Surveillance of Resistance in Bacteria Causing Community-Acquired Respiratory Tract Infections

Surveillance of resistance in bacteria causing community-acquired
respiratory tract infections

D. Felmingham1, C. Feldman2, W. Hryniewicz3, K. Klugman4, S. Kohno5, D. E. Low6, C. Mendes7 and
A. C. Rodloff 8
1
GR Micro Ltd, London, UK, 2University of the Witwatersrand, Parktown, South Africa, 3Sera and
Vaccines Central Research Laboratory, Warsaw, Poland, 4The Rollins School of Public Health, Atlanta,
GA, USA, 5Nagasaki University School of Medicine, Nagasaki, Japan, 6Mount Sinai Hospital, Toronto,
Canada, 7Fleury Medical Diagnostic Center, São Paulo, Brazil and 8University of Leipzig, Leipzig,
Germany
Bacterial resistance to antibiotics in community-acquired respiratory tract infections is a
serious problem and is increasing in prevalence world-wide at an alarming rate.
Streptococcus pneumoniae, one of the main organisms implicated in respiratory tract
infections, has developed multiple resistance mechanisms to combat the effects of most
commonly used classes of antibiotics, particularly the b-lactams (penicillin, aminopeni-
cillins and cephalosporins) and macrolides. Furthermore, multidrug-resistant strains of
S. pneumoniae have spread to all regions of the world, often via resistant genetic clones. A
similar spread of resistance has been reported for other major respiratory tract pathogens,
including Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. To
develop and support resistance control strategies it is imperative to obtain accurate
data on the prevalence, geographic distribution and antibiotic susceptibility of respira-
tory tract pathogens and how this relates to antibiotic prescribing patterns. In recent
years, significant progress has been made in developing longitudinal national and
international surveillance programs to monitor antibiotic resistance, such that the pre-
valence of resistance and underlying trends over time are now well documented for most
parts of Europe, and many parts of Asia and the Americas. However, resistance
surveillance data from parts of the developing world (regions of Central America, Africa,
Asia and Central/Eastern Europe) remain poor. The quantity and quality of surveillance
data is very heterogeneous; thus there is a clear need to standardize or validate the data
collection, analysis and interpretative criteria used across studies. If disseminated
effectively these data can be used to guide empiric antibiotic therapy, and to sup-
port—and monitor the impact of—interventions on antibiotic resistance.
Keywords Antimicrobial resistance, respiratory tract pathogens, surveillance principles
and practice, global situation
tious disease and has made possible many

INTRODUCTION
treatments that were previously either compli-
Antimicrobial chemotherapy has been one of the cated or limited by the risk of infection. However,
great areas of therapeutic success in clinical med- bacterial resistance to the effects of antibiotics is an
icine, particularly in the second half of the 20th increasing problem that threatens the utility of
century. Its use has resulted in dramatic reduc- these therapies and compromises patient care.
tions in both morbidity and mortality from infec- This paper outlines the mechanisms of bacterial
resistance and the principles of microbiologic resis-
Corresponding author and reprint requests: David Felming- tance surveillance. It reviews the results of ongoing
ham, GR Micro Ltd, 7–9 William Road, London, NW1 3ER,
surveillance programs assessing resistance in bac-
UK
Tel: þ44 (0)20 7388 7320 teria commonly implicated in community-acquired
Fax: þ44 (0)20 8388 7324 respiratory tract infections (RTIs), and explores
E-mail: [email protected] the issues regarding how surveillance programs
ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
Felmingham et al Surveillance of bacterial resistance 13
can best support strategies to control antibiotic penicillin-binding proteins (PBP), the targets for
resistance. penicillin and other b-lactam antibiotics, are pri-
Whilst some bacteria are known to be innately marily responsible for resistance to these agents.
resistant to specific classes of antibiotics, the major These alterations arise from hybrid PBP-encoding
health concern is the evolution and spread of genes, which have acquired DNA from other
resistant strains derived from species that in the Streptococcus spp. by the process of transformation.
past were fully susceptible. Mutations arising dur- Depending on which PBP is altered, strains with
ing DNA replication and the acquisition of DNA different characteristics with regard to b-lactam
from other species, either as extrachromosomal resistance (i.e. different ‘phenotypes’) are pro-
DNA (plasmids) or as chromosomal fragments, duced. Interestingly, Streptococcus pyogenes,
give rise to new bacterial strains capable of resist- another Streptococcus spp. implicated in commu-
ing the inhibitory activity of particular antibiotics. nity-acquired RTIs, has not become resistant to
These resistant strains have a selective advantage penicillin and other b-lactam antibiotics, the rea-
over nonresistant strains during antibiotic expo- sons for which are currently unclear [1,2].
sure, and may spread on a regional, national and With regard to macrolides, two main mechan-
eventually global scale. isms are responsible for resistance in S. pneumo-
Resistance to antibiotics is widespread among niae: target site modification and efflux [3].
the bacteria commonly implicated in com- Macrolides target areas on the ribosomal RNA
munity-acquired RTIs (Table 1). For example, in this organism. Modification of the target site,
in Streptococcus pneumoniae alterations in resulting from methylation of ribosomal RNA,
Table 1 Major mechanisms underlying antibiotic resistance in respiratory tract pathogens
Pathogen Clinical infection Antibiotics Major resistance mechanisms
Streptococcus pneumoniae Acute exacerbations of chronic b-lactams Mosaicism in DNA-encoding

bronchitis; community-acquired penicillin-binding proteins
pneumonia; acute sinusitis; otitis
media
Macrolides Modification (methylation) of
ribosomal RNA targets by erm
gene products. Efflux of 14- and
15-membered macrolides by mefA
gene products
Tetracyclines Protection of target by genes
encoding M protein
Chloramphenicol Inactivation by acetyl transferase
Co-trimoxazole Alterations in binding capacity
of dihydropteroate synthetase
and dihydrofolate reductase
Fluoroquinolones Mutations in genes encoding for
DNA topoisomerase IV (parC and
parE) and subsequently DNA
gyrase (gyrA). Hyperexpression of
endogenous multidrug efflux
system
Streptococcus pyogenes Pharyngitis Macrolides Modification (methylation) of ri-
bosomal RNA targets by erm
gene products. Efflux of 14- and
15-membered macrolides by mefA
gene products
Haemophilus influenzae Acute exacerbations of chronic b-lactams b-lactamase production
bronchitis; community-acquired
pneumonia; acute sinusitis;
otitis media
Moraxella catarrhalis Acute exacerbations of chronic b-lactams b-lactamase production
bronchitis; community-acquired
pneumonia; acute sinusitis
ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 8 (Suppl. 2), 12–42
14 Clinical Microbiology and Infection, Volume 8 Supplement 2, 2002
confers resistance to the entire macrolide–lincosa- ROB-1 have been reported [9]. BRO-1 and BRO-
mide–streptograminB (MLSB) family of antibiotics. 2 are the two b-lactamases found in M. catarrhalis;
This form of resistance is mediated by products of it is thought that BRO-1 evolved from BRO-2 [10].
the erm genes and can be inducible (i.e. activated Promoter-up mutations increase fitness of BRO-2,
on exposure to the antibiotic) or constitutive (i.e. explaining its present predominance. The random
expressed at all times). Efflux-mediated resistance, distribution of BRO among M. catarrhalis finger-
whereby the antibiotic is pumped out of the cell, is print types indicates that BRO has spread by
conferred by the mefA genes. It results in resistance horizontal transfer [10].
to the 14- and 15-membered macrolides (e.g. ery- Although very rare at present, some strains of
thromycin, clarithromycin and azithromycin), but H. influenzae do not produce b-lactamases, but are
not to the rest of the MLSB family. Both of these still resistant to ampicillin (and other b-lactam anti-
types of macrolide resistance are also important in biotics) and amoxycillin clavulanate. Resistance in
S. pyogenes. these b-lactamase-negative ampicillin-resistant
A further important feature of resistance in (BLNAR) strains of H. influenzae is mediated via
S. pneumoniae is the widespread occurrence of mul- altered PBPs or diminished permeability.
tiply resistant strains. Many penicillin-resistant The determination of the in vitro susceptibility
S. pneumoniae isolates are resistant not only to other of bacteria to antibiotics has always been funda-
b-lactams, but also to non b-lactam antibiotics, in- mental to the development and clinical usage of
cluding erythromycin A and other macrolides, these agents. Qualitative susceptibility testing
tetracycline, chloramphenicol and cotrimoxa- (usually using disk diffusion methods) is per-
zole (trimethoprim-sulfamethoxazole) (Table 1). formed routinely by laboratories across the world.
A recent publication has documented 16 penicil- Much less frequently, often only during the pre-
lin-resistant and multidrug-resistant clones of clinical and early clinical development of a com-
S. pneumoniae [4]. The most notable example of pound, susceptibility is measured quantitatively
these multidrug-resistant pneumococcal clones is by determination of the minimum inhibitory
the serotype 23F clone (Spain23F-1), which was first concentration (MIC). A particular strain of bacteria
identified in Spain in the early 1980s and is now is said to be ‘resistant’ to an antibiotic when the
found in most regions of the world. Two recent MIC of that agent exceeds a predefined ‘break-
studies showed that between 22% and 39% of all point’ concentration. Breakpoint concentrations
highly penicillin-resistant S. pneumoniae in the Uni- are influenced by the potency of the antibiotic,
ted States belong to this Spain23F-1 clone [5,6]. its pharmacologic/pharmacodynamic properties,
Furthermore, there are several serotype variants the site and type of infection, and the species of
of this clone that have been identified in various bacterium. However, breakpoint concentrations
countries across the world. Of particular concern have been defined by several different authorities
are recent reports of high-level resistance to fluor- [e.g. the National Committee for Clinical Labora-
oquinolones in S. pneumoniae isolates belonging to tory Standards (NCCLS), British Society for Anti-
international multidrug-resistant clones, includ- microbial Chemotherapy (BSAC), etc.), which
ing the Spanish 23F clone (Table 1) [7,8]. complicates the interpretation of MIC values.
b-lactamase production accounts for ampicillin Susceptibility testing has become increasingly
resistance in a notable proportion of Haemophilus important in recent years owing to the emergence
influenzae and is widespread in Moraxella catarrha- and spread of bacterial resistance. Local, national
lis. The b-lactamases act by cleaving the amide and international antimicrobial resistance preva-
bond of the b-lactam ring to produce an inactive lence data are now of fundamental importance in
penicilloic acid derivative. They confer resistance guiding empiric antimicrobial therapy (in indivi-
to penicillin and the aminopenicillins (e.g. ampi- dual patients and on a policy/guideline level), in
cillin and amoxycillin), and to some cephalos- researching the development of resistance, and in
porins. The most common b-lactamases in H. supporting and monitoring strategies to combat
influenzae are TEM-1 and ROB-1, both of which the spread of resistance. Surveillance is integral to
are inhibited by the b-lactamase inhibitor, clavu- national guidelines for resistance control and its
lanate. Generally, any one isolate of H. influenzae optimization has been highlighted as a key area for
produces only one of the two b-lactamases, action by the European Commission [11], the
although rare isolates with both TEM-1 and World Health Organization (WHO) [12] and the
Interagency Task Force on Antimicrobial Resis- undertaken by public health institutions and
tance in the United States [13]. financed by public funds, although an increasing
Despite the unanimous opinion regarding the number of studies are sponsored by pharmaceutical
importance of surveillance, there remain many un- companies. International surveillance, on the other
certainties and obstacles hindering the implemen- hand, has until recently been funded mainly by the
tation of optimal surveillance research [14–17]. pharmaceutical industry [20–22]. Exceptions to this
include research conducted by the WHO.
The situation is somewhat different in the Uni-
PRINCIPLES OF SURVEILLANCE
ted States, where the CDC agency runs several
Definition and aims major antimicrobial surveillance programs for
Public health surveillance is defined by the Cen- both community- and hospital-acquired microor-
ters for Disease Control and Prevention (CDC) as ganisms. The approach in the United States is
the ‘ongoing and systematic collection, analysis greatly facilitated by its governance by a single
and interpretation of health data essential to the political entity and by the use of standard suscept-
planning, implementation, and evaluation of pub- ibility testing procedures published by the NCCLS
lic health practice, closely integrated with timely [23,24]. The CDC also established the International
dissemination of these data to those who need to Nosocomial Surveillance Programme for Emer-
know; the final link of the surveillance chain being ging Antimicrobial Resistance (INSPEAR) in
the application of these data to the control and 1998, although this is hospital- rather than com-
prevention of human disease and injury’ [18]. munity-based [25].
Many aspects of this definition apply to microbio- The situation in Europe is changing as the Eur-
logic surveillance (Table 2). Therefore in the opean Union (EU) is now funding cross-border
following section, after considering the organiza- studies that involve member states and geogra-
tional aspects of surveillance, we will discuss the phically adjacent countries, thereby recognizing
criteria for good research in terms of the collec- the microbiologic irrelevance of national bound-
tion, analysis and interpretation of data as well aries. For example, the EU-funded European Anti-
as issues regarding dissemination and applica- microbial Resistance Surveillance System (EARSS)
tion of these data to support strategies to control is a European network of national surveillance
resistance. systems that aims to aggregate comparable and
reliable antimicrobial resistance data for public
health purposes (http://www.earss.rivm.nl).
Organization Industry-sponsored surveillance studies benefit
Surveillance studies are funded from a variety from high levels of financial funding. These pro-
of sources and the major studies currently in programs are generally performed on a large scale and
gress have been reviewed recently [14,17,19]. In involve many centers, centralized microbiologic
Europe, national resistance surveillance is generally testing, and the inclusion of a wide range of anti-
biotics. For example, the Alexander Project [20,21]
and the PROTEKT study [26] are both specifically
Table 2 Main functions of microbiologic surveillance focused on monitoring resistance in bacteria that
commonly cause community-acquired RTIs, while
Quantification of resistance Resistance prevalence/ the SENTRY Antimicrobial Surveillance Program
distribution
Changes over time
[22] collects a more diverse range of isolates.
New/emerging forms More recently, another financing approach to
Guidance for antibiotic use: Individual patient level the collection/production and dissemination of
Guidelines/policies antimicrobial resistance surveillance data has been
Research/education: Epidemiology of resistance
established [27]. Commercial organizations now
Link with antibiotic usage
Industry: Research and development collect these data and sell them to customers. The
Licensing primary customers are pharmaceutical companies,
Marketing/postmarketing although some national public health institutions
Resistance control: Design of strategies are also making use of these services.
Impact of strategies/
interventions Although surveillance data are available from
an increasing number of countries (as reviewed
below), data are still sparse from many areas, for high levels of resistance. Again, this type of
including Central Europe, sub-Saharan Africa research is usually limited to studies where resis-
and South-East Asia, where clinical microbiologic tance problems have been predefined by conven-
facilities are often limited [28]. tional surveillance [17].
Surveillance studies differ in terms of patient
selection, source of isolates, the range of pathogens
Study design and antimicrobials tested, microbiologic metho-
Surveillance of antimicrobial susceptibility can be dology and interpretative criteria. Any compari-
undertaken at many levels, ranging from small, sons of resistance between studies demand
local hospital or laboratory studies to extensive scrutiny of these variables to ensure comparison
national or international data programs. Indivi- of ‘like with like’. Unfortunately, details of such
dual studies may be organized as defined time- criteria in surveillance reports are often not clearly
period point prevalence observations or by means defined. The most robust studies for comparative
of long-term monitoring (i.e. ‘longitudinal’ stu- analysis are likely to be those in which suscept-
dies). In some studies all isolates are sent to a ibility testing is performed either in one laboratory
central laboratory for testing, while in others iso- using an internationally accepted standard proce-
lates are tested by local laboratories and the results dure, or in a number of laboratories applying the
are forwarded to a central database. Advances in same test procedures with external compliance
information technology now allow electronic and quality control audit [30]. The use of a single,
transmission of data and the WHONET program central laboratory is generally considered to be the
has facilitated the standardization of test data best of these options. However, this approach
presentation [29]. necessitates the transportation of isolates, which
Surveillance research can capture various types is technically demanding and costly, as well as
of data. Most fundamentally, surveillance aims to requiring knowledge of appropriate transporta-
establish the prevalence of different forms of anti- tion systems and familiarity with dangerous goods
microbial resistance, the geographic distribution transportation regulations and logistics.
of resistance, and the underlying trends over time.
Traditional methods of determining resistance are
phenotypic, i.e. they rely on the expression of Data collection
resistance by isolates. These methods are particu- Ideally, research to measure the prevalence of
larly useful for detecting novel resistance pheno- resistance among community-acquired RTI patho-
types. More recently, genotypic techniques, by gens requires population-based studies of patients
which resistance is detected by the analysis of presenting with these infections. In practice, such
resistance-conferring genes, have been developed. research is expensive and logistically difficult and
This technology is becoming more widely avail- most surveillance studies rely on isolates sent by
able, allowing epidemiologic research in many community prescribers for microbiologic testing.
more areas of the world where resistance rates This may introduce bias into the data collection
are high (e.g. Central/Eastern Europe). These because microbiologic testing has a limited role in
methods provide important information on the the treatment of community-acquired RTIs in out-
mechanisms responsible for resistance and how patients [31]. Initial antibiotic treatment for these
they are spreading and/or evolving. However, infections is usually prescribed empirically, i.e.
genotypic research is relatively expensive and without knowledge of the causative pathogen or
time-consuming so, within public health pro- its susceptibility profile. A microbiologic diagnosis
grams, this type of analysis is usually limited to is generally reserved for patients who are sicker or
specific studies of resistant isolates identified by who have failed to respond to initial antibiotic
routine surveillance. Genotypic analysis is being treatment, in whom identification of the causative
included as an integral part of some industry- pathogen and its susceptibility profile is clinically
sponsored surveillance systems, e.g. SENTRY important. Therefore, isolates analyzed in most
and PROTEKT. In addition to antibiotic suscept- surveillance studies tend to be from these more
ibility data, surveillance research can also collect problematic patients. As the risk of resistance in
information on risk factors for acquisition, coloni- community-acquired RTI pathogens is linked with
zation, and/or for infection of resistant strains or previous antibiotic usage [32–35], analysis of these
isolates may over-estimate the prevalence of resis- test. Although simple, economical and reproduci-
tance in the general patient population. Never- ble, this is essentially a qualitative method
theless, the data do provide an early indication whereby zones of inhibition are measured and
of the development of resistance and its potential translated into predetermined categories as ‘sus-
dissemination through the general population. ceptible’, ‘intermediate’ or ‘resistant’. Measuring
Some surveillance programs, particularly in the the inhibition of bacterial growth using broth or
public sector, use routine sampling data. This agar dilution generates quantitative data (i.e.
approach gives access to a very large data sample. MICs). The E test1 is a commercially available
However, in addition to the bias described above, method based on agar disk diffusion that provides
such data suffer from the lack of a common defini- MICs by incorporating a predefined antibiotic
tion of patients and infections. The collection of gradient on a plastic strip, which is transferred,
isolates from patients selected according to a accurately, to a surface-inoculated agar plate.
defined protocol provides a more homogeneous The results of these susceptibility tests are influ-
dataset. enced by the test conditions used, e.g. inoculum
Data collection must take account of a range of concentration, growth media and incubation con-
factors that influence bacterial resistance patterns. ditions. No test method is universally accepted as
The site of acquisition of infection is of fundamen- the standard and differences between them can
tal importance. Community- and nosocomially result in apparent differences in antimicrobial
acquired isolates of the same species can differ susceptibility [36]. The criteria established by the
markedly in their resistance profiles and must be NCCLS for use in the United States [23,24] are
clearly differentiated. Demographic and clinical widely used across the world by individual labora-
characteristics are also relevant and wherever pos- tories and international industry-sponsored sur-
sible these details should be collected in parallel veillance programs [20–22,26]. However, even in
with the clinical specimens. For example, the spec- the United States compliance with these proce-
trum of pathogens isolated from children (parti- dures may be suboptimal [37]. In Europe, several
cularly those attending day-care centers)—and the methods are in use and these undergo regular
resistance patterns therein—is different from that review and revision [38–41]. The European Com-
observed in adults. Clearly, details of recent pre- mittee on Antibiotic Susceptibility Testing
vious antibiotic usage are also important. Collec- (EUCAST) has been set up under the auspices of
tion of patient data can be difficult, however, the European Society of Clinical Microbiology and
because surveillance research is normally con- Infectious Diseases to try to ensure that suscept-
ducted by microbiology laboratories with limited ibility testing in Europe produces comparable
access to these data. The clinical source of isolates results and interpretations. EUCAST liaises with
provides another variable. Depending on the RTI NCCLS, the European Medicines Evaluation
under diagnosis, isolates may be collected from Agency and with standards organizations and
blood, bronchoalveolar lavage or middle ear fluid, has published several documents on methodology
sputum or nasopharyngeal material, sinus taps or and interpretation [42–44]. The European Study
throat swabs. Some studies are restricted to one Group on Antimicrobial Surveillance (ESGARS)
particular source of isolates, while others analyze was also established to aid efforts to improve the
isolates from several sources. Whatever their quality and standardization of susceptibility testing
source, recognition and removal of duplicate iso- across Europe, although its activities have been
lates from individual patients is essential so that limited to date. In France, the National Observatory
resistance levels are not overestimated. However, for the Epidemiology of Bacterial Resistance to Anti-
the definition of duplicates is not consistent among microbials (ONERBA: http://www.onerba.org)
studies [16]. Organisms causing infections should has also published a valuable document on the
also be differentiated from colonizing flora. technical aspects of surveillance research.
Internal and external standardization of test
procedures is an important concern in multicenter
Susceptibility testing surveillance programs. The use of a central labora-
Several tests for determining antimicrobial sus- tory in which a standard approved procedure,
ceptibility have been developed. One of the most subjected to rigorous quality control, is used to
widely used methods is the agar disk diffusion analyze all submitted isolates is advantageous in
this respect. In contrast, local testing of isolates in patterns—this approach requires continued aware-
individual laboratories raises concerns over qual- ness of the possibility of introduction and spread
ity and comparability of the methods used, of strains that differ from those of the local bacter-
although this level of standardization applies ial ecology. Furthermore, not all alterations in
more to qualitative than quantitative methodol- susceptibility occur as abrupt changes from ‘sus-
ogy. However, most laboratories are involved in ceptible’ to ‘resistant’. Others occur over time, with
national and international quality assurance pro- stepwise increases in MIC occurring until a pre-
grams and test-to-test variability has been greatly viously treatable infecting organism becomes
improved by the standardization of basic para- refractory to therapy with a particular agent. For
meters such as growth media, inoculum concentra- example, in S. pneumoniae penicillin resistance is
tions and incubation conditions. Furthermore, in generally manifested as incremental decreases in
routine laboratories, the introduction of instru- susceptibility over time. In contrast, high-level
mentation such as image analysis-based zone macrolide resistance in this species is acquired
readers and automated broth dilution systems abruptly in a single step. To anticipate these
together with electronic data handling may help changes, longitudinal research, providing detailed
to reduce assay variation and are labor-saving as knowledge of the quantitative susceptibility pat-
well [45]. Internationally, the WHO and the Inter- terns of strains in different countries over a period
national Society for Infectious Diseases conduct of time, is essential. Where possible, isolates
training programs to improve standards of profi- should be retained for future re-analysis using
ciency in microbiologic laboratories, particularly new analytical techniques and antimicrobials.
in developing countries. Data from 189 labora-
tories in 39 countries participating in the WHO
External Quality Assurance System for Antimicro- Interpretation
bial Susceptibility Testing suggest that there is MIC breakpoints are selected on the basis of drug
considerable scope for improving standards of pharmacokinetics, in vitro results with isolates of
proficiency, particularly in the detection of peni- known clinical responsiveness and nonrespon-
cillin resistance in S. pneumoniae [46]. siveness, any known resistance mechanisms, and
The choice of testing method used is dependent overall distribution of MICs and zone diameters
on the time and resources available as well as the with relevant clinical strains. Several sets of MIC
rationale for performing the test. Qualitative data breakpoints are currently in use in different coun-
are probably adequate for guiding the prescriber at tries and are reviewed with variable regularity
a local level and for monitoring changes in local [24,44,47,48]. Whilst the importance of standar-
patterns of resistance. However, quantitative dized criteria for breakpoints is well recognized,
determination of full end-point MICs is the most the impact of resistance defined on the basis of
useful in analytical terms, as this permits the MICs on clinical outcomes in patients with RTIs is
interpretation of laboratory data using existing not clear (discussed by Metlay and Singer in this
interpretative breakpoint MICs to define suscept- supplement [49]). Infection-site-specific break-
ibility and resistance while allowing a flexibility of points, based on the correlation of pharmacody-
analysis where differences of opinion exist. This namic/pharmacokinetic parameters with MICs
method also permits retrospective re-analysis in and clinical outcome data, may be more relevant
the light of changes in interpretative criteria. Most for guiding prescribing.
importantly, determination of full end-point MICs The optimal format for presenting surveillance
is essential if an assessment of the comparative data has not been resolved. Full MIC distributions
potency of antimicrobials and the relationship to are cumbersome but are the most comprehensive
their pharmacokinetic behavior is to be made. and are invaluable as a reference source. MIC data
The frequency with which surveillance should are frequently summarized as mode MICs, MIC50,
be undertaken is largely dictated by what is MIC90, and MIC ranges although condensing
required of the data. Continuous qualitative mon- information in this way is not ideal [50]. Resistance
itoring is probably adequate as an aid to local rates are expressed most commonly as the propor-
prescribing. In view of the ease of modern tra- tion of resistant isolates per total number of iso-
vel—which often occurs between areas with lates analyzed (prevalence). However, it is not
greatly differing antimicrobial susceptibility clear that the total number of isolates is the optimal
denominator for public health purposes. Resis- broad links with antimicrobial usage, and are
tance rates may also be expressed in the context useful for educational purposes in drawing atten-
of patients (e.g. the number of patients with resis- tion to what is a global problem. However, data
tant isolates/total number with positive cultures) collected and used at the local level also play an
or hospital admissions (number of patients with important role. Indeed, local surveillance studies
resistant isolates/number of admissions). Deno- often provide more reliable regional prevalence
minators that are time-based (e.g. the number of data than large international studies, which detect
resistant isolates/number of days of hospitaliza- resistance trends over a larger area. The balanced
tion or patient-days) may be more relevant to solution is an integrated network of local and
clinicians [17]. international surveillance systems [53].
Efforts to reassess the way surveillance data are Although the collection of surveillance data
interpreted and presented should be oriented serves to define the problem of antimicrobial resis-
toward their usefulness in supporting disease tance—and the need for continued and improved
management and efforts to control resistance. surveillance is imperative—collection of data
Thus, in moving beyond the present focus on alone will not serve to decrease resistance levels.
conventional in vitro analyses, there is a need to It is the interventions made in response to these
relate better the surveillance data to the clinical data that have the potential to contain the problem,
impact of resistance [51]. for example the optimization of antibiotic therapy,
the reduction of unnecessary prescribing, and the
use of better infection control measures. Routine
Dissemination surveillance studies will play a crucial role in
Patterns of antimicrobial resistance are continually demonstrating the impact of intervention pro-
evolving and it is important for the most up-to- grams. However, additional studies specifically
date information to be delivered promptly and in a designed for this purpose and using other out-
usable form to prescribers and workers involved comes may also be necessary [54,55].
in resistance control. Publication by traditional
means can take several months and the amount SURVEILLANCE DATA
of detail that can be presented in standard journal
articles is necessarily limited. The inclusion of data Western Europe
tables as supplementary appendices in electronic Several international surveillance surveys of bac-
versions of journal articles has been proposed terial resistance to antibiotics encompass Western
recently to address the latter issue [52]. Electronic European countries. The Alexander Project and
delivery of data is an excellent option as it allows the PROTEKT study are focused on community-
lengthy tables to be accessed. Accordingly, search- acquired RTI pathogens and include data from
able websites (with varying levels of data access) Austria, Belgium, Eire, France, Germany, Greece,
have been set up for several studies, e.g. the Italy, The Netherlands, Portugal, Spain, Sweden,
Alexander Project (http://www.alexander-net- Switzerland, and the UK (http://www.alexander-
work.com), LIBRA (http://www.librainitiative.- network.com; http://www.protekt.org). Together
com), PROTEKT (http://www.protekt.org), and with national and local surveys from individual
ESGARS (http://www.earss.rivm.nl). These sites countries, these ongoing studies provide substan-
are, or will be, regularly updated with the most tial information on antibiotic resistance patterns
recently available data and some are linked to local for most parts of Western Europe.
or national prescribing support systems. In addi-
tion, it should be noted that to promote resistance Streptococcus pneumoniae
control it is also important to disseminate surveil- The most recent data from international studies
lance data and its implications to patients and the estimate the overall prevalence of penicillin-non-
general public using various media. susceptible S. pneumoniae (PNSP) across Western
Europe at 25–30% [PROTEKT (1322 isolates): inter-
mediate 8.7%, resistant 16.0%; Alexander (1149
Application isolates): intermediate 9.9%, resistant 19.6%]
Data from international surveillance studies can (Figure 1) [21,56]. These data confirm previous
aid in identifying resistance trends, help make findings. For example, 31% of isolates (n ¼ 1537)
Figure 1 Prevalence of penicillin

nonsusceptibility in Streptococcus
pneumoniae across the world (var-
ious sources, data correct up to
February 2001).
collected from Germany, Spain, France, Italy 14.3% (intermediate 8.8%; resistant 5.5%). How-
and the UK in 1997–98 were penicillin nonsuscep- ever, in Northern Ireland and Eire, penicillin non-
tible [57]. The SENTRY antibacterial surveillance susceptibility has reached 25%. Highly resistant
system, which includes both nosocomial and isolates are also emerging in Germany, with point
community-acquired isolates, reported high-level prevalences ranging from 0.3 to 3.9% [21,56,61].
penicillin resistance in 10.4% of European isolates Pneumococcal penicillin resistance remains
during the same period [22]. However, these over- relatively uncommon in Scandinavia. In Finland,
all findings mask considerable heterogeneity no penicillin-resistant isolates were identified
within Western European countries. National pre- among middle-ear isolates collected from children
valence rates of PNSP range from <5% in The in 1987–90, whereas 1.2% of 807 isolates collected
Netherlands to >50% in France (Figure 1). in 1995 were penicillin-resistant and 4.2% were
Generally, pneumococcal penicillin resistance intermediate [62,63]. In Sweden, the prevalence of
occurs at a relatively low frequency in Northern penicillin resistance was 3–4% during 1994–97 and
Europe. International studies have recently only 1.3% in a population-based study conducted
reported a prevalence of PNSP of <15% in The in Stockholm in 1996 [64,65]. Higher prevalences
Netherlands, the UK and Sweden [21,56]. In con- were reported in southern Sweden (increasing
trast, penicillin nonsusceptibility is well estab- from 3.1% in 1993 to 7.6% in 1995) but these had
lished in France and Spain, where its prevalence stabilized by 1997, possibly as a result of preven-
exceeds 50%. Importantly, high-level resistance tive measures implemented in the area [66]. A
predominates in these countries [21,56]. A Spanish multidrug-resistant clone (serotype 6B) intro-
nationwide multicenter study of 1113 isolates col- duced into Iceland in 1989 made a major contribu-
lected in 1996–97 found that 23.6% were penicillin- tion to the emergence of pneumococcal resistance
intermediate while 36.5% were fully resistant. In in this country, which rose from close to zero in
Cádiz, 14.1% of isolates from 1995 were penicillin- 1989 to 20% in 1993, and accounted for more than
intermediate and 75.2% were fully resistant [58]. 70% of all penicillin-nonsusceptible isolates [67].
As mentioned previously, the Spanish 23F multi- During the 1990s across Europe there was a
drug-resistant S. pneumoniae clone has now spread steady increase in macrolide resistance in both
from Europe to Asia, the Americas and South penicillin-susceptible and -resistant S. pneumoniae
Africa [59]. isolates. Both the Alexander Project and the PRO-
In the UK, levels of pneumococcal penicillin TEKT study reported an overall prevalence of
resistance are rising in many regions, with high- erythromycin resistance of 25% in 1999–2000
level penicillin resistance increasing from zero in [21,56].
1988 to 3.3% in 1995 [60]. Longitudinal data from Macrolide resistance is most common in France,
the Alexander Project show a similar trend (0.1% Spain and Italy, where the respective prevalences
in 1992, 4.5% in 1996), while PROTEKT data from are 58%, 29–35%, and 32–43% [21,56,68,69]. The
2000 indicate an overall rate of PNSP in the UK of rate of macrolide resistance exceeds 25% in Eire,
Greece and Belgium but is <10% in Finland, Ger- b-lactamase-producing isolates of M. catarrhalis
many, the UK and Switzerland [21,56,63]. The are currently widespread across Western Europe,
MLSB phenotype, which usually results in high- with very similar prevalences of >85% to 100%
level resistance (MIC 64 mg/L), is the dominant being reported in most countries [56,57,73].
resistance phenotype in Europe [70,71].
In Spain, an analysis of antibiotic consumption Streptococcus pyogenes
between 1979 and 1997 revealed a significant Penicillin resistance in clinical isolates of S. pyo-
correlation between macrolide resistance and total genes remains unrecognized. With regard to
macrolide consumption, as well as between high- macrolide resistance, the UK was the first country
level penicillin resistance and b-lactam consump- to report resistance in S. pyogenes [76]. The levels of
tion, with use of long-acting macrolides and erythromycin resistance amongst S. pyogenes from
cephalosporins contributing most to the effect Western Europe are very variable. Among 499
[72]. In most of Western Europe, levels of penicillin isolates collected from the region in the PROTEKT
resistance tend to correlate with levels of macro- study, erythromycin resistance was detected
lide resistance. However, this pattern is not found most frequently in Italy (24.5%), Portugal (23.8%),
in Italy, where Alexander Project data suggest that Spain (21.2%) and France (12.9%), but was not
the national prevalence of macrolide resistance has found among isolates from Austria, Belgium, The
increased from <5% to >40% in the past decade Netherlands, or the UK. Similarly, national studies
whilst penicillin resistance remains at around 10% have highlighted high levels of macrolide resis-
[73]. This relatively modest and stable level of tanceinItaly(30–40%)[69],Portugal (35.8%)[77]and
penicillin resistance may be explained by the Spain (23.5% and 27%) [78,79]. Resistance was less
widespread use of parenteral cephalosporins in common in isolates from French children (6.2%) [80]
Italy [74]. It may also reflect the broad range of and from outpatients in Sweden (<1%) [65].
antibiotic classes used [69]. The rise in erythromycin resistance in S. pyo-
genes in Finland during the late 1980s has been
Haemophilus influenzae particularly well documented. This was attributed
Production of b-lactamase occurs in 11–19% of to a rise in macrolide usage—a subsequent reduc-
Western European H. influenzae isolates. Again tion in macrolide consumption was followed by a
there is considerable variation among countries, decrease in the prevalence of erythromycin resis-
with higher rates evident in the UK (15–18%), Eire tance [81,82]. Data from Spain (collected from 1986
(17–26%), France (22–31%) and Belgium (16–18%) to 1997) also support the hypothesis that wide-
and lower rates in Germany (3–7%), Italy (2–8%), spread use of macrolides, of which a large propor-
The Netherlands (3–6%) and Austria (3–4%) tion are those administered once or twice daily
[22,56,57,73]. In Finland, the proportion of b-lacta- (e.g. clarithromycin, roxithromycin, azithromycin
mase-positive isolates in children with otitis media and dirithromycin), leads to an increased preva-
increased from 8% to 24% from the 1980s to 1995 lence of erythromycin resistance in S. pyogenes [83].
[63]. BLNAR H. influenzae strains remain rare Macrolide resistance phenotypes vary from
[56,73]. country to country. The ribosomal methylation
High level resistance to the macrolides is very erm phenotype accounts for a substantial propor-
rarely observed. However, it should be noted that tion of resistant isolates in Italy and Portugal,
the potency of macrolides against H. influenzae is whereas the mefA efflux phenotype is dominant
relatively poor—the mode MIC for erythromycin, in Spain [69,77–79]. In Italy, the erm methylation
clarithromycin and azithromycin ranges between macrolide-resistant phenotype has been correlated
1 and 8 mg/L—and thus these agents are rarely with failure of macrolide treatment in children
used to treat life-threatening H. influenzae RTIs [75]. with acute pharyngitis [84].
Moraxella catarrhalis Conclusions

There has been a steady increase in the preval- There is considerable heterogeneity in the preva-
ence of b-lactamase-producing M. catarrhalis iso- lence of antibiotic resistance in community-
lates since the late 1980s, even in countries such acquired RTI pathogens both among and within
as The Netherlands where resistance among countries in Western Europe. However, although
other respiratory pathogens is relatively rare. some adjacent countries may have very different
levels of resistance (e.g. France and Germany, The Streptococcus pneumoniae

Netherlands and Belgium), there is a general trend Despite an overall increase in prevalence, the geo-
for resistance to be less common in countries in graphic differences between countries in Central
Northern Europe compared with those in South- and Eastern Europe with respect to penicillin sus-
ern Europe. ceptibility in S. pneumoniae remain as they were
Resistance among pneumococci is increasing several years ago (Figure 1). Data collected in 1992
and is now a major health concern even in coun- in Poland showed a relatively low prevalence of
tries where penicillin- and macrolide-resistant PNSP of 6.6% (2% resistant/4.6% intermediate)
S. pneumoniae were rare a decade ago. In Mediter- [87]; however, more recent data show an increase
ranean countries, such as France, Spain and Italy, in penicillin nonsusceptibility. The highest preva-
resistance among S. pneumoniae and/or S. pyogenes lence rates of PNSP strains in Central and Eastern
isolates is already well established and alarmingly Europe have been reported from Hungary and
high. b-lactamase-producing strains of H. influen- Romania (>40%), followed by Croatia (38%), the
zae are also increasingly prevalent in Western Slovak Republic (>25%) and Poland (20%) [88].
Europe, while production of this enzyme is ubi- The lowest prevalence rates have been found in the
quitous among M. catarrhalis isolates. Czech Republic (<5%).
Patterns of antibiotic resistance in Western Eur- Compounding the issue of increasing nonsus-
ope are mirrored by community antibiotic sales, ceptibility is the fact that prevalence rates may
which vary more than fourfold across the EU. Sales vary considerably within individual countries.
are highest in France, Spain, Belgium and Portugal For example in Russia, 9% of isolates from inpa-
and lowest in The Netherlands, Denmark, Sweden tients in Smolensk were reported to be penicillin
and Germany [85]. The analysis of surveillance nonsusceptible (unpublished data) compared with
data in conjunction with such information may 24% of those reported from Moscow [89]. Another
provide the basis for strategies to limit resistance at multicenter study in Russia, involving 305 naso-
a national and international level. pharyngeal isolates from healthy children attend-
ing day centers in Moscow, Smolensk and
Yartsevo, found an overall PNSP prevalence of
Central and Eastern Europe 8% and a range of 3–13% between the centers
Rates of antibiotic resistance in community- [90]. Published data from Estonia showed that
acquired RTI pathogens vary considerably within 9% of S. pneumoniae nasopharyngeal isolates were
and between Central and Eastern European coun- penicillin nonsusceptible [91]. Data indicate that
tries. Currently, few reports from this region have PNSP account for 20% of pneumococci isolated
been published in international peer-review jour- from patients with community-acquired RTIs in
nals, although the number of publications is grow- the Izmir area of Turkey and 36% of isolates
ing. Much of the data presented in this section are (n ¼ 77) collected from Ankara, Turkey in the
from national antibiotic reference centers, national PROTEKT study were nonsusceptible [56]. In most
institutes of public health and different labora- countries, the majority of PNSP strains show inter-
tories in Poland, Hungary, Romania, Bulgaria, mediate penicillin susceptibility (as defined by
the Slovak Republic and the Czech Republic. Spe- an MIC of 0.12–1 mg/L). However, in Poland
cifically, data have been obtained from the Alex- >50% of PNSP strains are fully resistant (i.e.
ander Project [21,73,86], single publications, and MIC 2 mg/L) [21].
from personal communications. The following are PNSP are often multiresistant, i.e. they are also
gratefully acknowledged for supplying data: Mar- resistant to other antibiotics including macrolides,
ianne Konkoly-Thege (Hungary), Paula Uraskova tetracycline, cotrimoxazole and chloramphenicol.
(Czech Republic), Leon Langsadl, Jan Trupl, The consumption of new macrolides (i.e. clarithro-
Helena Hupkova and Krkoska Drusan (Slovakia), mycin and azithromycin) has increased in recent
Bojka Markova (Bulgaria), Dace Rukzite (Latvia), years in most Eastern and Central European coun-
Vasilica Ungureanu, Olga Dorobat and Irina tries. This trend has been associated with an
Codita (Romania), Arijana Boras (Croatia), Leonid increase in macrolide resistance in some countries,
Strachounsky (Smolensk). Data from the PRO- for example Hungary [56,92]. Conversely, a
TEKT surveillance program [56] are also decrease in the prevalence of macrolide resistance
discussed. has been noted in Poland and the Slovak Republic
[21,86]. The reasons for this are unclear, particu- S. pyogenes strains recovered from older people
larly in light of the high consumption of generic (>65 years of age) in this country are macrolide
macrolides in these countries. resistant. Limited available data suggests that the
Resistance rates to tetracycline in S. pneumoniae prevalence of macrolide resistance in S. pyogenes
range from 12% in the Czech Republic and 16% in may be as low as 2% in Turkey (n ¼ 54 isolates) and
Hungary to 65% in Russia. The prevalence of approximately 18% in Hungary (n ¼ 28 isolates)
cotrimoxazole resistance is also increasing rapidly [56].
and in many countries now exceeds 50%. These
trends reflect the very high usage of these anti- Antibiotic consumption
biotics in Central and Eastern Europe, which is Antibiotic consumption data from Central and
mainly because of their low cost and local produc- Eastern Europe, expressed in defined daily doses
tion. Data from the Alexander Project (1996–97) (DDD)/1000 population/day (DID), show differ-
showed that the following proportions of fully ences among Russia, Byelorussia, the Slovak
penicillin-resistant isolates of S. pneumoniae were Republic, Poland and Hungary [93] (Figure 2).
resistant to various agents: Slovak Republic (dox- Consumption of virtually all antibiotics is low in
ycycline 30%, chloramphenicol 50%, cotrimoxazole
100%); Hungary (doxycycline 60%, chlorampheni-
col 53%, cotrimoxazole 100%); and Poland (dox-
ycycline 62%, chloramphenicol 39%, cotrimoxazole
77%) [21].
Haemophilus influenzae and Moraxella catarrhalis

b-lactamase-mediated ampicillin resistance in
H. influenzae is rare in Russia and Estonia (<1%
of isolates), but is increasingly prevalent in Poland,
and the Czech Republic (8% and 11%, respec-
tively). In comparison, this type of resistance is
more common in Romania (16%), Hungary (17%)
and, in particular, in the Slovak Republic (26%). In
the Central and Eastern European countries in-
volved in the Alexander Project (Czech Republic,
Slovak Republic and Poland) between 15% and
29% of isolates were resistant to cotrimoxazole,
whereas resistance to chloramphenicol and dox-
ycycline was 1% [73].
In most countries in this region, >90% of M. cat-
arrhalis isolates produce b-lactamases. An excep-
tion is Hungary, where the prevalence of b-
lactamase production in M. catarrhalis has been
reported to be 61%.
Streptococcus pyogenes
Streptococcus pyogenes remains uniformly sensitive
to penicillin in Central and Eastern European
countries. Unpublished data suggest that resis-
Figure 2 Consumption of b-lactam (A) and macrolide (B)
tance of S. pyogenes strains to macrolides is not antibiotics in Central and Eastern European countries
found in Bulgaria and remains uncommon in (various sources). Abbreviations: AMP ¼ ampicillin;
Slovakia and Romania (<10%). Somewhat higher AMX ¼ amoxicillin; AMX/CLAV ¼ amoxicillin–clavulanate;
rates of macrolide resistance have been observed AZI ¼ azithromycin; CLA ¼ clarithromycin; CLIN ¼ clinda-
mycin; DDD ¼ defined daily doses; ERY ¼ erythromycin;
in Russia (13%) and Poland (13%). While a similar
LINC ¼ lincomycin; PEN G ¼ penicillin G (benzylpenicillin);
rate is observed among the overall population PEN V ¼ penicillin V (phenoxymethylpenicillin); SPIR ¼
in the Czech Republic (13%), more than 20% of spiramycin.
Russia and Byelorussia (<12 DID) compared with and the macrolides may be particularly impor-
the Slovak Republic, Poland and Hungary tant in countries such as Poland and the Slovak
(>21 DID). With regard to the macrolides and Republic.
lincosamides, there is a high (2.9–3.2 DID) con- Education on the rational usage of antibiotics,
sumption of these agents in Hungary, Poland particularly amongst general practitioners, is
and the Slovak Republic. In contrast, in Byelorus- clearly a high priority in this region.
sia, consumption of lincomycin is low (0.08 DID)
and the use of clindamycin is virtually nonexistent
[90]. The same low usage has been observed for the North America
fluoroquinolones in Russia, compared with high Antibiotic resistance in community-acquired RTI
usage of these agents in other countries. These pathogens in North America first became evident
intercountry variations in antibiotic usage are in the early 1980s with the emergence of b-lacta-
likely to be influenced by the pharmaceutical mase resistance in H. influenzae and M. catarrhalis
companies operating in a particular area, the [95,96]. With the exception of the pneumococcal
availability of generic antibiotics and budget surveillance program conducted by the United
considerations. States CDC, surveillance essentially consisted of
Optimal antibiotic usage in many Central and local point prevalence studies. At that time, non-
Eastern European countries is hampered by a lack susceptibility rates were <5%, with essentially no
of education among prescribers. Collaboration resistant strains being observed (MIC 2 mg/L)
between microbiology laboratories and clinicians [97]. Indeed, the prevalence of PNSP was so low
is generally poor. Indeed, the microbiology labora- that the CDC suspended surveillance between
tory is not often viewed as an important aspect of 1987 and 1992 [98].
medicine and very few physicians specialize in However, the need for surveillance became evi-
clinical microbiology. Many countries do not have dent in the early 1990s with the rapid emergence of
formal antibiotic policies [94] and most of the multidrug resistance in pneumococci and high
knowledge about antibiotics among general prac- rates of resistance in H. influenzae and M. catarrhalis.
titioners is gained from promotional materials During the last decade, numerous national and
provided by pharmaceutical companies. international hospital-based, community and hos-
pital-based, and community-based surveillance
Conclusions systems have been established with the objective
Very few resistance surveillance data from Central of tracking antibiotic resistance in RTI pathogens.
and Eastern Europe are published in international Many of these programs have been in existence
peer-review journals. The available data are lim- for 2 or more years and can therefore provide
ited to local studies and there is considerable longitudinal data. These programs include: The
methodological variation. Importantly, in some SENTRY Antimicrobial Surveillance Program
Eastern European countries, limited resources [99]; Focus Technologies (formerly MRL) [100];
do not allow the use of standardized quantitative CROSS (Canadian Respiratory Organism Surveil-
techniques of susceptibility testing (i.e. MIC mea- lance Study) [101]; ABC (Active Bacterial Core
surement). Consequently, it is difficult to quantify Surveillance program of the CDC) [102]; the
the problem regionally. Despite these limitations, Alexander Project [21]; the CBDN (Canadian Bac-
the available data indicate that: terial Surveillance Network) [103]; and PROTEKT
Rates of antibiotic resistance vary consider- [56].
ably between countries in Central and Eastern
Europe. Streptococcus pneumoniae
Resistance rates are higher for older antibiotics Canada. In Canada, a strain of S. pneumoniae with
(e.g. tetracycline, cotrimoxazole and chloram- decreased susceptibility to penicillin was first
phenicol). reported by Dixon in 1977 [104]. However, PNSP
Penicillin and macrolide resistance appears to be were recovered infrequently until the late 1980s.
increasingly common in S. pneumoniae. Jette and Lamothe [105] performed susceptibility
Nonsusceptibility to penicillin is compounded testing on 468 strains collected between 1984 and
by cross-resistance to other antibiotics. For 1986. No resistant strain was identified, and
example, cross-resistance between penicillin only 1.3% showed intermediate susceptibility
(MIC 0.12–1 mg/L). In 1995, Simor et al. [106] susceptibility to penicillin and no strain was
tested 1089 isolates of S. pneumoniae collected from found to be resistant. These low levels of resistance
across Canada between 1994 and 1995 and found continued to be seen throughout the 1980s. Nation-
8.4% to be of intermediate susceptibility and 3.3% wide studies by the CDC found rates of PNSP of
to be resistant. <5% and recovered only one isolate with high-
Not only did the prevalence of PNSP rise during level resistance. However, this era of low-preva-
the late 1990s, but resistance to other classes of lence resistance in the United States came to an end
antibiotic also increased. From October 1997 to with the recognition in 1993 of antibiotic-resistant
November 1998, 1180 respiratory tract isolates of pneumococci in the community in Kentucky and
S. pneumoniae were collected from 18 medical cen- Tennessee [112]. In Kentucky, 28% of pneumococci
ters in nine of the 10 Canadian provinces [107]. cultured from middle-ear fluid were penicillin
Penicillin-intermediate and -resistant isolates nonsusceptible. In Tennessee, 29% of pneumococci
occurred with prevalences of 14.8 and 6.4%, isolated from nasopharyngeal swabs from children
respectively. Rates of nonsusceptibility to cotri- with otitis media enrolled at 17 sites in Memphis
moxazole, tetracycline and macrolides were were nonsusceptible. A total of 19% of the PNSP
12.2%, 10.6% and 9.3%, respectively. Of concern were penicillin-resistant and 25% were multidrug-
was the observation by Chen et al. [103] that the resistant. By 1994–95, the proportion of PNSP
prevalence of fluoroquinolone resistance among strains nationwide had increased to >23% [113].
pneumococci had increased in association with the Since then, numerous studies have documented
increased use of these agents. They found that the the increasing prevalence of PNSP and multidrug
prevalence of ciprofloxacin-resistant pneumococci resistance [21,22,102,114–116]. Doern et al. con-
(MIC 4 mg/L) increased from 0% in 1993 to 1.7% ducted susceptibility testing on a total of 1531
in 1997–98 (P ¼ 0.01). In adults, the prevalence recent clinical isolates of S. pneumoniae from 33
increased from 0% in 1993 to 3.7% in 1998. Of medical centers nationwide during the winter of
even greater concern was their observation that 1999–2000. Of these isolates, 34.2% were penicillin
the degree of resistance significantly increased nonsusceptible and 21.5% were resistant (Figure 1).
over the same time period. As a result of cross- MICs to all b-lactam antibiotics increased as peni-
resistance, this threatens the activity of the new cillin MICs increased. Rates of resistance to non b-
respiratory fluoroquinolones. Indeed, pneumococ- lactam agents were: macrolides 25.2–25.7%, clin-
cal resistance to the respiratory fluoroquinolones damycin 8.9%, tetracycline 16.3%, chlorampheni-
has recently been associated with clinical failures col 8.3%, and cotrimoxazole 30.3%.
[108].
There has been a significant overall reduction in Haemophilus influenzae
the use of oral outpatient antibiotics, especially the Ampicillin resistance in H. influenzae was first
aminopenicillins, in Canada since 1995. This has documented in North America in 1975 and was
been associated with a stabilization in the preva- a result of the TEM-1 b-lactamase [117]. ROB-1 was
lence of PNSP [109]. Current figures obtained from subsequently isolated in 1981 from an ampicillin-
a total of 2245 clinical isolates of S. pneumoniae resistant isolate of H. influenzae [118]. This subtype
collected from 63 microbiology laboratories across of b-lactamase is considerably less prevalent than
Canada during 2000 show a prevalence of 12.4% TEM-1. BLNAR strains have recently been
and 5.8% for penicillin nonsusceptible and peni- reported in the United States [119], but still appear
cillin-resistant isolates, respectively (Figure 1) [110]. to be relatively uncommon according to national
Unfortunately, since 1993 the reduction in amino- and multinational surveillance studies [120]. In
penicillin use has been offset by an increase in addition, resistance to orally administered cepha-
macrolide use which, in turn, has been associated losporins, macrolides and other antibiotics (e.g.
with an increase in macrolide resistance. Macro- chloramphenicol and tetracycline) has been
lide resistance in S. pneumoniae has increased from described, but no increase in their prevalence has
<3% in the early 1990s to 11% in 2000 [106,110]. been noted.In contrast,the frequency of H. influenzae
isolates resistant to cotrimoxazole is increasing.
United States. In 1978, Maki et al. [111] tested 243
isolates of pneumococci recovered from Madison, Canada. In Canada, the rate of b-lactamase produc-
Wisconsin. Only six strains had intermediate tion in H. influenzae was approximately 20% by the
mid-1980s [121] and quickly rose from 24.0% to However, macrolide resistance in S. pyogenes now
31.3% during the 1990s [9,120,122,123]. Since 1995, appears to be increasing in association with increa-
rates of b-lactamase production in H. influenzae sing macrolide consumption [134,135]. Weiss et al.
have actually decreased in association with a [135] found rates of macrolide resistance of 4.6% in
reduction in aminopenicillin use in the outpatient the province of Quebec. In the San Francisco Bay
setting [124]. Rates of resistance to cotrimoxazole area of northern California, 32% of S. pyogenes
were approximately 13% by the end of the 1990s isolates from invasive disease were macrolide
[123]. resistant, compared with 9% of those from throat
cultures [136].
United States. b-lactamase-mediated resistance in
H. influenzae has become increasingly prevalent in Conclusions
the United States. In 1983–84, the percentage of The number of surveillance programs established
b-lactamase-producing H. influenzae isolates was in recent years has allowed us to not only track
15% [125]. In a subsequent surveillance study the prevalence of antibiotic resistance in RTI
performed in 1986, the overall rate of b-lactamase pathogens, but also to define the mechanisms
production was 20% [126]. By 1994–95, 36% of of resistance so that we might better understand
H. influenzae isolates produced a b-lactamase their epidemiology and the forces driving resis-
[119]. Since 1996–97, no significant change in these tance. The available data indicate that in North
figures has been noted; contemporary percentages America:
of b-lactamase-producing H. influenzae range from Penicillin resistance in S. pneumoniae is increas-
33.4% in 1996–97 to 31.1% in 1997–98 [127,128]. The ingly common and is associated with increasing
prevalence of BLNAR has remained stable at <2% MIC levels and resistance to other agents, includ-
[129]. The prevalence of cotrimoxazole resistance ing macrolides. The recent emergence of fluor-
has increased from almost zero in the 1980s to oquinolone resistance in this organism is also an
>30% at present [129,130]. important concern.
Up to a third of H. influenzae isolates are resistant
Moraxella catarrhalis to aminopenicillins and cotrimoxazole.
The first b-lactamase-producing M. catarrhalis iso- Macrolide resistance in S. pyogenes is increasing.
late was identified in North America in 1977 [131]. As with macrolide resistance in S. pneumoniae,
The dramatic rise in BRO b-lactamase-producing this has occurred in association with increasing
M. catarrhalis strains observed in the last decade is macrolide consumption.
without precedent. The prevalence of BRO-produ-
cing M. catarrhalis is now almost universally >90%
[22,120,123,129]. As with H. influenzae, resistance to Latin America
other classes of antibiotic, with the exception of Resistance to antibiotics in RTI pathogens appears
cotrimoxazole, was nonexistent. Co-trimoxazole to be increasing in many countries in Latin Amer-
resistance is found in <8% of isolates in both ica. Streptococcus pneumoniae, H. influenzae and
Canada and the United States [120,123,129]. M. catarrhalis are the most common bacterial
pathogens isolated from community-acquired
Streptococcus pyogenes lower RTIs. The prevalence of lower RTIs caused
Although resistance to penicillin has not been by these pathogens is known to vary greatly
reported in S. pyogenes, significant levels of resis- depending on geographic location and the same
tance to some other antibiotics have developed in is true for the rates of resistance to antibiotics
certain geographic areas. This has been temporally (Figure 1). Important differences exist between
related to increased or excessive use of specific the rates of resistance in different Latin American
antibiotics. countries and even between the rates in different
The best example is the development and cities within each country.
spread of macrolide resistance among S. pyogenes
in certain countries, which has been observed since S. pneumoniae
the 1960s [82]. Despite this, the prevalence of Approximately 6000 strains of S. pneumoniae have
macrolide resistance in Canada and the United been studied in Latin and South America since the
States remained <3% until recently [132,133]. late 1980s (Table 3). All studies used NCCLS
Table 3 Susceptibility of Streptococcus pneumoniae in major recent surveillance studies performed in Latin America
No. of
Study Reference Location strains Year S (%) I (%) R (%)
PROTEKT PROTEKT 2001 [56] Argentina, 518 2000 57.9 26.8 15.3
(Latin America) Brazil and Mexico
Azithromycin group Mendes et al. [148] Brazil 114 1999–2000 87.7 12.3 0
GSMART Sader et al. [141] Latin America 244 1999–2000 72.0 23.0 5.0
LSMART Mendes et al. [148] Brazil 130 1999–2000 73.1 23.8 3.1
SIREVA Hortal et al. [145] Latin America 1409 1994–99 65.7 19.7 14.6
Alexander Project Felmingham et al. [21] Brazil and Mexico 257 1998 54.1 28.0 17.9
SENTRY Sader et al. [144] Brazil 176 1997–98 71.6 26.1 2.3
SENTRY Sader et al. [139] Latin America 553 1997–98 61.0 28.7 10.3
Artemis Orrantia-Gradin et al. [140] Latin America 643 1997–98 81.5 10.3 8.2
MRL Critchley et al. [143] Brazil 361 1997–98 76.6 18.6 4.7
LASER Jacobs & Appelbaum [137] Latin America 1100 1997 76.4 16.6 7.0
SENTRY Odland et al. [138] Latin America 264 1997 44.3 45.8 9.9
S, susceptible; I, intermediate; R, resistant.
breakpoints, and almost all isolates were collected 42.1% of S. pneumoniae were nonsusceptible to
from patients in the community. The prevalence of penicillin: 15.3% were resistant (MIC 2 mg/mL)
penicillin nonsusceptibility ranged from 2.8% in and 26.8% were intermediate (MIC 0.12–1 mg/L).
some countries to around 50% in others. In 1997, In addition, 15.3% of isolates were resistant to
the LASER study group surveyed 1100 S. pneumo- erythromycin (MIC 1.0 mg/L).
niae isolates from seven Latin American and
Caribbean countries [137]. Of these, 23.5% were Brazil. A multicenter survey conducted in 1995–96,
nonsusceptible to penicillin (6.9% resistant/16.6% involving 10 Brazilian medical centers, found that
intermediate) and a high prevalence of cross-resis- only 12.1% of 199 pneumococcal isolates were
tance to cotrimoxazole (44.6%) was observed. In nonsusceptible to penicillin [142]. In a slightly later
the same year, Odland et al. [138] analyzed 264 study conducted in 1997–98 by Focus Technolo-
isolates from Latin American countries within the gies, involving 361 S. pneumoniae isolates from five
SENTRY surveillance program. Among these, Brazilian hospitals, 4.7% were resistant to penicil-
9.9% were penicillin resistant and 45.8% were lin and 18.6% were intermediate [143]. Almost
penicillin intermediate. Sader et al. [139] also con- 100% of the isolates in both of these studies were
ducted a similar study involving seven Latin inhibited by newer fluoroquinolones (sparfloxacin
American countries during 1997–98. In this sur- and levofloxacin). During the same period, Sader
vey, of 553 S. pneumoniae isolates, 10.3% were fully et al. [144] analyzed 344 community-acquired RTI
resistant to penicillin and 28.7% were intermedi- isolates from Brazilian hospitals within the SEN-
ate. Similarly, in the Artemis project, which TRY program. Among these, 2.3% of the 176 pneu-
included 643 S. pneumoniae isolates collected from mococcal isolates were penicillin resistant and
10 Latin American countries in 1997–98, penicillin 26.2% were intermediate. In the SIREVA-Vigı́a
resistance was found in 8.2% of isolates and 10.3% program, conducted from 1993 to 1998, 2% of
were intermediate [140]. S. pneumoniae isolates from Brazil were resistant
During 1999/2000, 244 pneumococcal isolates and 21.3% were intermediate [145].
from five Latin American countries were analyzed In the Alexander Project, the prevalence of peni-
in the Global SMART (GSMART) surveillance cillin nonsusceptibility in isolates (n ¼ 76) collected
study [141]. Of these, 28% were nonsusceptible in 1997 reached 30.3% (1.3% resistant/28.9% inter-
to penicillin and 5% were fully resistant. Resis- mediate) [86]. Similarly, in the LSMART program,
tance to cefotaxime was also observed in 10% of 3.1% of 130 pneumococcal isolates collected from
isolates. Most recently, in the ongoing PROTEKT five Brazilian centers in 1999 were resistant to
program, 518 pneumococcal isolates from commu- penicillin and 23.8% were intermediate [146].
nity-acquired RTIs were provided by centers in Among the resistant strains, 25% were also resis-
Brazil, Argentina and Mexico in 2000 [56]. Overall, tant to cefotaxime. High levels of cross-resistance
to cotrimoxazole were also observed, but all macrolides (27.6%) and tetracyclines (32.5%) was
isolates were susceptible to levofloxacin and gati- also slightly more common in Mexico compared
floxacin. with Brazil and Argentina.
Most recently, PROTEKT data from 2000 indi-
cate that 8.1% of 260 isolates from Brazil were fully Haemophilus influenzae
resistant, with a further 25.8% being intermediate Fewer surveillance studies have been conducted
[56]. Only 6.5% were resistant to erythromycin, but on H. influenzae than on S. pneumoniae in Latin
66.5% were nonsusceptible to cotrimoxazole. America. Overall, the rate of b-lactamase produc-
tion rarely exceeds 20% among the countries sur-
Argentina. In an Argentinian surveillance program veyed.
conducted in 13 centers in 1995–96, 23% of pneu- In the Artemis project (1997–98), the percentage
mococcal isolates recovered from blood were non- of b-lactamase-producing strains ranged from 6%
susceptible to penicillin [147]. Similarly, in the in Colombia to 24% in Argentina [140]. Overall,
SIREVA-Vigı́a program, 20% of S. pneumoniae iso- 16% of the 605 isolates were b-lactamase positive.
lates from Argentina during 1993–98 were fully In the SENTRY program conducted in the same
resistant to penicillin [145]. Data from the Artemis region during the same period [144], 12.7% of 361
project (1997–98), involving 10 Latin American H. influenzae isolates were found to be b-lactamase
countries, showed that Argentina had the highest producers. Among the participating countries,
rate of penicillin nonsusceptibility (27%), followed rates of ampicillin resistance were highest in
by Mexico (21%), Venezuela (11%) and Brazil (3%) Mexico (26%), followed by Argentina (17.1%),
[140]. According to PROTEKT data from 2000, Chile (12.5%) and Brazil (9.3%). A high level of
more isolates of S. pneumoniae (16.4%; n ¼ 55) are cross-resistance to cotrimoxazole (40%) was also
resistant to penicillin in Argentina than in Brazil, observed. Also during 1997–98, 9.4% of the 223
although the number of isolates from Argentina is Brazilian isolates analyzed by Focus Technologies
small [56]. Patterns of resistance to other classes of were resistant to ampicillin and 2.2% were inter-
antibiotic are similar between the two countries. mediate [143]. Again, resistance to cotrimoxazole
(47.1%) was common in this study.
Mexico. Most studies have shown Mexico to have In a survey of 112 strains of H. influenzae from 10
the highest prevalence of penicillin resistance Brazilian medical centers in 1995–96, 12% were
in S. pneumoniae among the countries of Latin found to be b-lactamase producers [142]. In the
America. LASER study data from 1997 demon- Alexander Project, b-lactamase production was
strated a higher rate of penicillin nonsusceptibility detected in 10.3% of 126 Brazilian isolates collected
in Mexico (40.8%) compared with Argentina in 1996 [20]. Resistance to chloramphenicol was
(19.1%) and Brazil (13%) [137]. Similarly, in the relatively uncommon (11.9%) compared with
SIREVA-Vigı́a program in Latin America (1993– resistance to cotrimoxazole (29.1%). Similarly,
98), 20.8% of S. pneumoniae isolates from Mexico the Azithromycin Study Group found that 9.7%
were fully resistant to penicillin, and 28.6% were of 247 Brazilian isolates of H. influenzae collected in
intermediate[145]. This comparedwith correspond- 1999–2000 were b-lactamase producers [148].
ing rates of 18.5% resistant/24.4% intermediate in More recently, of the 520 isolates of H. influenzae
Uruguay and 20.0% resistant/15.5% intermediate from Latin America analyzed in the PROTEKT
in Argentina. Sader et al. found an even higher study, the prevalence of ampicillin resistance
nonsusceptibility rate of 66.6% in isolates collected (16.9%) was similar to levels in other major studies
during 1997–98 [139]. [56]. The highest rate was found in Mexico (24.6%;
The latest published Alexander Project data n ¼ 195), followed by Argentina (19.2%; n ¼ 52),
from 1998 indicate that 52.5% of 181 S. pneumoniae and Brazil (11.0%; n ¼ 273). Among ampicillin-
isolates from Mexico were penicillin nonsuscepti- resistant H. influenzae isolates, resistance to cotri-
ble (24.9% resistant/27.6% intermediate) [86]. moxazole varied from 30 to 70% in these countries.
More recently, the highest proportion of penicillin
nonsusceptible isolates in the PROTEKT Latin Moraxella catarrhalis
American database was also observed in Mexico The rate of b-lactamase production in M. catarrhalis
(56.6%; n ¼ 203), of which 24.1% were resistant has been relatively constant, exceeding 90% in
and 32.5% were intermediate [56]. Resistance to most surveillance studies. Pan-Latin America data
from the Alexander Project showed a steady this is an important factor to consider because
increase in the proportion of b-lactamase-positive these countries are characterized by very densely
isolates from 75.7% in 1992 to 90.4% in 1996 [20]. populated urban areas and low-density popula-
Mendes et al. reported a similar prevalence of tions in rural areas.
89.4% in 1995–96 [142]. Since then, the rate of b-lactamase production by H. influenzae was
b-lactamase production in this organism has been highest among isolates from Mexico (24.6% com-
documented at 91.8% in the Latin America SEN- pared with 19.2% and 10.9% in Argentina and
TRY study (1997–98) [144], 89% in the Artemis Brazil, respectively). For M. catarrhalis, in surveys
project (1997–98) [140], and, in Brazil, at 100% held in major Brazilian metropolitan areas with
by the Azithromycin Study group [140,148]. PRO- populations of more than 3 million, the percentage
TEKT study data from 2000 support these find- of b-lactamase-producing strains is greater than
ings, with b-lactamase production in Argentina, 95%.
Brazil and Mexico ranging from 97 to 100% [56].
Conclusions Asia-Pacific
The development and spread of resistance to Rates of antibiotic resistance in community-
selected classes of antibiotics in community- acquired RTI pathogens in some countries within
acquired RTI pathogens in Latin America is rising. the Asia-Pacific region are among the highest in
Several surveillance studies have been conducted the world. However, wide variations exist across
in the region and have yielded alarming results this region.
and interesting variations.
The prevalence of infection caused by penicillin- Streptococcus pneumoniae
resistant pneumococci has increased dramatically Resistance in S. pneumoniae is a particular con-
during the past two decades, particularly during cern in Asia. From the PROTEKT Study, only
the last 5 years. Data from PROTEKT 2000 show a 32% of respiratory S. pneumoniae isolates from
penicillin nonsusceptibility rate of 42.1% among across Asia are fully susceptible to penicillin
pneumococcal isolates from the Latin American [56]. Fifty-three percent exhibit high-level
countries surveyed (Argentina, Brazil and Mexico). resistance (MIC 2.0 mg/L), while an addi-
It is also important to note that a particularly high tional 15% are of intermediate susceptibility
rate of penicillin nonsusceptibility (56.6%) was (MIC 0.12–1.0 mg/L). Moreover, full macrolide
detected among Mexican pneumococcal isolates, resistance (erythromycin MIC 1.0 mg/L) is wide-
with 24.1% fully resistant to penicillin. spread, occurring in 81% of S. pneumoniae isolates.
Antibiotic resistance in S. pneumoniae is not con- Behind these worrying figures lies considerable
fined to the b-lactams; many studies have docu- variation in the prevalence of resistance (Figure 1).
mented the emergence of multiresistant strains of
pneumococci. In some countries, levels of macro- Korea and Japan. The highest rates of penicillin and
lide resistance are currently as high or higher than macrolide resistance encountered in the PROTEKT
levels of penicillin resistance. While macrolide database are in South Korea. Here, 81% of S. pneu-
consumption varies from country to country, those moniae isolates are penicillin nonsusceptible—70%
countries with the highest consumption have the are fully resistant and 11% are intermediate (Fig-
highest overall prevalence of macrolide resistance. ure 3) [56]. At least three-quarters of S. pneumoniae
By comparing penicillin resistance rates in isolates are also fully resistant to oral cephalospor-
S. pneumoniae from several studies carried out ins such as cefuroxime, cefpodoxime and cefixime.
between 1992 and 2001 quoted in this paper, we Moreover, 86% are fully resistant to erythromycin
notice slight variations throughout the period. The and the newer macrolides azithromycin and clar-
highest rate (55.7%) was reported by Odland and ithromycin.
colleagues in the SENTRY study carried-out in These findings are in agreement with those of
1997 [138]. These variations are possibly because the Asian Network for Surveillance of Resistant
of the origin of studied strains. As we know, the Pathogens (ANSORP) Study, which surveyed
rates of resistance may vary within the same resistance rates in S. pneumoniae isolates collected
country and even between different cities within from 11 countries in Asia between 1996 and 1997
the same country. In Latin American countries, [149]. Korea again showed the highest prevalence
Thailand (36% intermediate/22% resistant) [149].

Rates were lower in Indonesia (intermediate 3%/
resistant 18%) and Malaysia (intermediate 6%/
resistant 3%). Singapore has shown rates of peni-
cillin nonsusceptibility, from 23% (intermediate
5%/resistant 18%) in ANSORP [149] to 53% (inter-
mediate 17%/resistant 36%) in the Alexander Pro-
ject [86]. Erythromycin and tetracycline resistance
is often more common than penicillin resistance in
this region.
China. Available data suggest that penicillin non-

susceptibility in S. pneumoniae is relatively infre-
quent (10–15%) in mainland China and is largely
intermediate in level [149,152]. Macrolide and tet-
racycline resistance is more common, however,
Figure 3 Prevalence of nonsusceptibility to penicillin occurring in 30–50% of isolates, regardless of their
(PEN), erythromycin (ERY) and tetracycline (TET) among
susceptibility to penicillin.
Streptococcus pneumoniae isolates from Asian countries
participating in PROTEKT [56]. By contrast, Hong Kong is a major focus of
penicillin resistance. Current PROTEKT data show
that 57% of isolates are fully penicillin resistant
of penicillin nonsusceptible isolates (79%: 55% (Figure 3) [56]. Other national and international
resistant/24% intermediate). Moreover, >60% of studies have documented even higher rates of
penicillin-nonsusceptible isolates were resistant to nonsusceptibility [21,86,153]. For example, the
all other antibiotics tested, except vancomycin and Alexander Project documented an increase from
chloramphenicol. 59% in 1996 to 80% in 1999 [21,86]. Of particular
Penicillin nonsusceptibility in S. pneumoniae is concern is the high prevalence of full resistance in
also very common in Japan. The prevalence of Hong Kong—74% in 1999 [21]—and the high
penicillin nonsusceptibility increased in Nagasaki levels of resistance to broad-spectrum b-lactams
from 9% in 1988 to 37% in 1995 [150]. Ikemoto et al. [56,86,153]. Penicillin resistance is also coupled
have also documented a steady rise in resistance in with high-level macrolide resistance, currently
S. pneumoniae in Japan over the last 20 years. Most found in approximately 75–80% of isolates (Figure
recently, this group reported that the rate of peni- 3) [21,56,153]. Moreover, 16% of PROTEKT isolates
cillin nonsusceptibility had increased from 31% in from Hong Kong were reported as resistant to the
1997 to 46% in 1998 [151]. newer fluoroquinolones, moxifloxacin and levo-
Current PROTEKT data show that 65% of floxacin, suggesting that clonal spread has
S. pneumoniae isolates in Japan are now nonsuscep- occurred.
tible (20% intermediate/45% resistant) (Figure 3). Taiwan showed a rate of penicillin nonsuscept-
Similar rates have also been reported by the ibility of 38% (9% intermediate/29% resistant) in
ANSORP study (38% intermediate/27% resistant) the ANSORP study [149]. However, national stu-
[149] and the Alexander Project (23% intermedi- dies have shown an increase from approximately
ate/40% resistant) [86]. Macrolide and tetracycline 40% in 1995 to 54–56% in 1996–97 [154,155] and to
resistance are correspondingly common in Japan, 76% (25% resistant/51% intermediate) in 1998–99
each being found in around 80% of isolates in [156]. Macrolide resistance is especially common
PROTEKT (Figure 3) [56] and other studies in Taiwan and is generally found in 60–95% of
[86,149]. S. pneumoniae isolates [149,154–156].
South-East Asia. Relatively few surveillance data Indian subcontinent. Relatively low rates of penicil-
are available for countries in South-East Asia lin nonsusceptibility in S. pneumoniae have been
(Figure 1). The ANSORP Study revealed high reported in India (4%) [149,157], Bangladesh
levels of penicillin resistance in S. pneumoniae in (13%) [158] and Pakistan (20%) [159]. In contrast,
Vietnam (intermediate 28%/resistant 32%) and 41% of isolates from Sri Lanka were reported to be
penicillin intermediate [149]. Cotrimoxazole resis- been shown to be resistant to newer cephalospor-
tance is common in the Indian subcontinent and ins such as cefpodoxime and cefdinir [164]. Hae-
has been reported in over 50% of isolates in India mophilus influenzae remains uniformly susceptible
and Bangladesh. to fluoroquinolones and macrolides in Asia [56].
Middle East. The Middle East is emerging as an Moraxella catarrhalis

area of increasing penicillin resistance. Over half of b-lactamase production is highly prevalent in
S. pneumoniae isolates from Israel (resistant 36%/ M. catarrhalis, with rates exceeding 90% in most
intermediate 18%) [86], and Saudi Arabia (resis- countries. However, M. catarrhalis generally
tant 18%/intermediate 44%) are nonsusceptible remains susceptible to the newer cephalosporins
[86], and >60% from Lebanon (13% resistant/ and all isolates tested were also susceptible to
48% intermediate) [160] may be nonsusceptible. macrolides and fluoroquinolones.
However, macrolide resistance is less common at
present. Streptococcus pyogenes
The PROTEKT study has not documented any
Australasia. Antibiotic resistance in S. pneumoniae S. pyogenes isolates with resistance to penicillin
has increased rapidly in Australia. The percentage or fluoroquinolones [56]. However, 18% of isolates
of penicillin nonsusceptible isolates rose from 1% were resistant to erythromycin and the newer
in 1989 to 25% (17% intermediate/8% resistant) in macrolides. This prevalence is similar in Japan,
1999 [161]. Around 16% of isolates are now resis- South Korea and Hong Kong. Approximately
tant to erythromycin and tetracycline, while 45% 30–40% of isolates are fully resistant to tetracycline.
are resistant to cotrimoxazole [161].
Conclusions
Haemophilus influenzae Resistance to antibiotics is clearly increasing in
As in other parts of the world, b-lactamase pro- many Asian countries and is of particular concern
duction by H. influenzae, conferring resistance to b- in S. pneumoniae. The patterns of antibiotic resis-
lactams such as ampicillin and amoxicillin, is a tance in Asia may be dependent on three factors:
concern in Asia. However, like penicillin resis- There is a high prevalence of certain resistant
tance, the rates of b-lactamase production are serotypes of S. pneumoniae in some areas, e.g.
highly variable. South Korea.
Latest PROTEKT data show that over 80% of The genetic relatedness between penicillin-resis-
H. influenzae isolates from across Asia are suscep- tant S. pneumoniae strains from across Asia [149]
tible to ampicillin (MIC 1 mg/L) [56]. However, suggests that resistant clones have spread within
59% of H. influenzae isolates from South Korea and between countries.
are fully ampicillin-resistant. Approximately one- Genetic evidence also suggests that a nonsuscep-
third of isolates are resistant to cotrimoxazole or tible clone related to isolates from Spain and
tetracycline. South Africa has been disseminated in Asia
Other studies have reported ampicillin resis- [149,165].
tance in 55–58% of isolates of H. influenzae in Tai-
wan [154,156], 41% in Singapore [162], and 29% in
Hong Kong [21]. Rates of ampicillin resistance are Africa
relatively low in Japan, at around 12–16% [56,163]. Data concerning antibiotic resistance in commu-
Recently, two new important trends have nity-acquired RTI pathogens for most of Africa are
emerged in ampicillin resistance in H. influenzae, limited in comparison with those from Western
particularly in Japan. Firstly, some strains now Europe and North America. In particular, no pan-
produce b-lactamases that are resistant to inhibi- African studies have been performed to assess resis-
tion by the b-lactamase inhibitor clavulanate. tance patterns across the continent and the region
Hence, resistance to the widely used combination has relatively little representation in international
of amoxicillin–clavulanate has been reported studies. Currently only two African nations, South
[163]. Secondly, resistance has been reported in Africa and Kenya, are involved in the Alexander
BLNAR (ampicillin MIC 4 mg/L) strains of Project and only one, South Africa, in the PROTEKT
H. influenzae [163,164]. BLNAR strains have also study (with effect from 2001/2002).
Consequently, our present knowledge for much increasing problem in Kenya. Data published in
of the continent is largely based on smaller local 1996 indicate that 25% of sputum and blood iso-
studies prompted during the last decade by the lates collected from outpatients in Nairobi with
global concerns over resistance, particularly in pneumonia, most of whom were human immuno-
S. pneumoniae. deficiency virus (HIV) positive, were penicillin
nonsusceptible [173]. Reduced penicillin suscept-
Streptococcus pneumoniae ibility was significantly more common in sputum
The prevalence of penicillin resistance in S. pneu- isolates (35%) than blood isolates (18%; P ¼ 0.013).
moniae varies between different African nations More recently, the Alexander Project has indi-
(Figure 1). cated that penicillin nonsusceptibility is increas-
ingly prevalent in Kenya. Almost half of isolates
North Africa. Despite its geographic proximity to collected in 1999 were penicillin nonsusceptible
southern Europe, where penicillin-resistance rates [21]. However, resistance was largely intermediate
are amongst the highest in the world, Morocco (47% of isolates), with full resistance uncommon
appears to have relatively low rates of resistance (1.4%). Although penicillin-intermediate and
[166]. Further eastwards across North Africa the -resistant isolates are often also resistant to macro-
prevalence of penicillin resistance increases. The lides, this has so far not been shown to be the case
percentage of nonsusceptible strains in Tunisia in Kenya, and macrolide resistance remains rare.
was reported to have almost doubled to 14%
between 1994 and 1995 [167]. In Egypt, approxi- Central Africa. Resistance patterns in nasopharyn-
mately 25% of isolates collected from children with geal isolates collected from ill pediatric outpatients
pneumonia (n ¼ 1635) between 1991 and 1993 were (n ¼ 371) in the Central African Republic were
penicillin nonsusceptible [168]. A similar percen- recently reported [174]. This survey, conducted
tage of isolates were resistant to cotrimoxazole. in 1995 as part of a governmental and WHO acute
respiratory infection program, suggested that
West Africa. Recent data for resistance patterns in resistance in S. pneumoniae is not yet a major con-
West Africa are particularly scarce. Penicillin resis- cern in this region. Intermediate penicillin resis-
tance may be rare in Senegal and the Ivory Coast, tance was found in 9% of S. pneumoniae isolates
but may reach 20% in Nigeria [166]. In Ghana, 31% and none were fully resistant. The rate of resis-
of S. pneumoniae clinical isolates collected between tance to cotrimoxazole (7%) was comparable,
1994 and 1996 were resistant to penicillin [169]. while tetracycline resistance was far more preva-
Resistance to erythromycin and cotrimoxazole was lent (42%).
less common and all isolates were susceptible to Further south, 21% of S. pneumoniae clinical iso-
ceftriaxone. A pediatric study in a rural region of lates collected from Rwanda between 1984 and
the Gambia showed a low prevalence (<10%) of 1990 were penicillin intermediate, but tetracycline
resistance to penicillin, cotrimoxazole and chlor- resistance was common [175]. In Zambia, high-
amphenicol, suggesting that pneumococcal anti- level tetracycline resistance was found in 23% of
biotic resistance is not a major problem in this area nasopharyngeal isolates from children (n ¼ 126),
[170]. while 14% were penicillin intermediate [176].
Overall, a third of nasopharyngeal isolates in the
East Africa. With regard to East Africa, evidence latter study showed some resistance to at least one
from the early 1990s suggested that pneumococcal type of antibiotic. Likewise, in Botswana, approxi-
penicillin resistance is rare or even absent in Ethio- mately half of nasopharyngeal isolates from chil-
pia [171]. However, a more recent hospital-based dren (n ¼ 249) were resistant to at least one
study of pyogenic meningitis-causing bacteria antibiotic although only 7% showed multiresis-
from 1993 to 1995 has reported a 17% prevalence tance to three or more agents [177]. Almost a
of S. pneumoniae with intermediate penicillin sus- quarter of isolates were penicillin nonsusceptible.
ceptibility [172]. In the same study a 13% suscept- Finally, a small study in Zimbabwe showed that
ibility to cotrimoxazole (0% resistant/13% 7% of S. pneumoniae isolates were penicillin non-
intermediate) and chloramphenicol (11% resis- susceptible [178]. Notably, these isolates mostly
tant/2% intermediate) was also reported. By con- showed full penicillin resistance and were also
trast, penicillin resistance appears to be an resistant to erythromycin.
South Africa. The primary site of pneumococcal S. pneumoniae expressed erm genes and 13%
penicillin resistance in Africa, and the country in expressed mef genes [165]. Moreover, 31% of the
which most research has been performed, is South erythromycin-resistant S. pneumoniae expressed
Africa. Indeed, the first global reports of multi- both erm and mef genes and were highly resistant
resistant S. pneumoniae came from South Africa in to erythromycin and clindamycin. Most (83%) of
the late 1970s. these strains belonged to a single multiresistant
Since then, the prevalence of resistance in serotype 19F clone. Fifteen to 20% of isolates from
S. pneumoniae in South Africa has increased alar- 1996 to 1997 tested in the Alexander Project were
mingly. Between 1979 and 1986, the prevalence of resistant to doxycycline or cotrimoxazole [86].
resistance to one or more agents in pneumococcal Interest in pneumococcal infection in Africa has
blood isolates increased from 4% to 14% [179]. By increased in recent years not only because of the
1992, 40% of isolates (n ¼ 207) causing community- spread of antibiotic resistance, but also because of
acquired meningitis or bloodstream infections in its association with HIV infection [181]. HIV is a
South African children were penicillin-intermedi- major health-care problem in many areas of Africa,
ate (38.6%) or -resistant (1.4%) [180]. Four percent including South Africa. HIV-infected adults and
of isolates were multiresistant to three or more children are at increased risk of S. pneumoniae
agents tested. infection and the causative strains are more likely
The Alexander Project has shown that the pre- to be penicillin resistant than those causing infec-
valence of penicillin resistance in South Africa has tions in non-HIV-infected patients [182–184]. Vac-
continued to rise (Figure 4) [21,86]. Centres in cination against pneumococcal infection may
Johannesburg have participated in the Alexander reduce its impact in HIV-positive patients, but
Project since 1996. Of the isolates collected in 1999, further research is required to establish the efficacy
79% were penicillin nonsusceptible [86], indicating of this approach.
that South Africa remains a global focus of peni-
cillin nonsusceptibility in S. pneumoniae. However, Other pathogens
penicillin resistance in South Africa remains There are few data concerning resistance rates in
mainly intermediate in level; full resistance is far other community-acquired RTI pathogens in Africa.
less prevalent here than in Hong Kong or southern Evidence suggests that ampicillin resistance is
Europe. uncommon (10%) in H. influenzae in Egypt
Almost a quarter of S. pneumoniae isolates from [168], Ethiopia [171,172], Nigeria [185–187], Gam-
South Africa now show full erythromycin resis- bia [188], and the Central African Republic [174].
tance, with 40–50% of penicillin nonsusceptible Similarly, resistance rates of H. influenzae to cotri-
isolates showing cross-resistance to macrolides. moxazole and chloramphenicol in Ethiopia are
Over 90% of erythromycin-resistant isolates are also low (6% and 3%, respectively) [172]. Around
also resistant to clindamycin. In terms of genetic 30% of M. catarrhalis respiratory isolates in Nigeria
phenotypes, a study from South Africa carried out were resistant to ampicillin in one study [187].
in 1999 showed that 57% of erythromycin-resistant Further south, ampicillin resistance was present
in around a quarter of nasopharyngeal H. influen-
zae isolates in Botswana [177]. In South Africa 11–
14% of H. influenzae isolates are ampicillin resis-
tant, largely on account of b-lactamase production
[189,190]. Resistance to cotrimoxazole is found in
10–20% of isolates, while erythromycin resistance
is widespread, occurring in around 85% of isolates
[189,190]. A third study from South Africa has
reported a similar low prevalence of resistance of
H. influenzae to a wide range of antibiotics, includ-
ing ampicillin (8%), cotrimoxazole (10%), tetracy-
cline (12%) and chloramphenicol (8%), while
Figure 4 Changes in penicillin and macrolide-resistance
resistance to erythromycin was reported at 43%
prevalence in respiratory Streptococcus pneumoniae isolates [191]. However, 22% of isolates collected in this
in South Africa [21,86]. study were resistant to three or more agents.
Antibiotic usage and resistance quantity and quality of resistance surveillance data
There can be little doubt that the spread of anti- from many areas, especially developing regions of
biotic resistance in S. pneumoniae is due, at least in Central America, Africa, Asia and Central/Eastern
part, to the use of antibiotics. A study conducted in Europe, remain poor. Mortality from RTIs is highest
the southern African nation of Lesotho showed in these regions and limited therapeutic options and
that children in the capital city of Maseru (n ¼ 196) poorly regulated prescribing practices are likely to
were significantly more likely than rural children fuel the spread of resistance.
(n ¼ 324) to carry penicillin- or tetracycline-resis- Furthermore, there are still considerable chal-
tant pneumococcal nasopharyngeal isolates [192]. lenges to the provision of reliable surveillance
In association with this finding, city-dwelling chil- data, in relating these data to antibiotic-prescrib-
dren tended to visit clinics at an earlier age, had ing patterns, and in the application of this infor-
greater antibiotic exposure, were more frequently mation to support resistance control strategies.
hospitalized and attended day-care centers more
often than their rural counterparts.
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Surveillance of Resistance in Bacteria Causing Community-Acquired Respiratory Tract Infections

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Surveillance of Resistance in Bacteria Causing Community-Acquired Respiratory Tract Infections

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Surveillance of resistance in bacteria causing community-acquired

respiratory tract infections

tious disease and has made possible many

Table 1 Major mechanisms underlying antibiotic resistance in respiratory tract pathogens

Pathogen Clinical infection Antibiotics Major resistance mechanisms

Streptococcus pneumoniae Acute exacerbations of chronic b-lactams Mosaicism in DNA-encoding

Figure 1 Prevalence of penicillin

Moraxella catarrhalis Conclusions

levels of resistance (e.g. France and Germany, The Streptococcus pneumoniae

Haemophilus influenzae and Moraxella catarrhalis

S, susceptible; I, intermediate; R, resistant.

Thailand (36% intermediate/22% resistant) [149].

China. Available data suggest that penicillin non-

Middle East. The Middle East is emerging as an Moraxella catarrhalis

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