasive isolates studied in the period 1994–2001.30
Table 1 summarises the average high resistance rate and
the 11 serotypes (6A and 6B were considered as the same
serotype) responsible for approximately 80–85% of pneumococcal invasive diseases in the main collaborative international study carried out in six Latin American countries
(data represent 1998–1999 figures).4
Interestingly, serotypes 14, 5, 6A, 6B, 1, and 7F showed a
similar distribution in southern countries (Chile, Argentina,
and Uruguay). In northern latitudes there was a decrease in
the prevalence of types 1 and 5 – both uncommon in North
America – and an increase in serotype 23F, one of the
seven main existing serotypes in the United States.4
MOLECULAR EPIDEMIOLOGY
The Pneumococcal Molecular Epidemiology Network
(PMEN) was established in 1997 to carry out global surveillance of antibiotic-resistant Strep. pneumoniae and currently
recognises 26 international clones. The occurrence and
dissemination of four different clones showing MIC
2.0 mg/mL have been verified in six Latin American countries (Table 2). Relatively few clones are responsible for most
infections due to penicillin-resistant pneumococci in Latin
America. These clones, however, are widely distributed in
different countries (especially clones Spain23F-1 and
Spain9V-3) and contribute to the dissemination of resistance.
Other clones might be circulating undetected and slowly
spreading resistance. These data demonstrate the need
for continuous surveillance, based on serotyping and
tools of molecular epidemiology, such as pulsed field gel
Resistance rate, distribution of serotypes, and serotypes related to penicillin resistance in Latin America
Resistance
rate (%)
Serotypes
Main serotypes
related to
penicillin
resistance
Argentina
Brazil
Chile
Colombia
Mexico
Uruguay
16.1
2.0
16.0
25.0
20.0
21.0
1,5, 6A/6B, 7F,
9N, 9V, 14,
18C, 19A, 19F,
23F
6A, 6B, 9V, 14,
19A, 19F, 23F
1, 3, 5, 6A/6B,
9N, 9V, 14,
18C, 19A, 19F,
23F
6A, 6B, 14,19A,
19F, 23F
1, 3, 5, 6A/6B,
7F, 9V, 14, 18C,
19A, 19F, 23F
1, 4, 5, 6A/6B,
7F, 9V, 14, 18C,
19A, 19F, 23F
1, 3, 4, 5, 6A/6B,
9V, 14, 18C,
19A, 19F, 23F
1, 3, 5, 6A/6B,
9N, 9V, 14, 18C,
19A, 19F, 23F
6A, 6B, 9V, 14,
19A, 19F, 23F
6A, 6B, 9V, 14,
19F, 23F
6A, 6B, 9V, 14,
19A, 19F, 23F
6B, 9V, 14,19A,
19F, 23F
212
P. CAMARGOS ET AL.
Table 2 International clones of penicillin-resistant (MIC 2.0 mg/mL) pneumococci in Latin America
Clone
Minimal inhibitory
concentration (mg/mL)
Countries with documented occurrence
Spain23F-1
Spain6B-2
Spain9V-3
Czech Republic14-10
2.0
2.0
2.0
8.0
Argentina, Brazil, Chile, Colombia, México, Uruguay
Brazil, Chile, Colombia
Argentina, Brazil, Chile, Colombia, México, Uruguay
Colombia
Source: Pneumococcal Molecular Epidemiology Network (www.sph.emory.edu/PMEN)
electrophoresis and multilocus sequencing typing, to better
understand the dissemination of pneumococcal resistance in
Latin America.
PNEUMOCOCAL RESISTANCE AND
CLINICAL PRACTICE
There are conflicting data regarding the clinical relevance of
penicillin resistance. A strain with reduced susceptibility (e.g.
MIC >1.0 mg/mL) behaves as a susceptible organism when it
causes pneumonia but not when it causes meningitis. So the
definition of susceptibility might depend on the site infected,
although studies on the relevance of Strep. pneumoniae with a
MIC of <4 mg/mL to mortality rates have shown conflicting
results.31 Furthermore, there is evidence that a dosage of
aminopenicillin which achieves sufficient serum concentration ensures efficacy against Strep. pneumoniae with MICs to
amoxicillin of 4 mg/mL 1 in the treatment of pneumonia.31
FACTORS RELATED TO PENICILLIN
RESISTANCE
There is a statistical correlation between penicillin resistance and the following risk factors: age <2 years;8,32 use of
penicillin or ampicillin within 3 months of illness [odds ratio
(OR) 3.0] and serotype 14 [OR = 6.3; 95% confidence
interval (95% CI): 1.7 to 23.3].6 Isolates from male patients
were 40% more likely to be resistant than isolates from
female patients.4 Non-bacteraemic illnesses seem to be a
protective factor (OR: 0.34, 95% CI: 0.14 to 0.84).32
Reduced susceptibility to penicillin was considered to be
a reliable marker for the higher probability of multidrug
resistance, thus requiring in vitro tests to guide chemotherapy or the choices of parenteral extended spectrum
cephalosporins or newer respiratory quinolones.29
Moreover, in pneumonias caused by Strep. pneumoniae
not susceptible to penicillin, the therapeutic regimen should
be similar to that prescribed for susceptible organisms, as this
approach does not necessarily result in a worse clinical
outcome.5,6,10
ANTIPNEUMOCOCCAL
VACCINATION
The major limitation of the polysaccharide pneumococcal
vaccine is that it is not immunogenic for children younger
than 2 years of age, the age group with the highest
incidence of invasive pneumococcus disease. In part, this
is because it elicits an independent T cell response.33
Pneumococcal conjugate vaccines were developed to
overcome this but the number of serotypes is limited. This
means that a vaccine that is effective in one region might be
less so in another and it is therefore necessary to determine
the local/regional epidemiology of invasive pneumococcal
disease, especially in developing countries.4
Following a landmark clinical trial demostrating 89%
efficacy against vaccine serotypes, the seven-valent pneumococcal conjugate vaccine (PCV7), containing serotypes
4, 6B, 9V, 14, 18C, 19F e23F, was licensed and introduced in
2000 in the United States for universal administration to
children younger than 2 years of age and in children 2–5
years of age with risk factors. These seven types represented 82% of the Strep. pneumoniae strains isolated from
invasive infections in northern California.34
The data generated by SIREVA-Vigı́a made it possible to
estimate the expected coverage of three conjugated vaccines by country and region for pneumonia and meningitis
prevention.4 In Latin America, the coverage of the sevenvalent formulation was a maximum of 58% for these
diseases, because serotypes 1 and 5 were not included
in the formulation. The overall percentage would have
increased to 76.2 and 80.7% with the nine- and elevenvalent vaccines, respectively. These three different vaccine
formulations have good coverage of Strep. pneumoniae
penicillin-resistant capsular types; however, type 19A,
which is missing in all formulations, was relevant in all Latin
American countries with the exception of Colombia.4
In Latin America, the seven-valent vaccine covers 89% of
penicillin-resistant pneumococci. However, even if these
conjugate vaccines prove to be highly immunogenic, they
still might not offer enough protection against all pneumococcal infection.
Some studies suggest that there is some cross-protection
for different serotypes belonging to the same serogroup (6A,
9A, 9L, 18B 19A, and 23A).35,36 Dagan et al. showed that
carriage rates for penicillin-resistant and non-resistant pneumococci were significantly reduced for vaccine serotypes.37
Additionally, nasopharyngeal carriage of the vaccine-specific
serotypes decreased in the group which had received sevenvalent or nine-valent formulation.36,37
These results suggest that conjugate vaccines are able to
reduce the carriage of the vaccine-related serotypes in
PENICILLIN RESISTANCE AND SEROTYPING OF STREPT. PNEUMONIAE IN LATIN AMERICA
children as well as decrease the burden of antibioticresistant strains.38 The vaccine could therefore help reduce
the dissemination of these bacteria, as well as reducing the
need for antibiotics. However, carriage of non-vaccinespecific serotypes was found to be more prevalent, suggesting the possibility of replacing nasopharyngeal by serotypes not included in the vaccine.36 There is agreement
that the seven-valent vaccine should be used in children less
than 2 years of age with diseases such as cystic fibrosis,
asplenia, and immunodeficiency (including HIV).
Although pneumococcal conjugate vaccines present
undeniable benefits, the remaining difficulties include: the
biochemical issues involved in the construction of the
optimal vaccine, and their cost of production and their
diminished effectiveness in developing countries. There is a
need for different formulations, dosages and combinations
of serotypes to cover different populations, age groups and
geographical characteristics in Latin America.
PRACTICE POINTS
Request blood culture and sensitivity tests (disc
diffusion, E-test, MIC) in children suffering from
pneumonia.
Pneumococcus resistance is increasing in Latin
America.
The overuse of antibiotics must be reduced if
resistance figures are to decrease.
Pneumococcal vaccination in children with an underlying disease should be implemented in the region.
RESEARCH DIRECTIONS
Enlarge regional/local surveillance of invasive
pneumococcal disease for clinical purposes to
develop evaluate protein–polysaccharide conjugate vaccines for children.
Evaluate the reduction in paediatric admissions
related to invasive pneumococcal pneumonia following a vaccination programme.
Assess the cost-effectiveness of conjugate pneumococcal vaccines in developing countries.
Investigate, both in hospitalised and in ambulatory
patients, the clinical relevance of in vitro findings of
resistance of pneumoccus to penicillin.
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