Anti b iotic res istant Streptococcus pneumoniae

Background. Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, and strains with resistance to cephalosporin are being reported. The appropriate antibiotic for pneumococcal pneumonia due to resistant strains remains controversial. Methods. To examine the effect of resistance to penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelona of 504 adults with culture-proved pneumococcal pneumonia. Results. Among the 504 patients, 145 (29 percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] of penicillin G, 0 12 to 4.0 ug per milliliter), and 31 patients (6 percent) had cephalosporin-resistant strains (MIC of ceftriaxone or cefotaxime, 1.0 to 40 pum per milliliter). Mortality was 38 percent in patients with penicillin-resistant strains, as compared with 24 percent in patients with penicillin-sensitive strains (P= 0.001). However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95 percent confidence interval, 0.5 to 1 9: P= 0*84). Among patients treated with penicillin G or ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent in the 126 with penicillin-sensitive strains (P= 0.51). Among patients treated with ceftriaxone or cefotaxime, the mortality was

For many years penicillin provided very effective treat- ment for pneumococcal infections.However, the last two decades have seen the emergence of pneumococcal strains with resistance not only to penicillin, but also to other antibiotics.'This has contributed to treatment failure, at least in pneumococcal meningitis.2In spite of this, it has been suggested that penicillin may still be an effective treatment for pneumococcal pneumonia as very high tissue concentrations of antibiotic can be achieved.3 In August 1995 Pallares and colleagues, working in Barcelona where the incidence of penicillin resistance in pneumococci is particulary high, published a study comparing mortality from pneumonia due to penicillin sensitive pneumococci with that due to peni- cillin resistant strains.4Their results suggest that there may be little difference in mortality between the two groups after correction for an increased incidence of poor prognostic factors amongst those patients with resistant infections.
In this review we will provide a general introduction to the topic of antibiotic resistant pneumococci, discuss the paper by Pallares et al in more detail, and finally make our own suggestions on how to deal with the difficult clinical problem of increasing antibiotic re- sistance in pneumococci.
of community acquired pneumonia in the UK (76% of adult hospital admissions for community acquired pneumonia in Nottingham in 19825).In the USA there are approximately half a million episodes of pneumo- coccal pneumonia each year with 40 000 deaths.67In developing countries over a million children under the age of five years die annually from pneumonia, most commonly due to Streptococcus pneumoniae.8Pneumonia due to pneumococci is commoner in the elderly,9 in those with underlying disease particularly immuno- suppression such as hyposplenism and HIV disease,o101 and in alcoholics and vagrants.'2There is a marked seasonal variation with peak incidence in the winter months.'2 13PATHOGENISIS OF PNEUMOCOCCAL PNEUMONIA Streptococcus pneumoniae is found as normal nasopharyngeal and oropharyngeal flora in approximately 15% of children and 5% of adults.'4It is thought to be passed from person to person via respiratory secretions and aerosols.Impairment of host defence mechanisms within the bronchial tree such as ciliary movement, cough and secretory immunoglobulin (for example, in chronic lung disease or an acute viral infection) may allow pneumococci to gain access to the lower res- piratory tract.The organisms are surrounded by a cap- sule composed ofpolysaccharide antigens (used in strain typing) which inhibits phagocytosis.Antibodies to the polysaccharide capsule are protective, suggesting that this is an important virulence factor.Other virulence factors include pneumolysin 0, a toxin which causes cell lysis, and a neuraminidase which degrades host cell surface structures.Components of the pneumococcal cell wall are able to interact with C-reactive protein resulting in the activation of host non-specific immune responses. 14

DEVELOPMENT OF TREATMENT FOR PNEUMOCOCCAL INFECTION
At the beginning of this century the mortality from pneumococcal pneumonia approached 75%.15Initial treatment was optochin, a drug related to quinine which, although effective, had to be abandoned for clinical use because of ocular toxicity.'6(It is still used for the identification of pneumococci in the laboratory today.)Pneumococcal antisera and sulphonamides both im- proved the survival from pneumococcal disease, but the introduction of pencillin reduced the overall mortality rate to approximately 25%,'7 which has remained con- stant for many years in spite of development of intensive care techniques including positive pressure ventilation.'8 APPEARANCE OF PENICILLIN RESISTANT PNEUMOCOCCI Not long after the introduction of penicillin in 1940 the first penicillin resistant pneumococcus was produced in vitro,'9 but the first clinical isolate did not appear until 20 years later in Boston, USA.20 In the late 1960s a number of penicillin resistant strains were isolated in Australia and New Guinea, possibly related to a trial of prophylactic oral penicillin in an attempt to reduce the incidence of pneumococcal disease.2122In the 1970s an epidemic of penicillin and later multidrug resistant pneumococci was seen in paediatric wards in South Africa and in Europe, particularly Spain and Hungary (fig 1).1 [23][24][25] Figure 1 Worldwide prevalence and distribution of penicillin resistance of Streptococcus pneumoniae.Data compiled from references 1, 23-25, 33, 36, 53-57.DIAGNOSIS AND DEFINITION OF PENICILLIN RESISTANT PNEUMOCOCCAL INFECTION Pneumococci may be identified by Gram staining of specimens such as respiratory secretions, followed by conventional culture techniques, looking for char- acteristic colonial morphology, oc-haemolysis and op- tochin sensitivity, plus specific reactions with antisera to capsular polysaccharides.14Penicillin sensitivity is screened for by disc diffusion techniques.Filter paper discs containing a standardised amount of antibiotic are applied to an agar plate inoculated with the bacterial isolate.After incubation a zone of growth inhibition is present around the disc if the isolate is sensitive to the antibiotic.More sensitive isolates have larger inhibition zones which may be quantified approximately by com- parison with a previously characterised strain.In order to quantify accurately the minimum inhibitory con- centration of antibiotic (MIC) for a particular isolate, more time consuming microdilution techniques are necessary.A pneumococcal isolate is considered to be sensitive to penicillin if the MIC is <06 g,g/ml.An isolate with intermediate resistance has an MIC of 0 6-1 ,ug/ml, while the term "high level resistance" is used to describe isolates with MICs of > 2 gig/ml.The E-test, a strip of paper impregnated with increasing concentrations of an antibiotic, is a newer less laborious method based on antibiotic diffusion techniques which allows an approximate estimate of the MIC.26

MECHANISMS OF ANTIBIOTIC RESISTANCE
Penicillins work by binding to a number of proteins (usually enzymes) essential for the synthesis of the bacterial cell wall and inhibiting their function.Penicillin resistant pneumococci have been shown to have peni- cillin binding proteins (PBPs) with much reduced affinity for penicillin, so that the presence of penicillin does not interfere with bacterial wall synthesis (fig 2).27There are thought to be at least two mechanisms whereby low affinity PBPs are acquired by pneumococci.Other bacteria, particularly viridans streptococci, may transfer genetic material encoding low affinity PBP genes to pneumococci."Both types of bacteria may be carried in the oropharynx so that they may come into close proximity.In addition, the presence of penicillin exerts a selective pressure on pneumococci favouring point mutations causing a reduction in PBP affinity and thus an increase in MIC. 29Cephalosporin resistance is also mediated by changes in PBP affinity, but fewer genetic changes are required for resistance to occur. 30The genes for antibiotic resistance may be spread amongst different pneumococcal clones or serotypes by exchange of gen- etic information.31In addition, a resistant strain can be spread geographically by colonisation of new hosts, as (B) Penici lin (P) inhibits cross linking of peptidoglycan chains.(C) Penicillin is unable to interact with altered binding site and therefore cannot inhibit cross linking.
seen in Iceland when penicillin resistant pneumococci were isolated of a type similar to that initially observed in Spain.Presumably the strain was acquired by Icelanders while on holiday in Spain and then transported home.32

EPIDEMIOLOGY OF ANTIBIOTIC RESISTANT PNEUMOCOCCAL INFECTION
The prevalence of penicillin resistant pneumococci var- ies throughout the world and is particularly high in South Africa, Spain, Hungary, Israel, and the USA (fig 1).'In the UK the level of penicillin resistance is fairly low (1-7% of isolates in 1993).33However, the pre- valence can vary markedly between districts of one countryfor example, in Hungary penicillin resistance in clinical isolates of pneumococci ranges from 3% to over 60% according to region.25In the USA the rate of penicillin resistance reaches 25% in some areas -for example, Atlanta where 9% of pneumococcal isolates in a recent study were also resistant to extended spectrum cephalosporins.34This study also noted that, while the overall incidence of invasive pneumococcal disease was more common in blacks than whites, antibiotic resistant Streptococcus pneumoniae were more readily isolated from white children living in suburban areas than from black children living in an urban setting.Thus, although lower socioeconomic status may predispose to pneumococcal disease, access to medical care and prior exposure to antibiotics may be a more important predisposing factor for infection with antibiotic resistant pneumococci.Some of the first isolates of penicillin resistant pneu- mococci were found in a village in New Guinea after prophylactic penicillin had been used in an attempt to reduce the incidence of pneumococcal disease.22This observation also suggests that exposure to antibiotics increases the likelihood of infection with a resistant rather than a susceptible strain of pneumococci.Re- sistant pneumococci are again more readily isolated from patients who are already in hospital or who have been in hospital within the previous few months.3 Often they have serious underlying disease such as cancer or renal insufficiency.35Such patients are also more likely to have received antibiotics and perhaps to have come into contact with other patients already colonised with resistant bacteria.In South Africa the rate of spread of resistant pneumococcal isolates was found to be related to the degree of overcrowding on paediatric wards, suggesting that the pneumococcus is readily spread by contact with colonised individuals.23Penicillin re- sistance may be found in any of the different pneumococcal serotypes but 80-90% consist of strains covered by the current pneumococcal vaccine Pneumovax II.Just four serotypes (6B, 14, 19A, and 23F) have so far been associated with multidrug resistance.36Introductory article by Pallares et al4 STUDY DESIGN   Pallares and colleagues have carried out a large pro- spective survey over 10 years of patients with definite bacteriological diagnoses of pneumococcal pneumonia based on isolation of pneumococci from blood or lower respiratory tract secretions, together with clinical and radiographic evidence of pneumonia.Patients were ad- mitted under the care ofan attending (general) physician who decided on the initial antibiotic regime.Once culture and sensitivity results were available they were reviewed by respiratory or infectious disease physicians who advised on subsequent antibiotic prescribing.The investigators collected data on factors thought likely to influence the outcome, including clinical factors such as age, presence of shock, underlying disease, and whether the infection was acquired in hospital or in the community.Laboratory data collected included white cell counts, multilobar appearance on the chest radiograph, and whether the infection was polymicrobial.The sole outcome examined was mortality with 28 days of diagnosis which was analysed in relation to the antibiotic sensitivity of the pneumococcal isolate and the antibiotic used to treat the infection.Both univariate and multivariate analyses were applied to the data.

TRENDS IN PNEUMOCOCCAL INFECTION OVER THE STUDY PERIOD
The overall incidence of pneumococcal pneumonia in- creased, probably because of larger numbers of in- fections seen in HIV patients in the latter part of the study.Such patients have previously been shown to be more susceptible than immunocompetent individuals to bacterial pneumonia, especially pneumococcal infection.01' 1 The proportion of resistant pneumococcal isolates increased, not only to penicillin but also to cephalosporins, erythromycin, and to second line agents such as imipenem.The number of patients with high level penicillin resistant isolates also increased from 6% to 15%.Cephalosporin resistance was usually found in association with resistance to penicillin.No vancomycin resistance was seen.

MORTALITY
Overall mortality was significantly greater for those patients infected with penicillin resistant pneumococcal strains (38%) than penicillin susceptible strains (24%).However, multivariate analysis revealed a number of independent predictors of poor prognosis including age >70, shock, and multilobar, nosocomial and poly- microbial infections.These factors occurred with greater frequency in the group of patients infected with penicillin resistant pneumococci.Once such poor prognostic fac- tors were taken into account there was no significant difference in mortality between the penicillin resistant and penicillin susceptible groups.Thus, the isolation of penicillin resistant pneumococci from a patient may be a marker for poor prognosis, as has been observed for vancomycin resistant enterococci.37No difference in severity of infection at presentation was found between the two groups, which suggests that the presence of penicillin resistance has no effect on pneumococcal virulence.No difference in mortality (uncorrected) was found between patients infected with cephalosporin sensitive in comparison to cephalosporin reistant strains.The patients who were HIV positive had a lower overall mortality, perhaps because these patients were younger than the study group as a whole.

RESPONSE TO ANTIBIOTIC THERAPY
This study was not carried out as a randomised con- trolled trial, so only limited conclusions can be drawn about the effectiveness of different antibiotic strategies.In addition, the antibiotic treatment of patients was reviewed and sometimes changed in the light of culture results, but this has not been taken into account in the data analysis.In such cases it is not clear whether the data were analysed with regard to initial or final choice of antibiotic.With these caveats, there was no significant difference in mortality rates for patients treated with penicillin or ampicillin regardless of whether they were infected with a penicillin sensitive or resistant pneu- mococcal strain.This was so for both overall mortality rates, and mortality rates adjusted for the presence of poor prognostic factors.Likewise, penicillin resistance did not appear to have any effect on the outcome of patients treated with ceftriaxone or cefotaxime, or with other antibiotic regimes.The authors point out that eight ofnine patients receiving penicillin for isolates with MICs of > 2 ig/ml (high level resistance) recovered.In addition, of eight patients who received cephalosporins for high level penicillin resistant isolates all but one patient survived.However, the numbers of patients with high level penicillin resistance were small so that treatment failures here might not be apparent.
For those patients with cephalosporin resistance the number of patients (n = 5) treated with cephalosporin was too small to judge whether cephalosporins are effective despite the presence of resistance.Nonetheless, there was little difference in overall mortality for cephalosporin resistant isolates regardless of the anti- biotic treatment regimen used.
Approaches to the management of pneumococcal antibiotic resistance TREATMENT OF ANTIBIOTIC RESISTANT STREPTOCOCCUS PNEUMONIAE Apart from the study by Pallares and colleagues, there is other evidence that P-lactam antibiotics are effective against pneumococci with intermediate penicillin resist- ance.A study of South African children with pneumo- coccal pneumonia showed no significant difference in mortality between those with fully sensitive pneumo- coccal strains (11 %) and those with intermediate resist- ant strains (14%) when both received ,B-lactam antibiotics.38Studies in Spain and in Houston similarly failed to show any difference in outcome.339Thus, as suggested by Pallares et al, high dose penicillin remains the treatment of choice for pneumococcal pneumonia, provided the MIC of the isolate is <1 jIg/ml.In patients from whom pneumococci with high level resistance have been isolated, failure ofpenicillin has been documented, particulary in subjects with underlying disease.340In this situation high dose third generation cephalosporins, vancomycin or imipenem may be used, perhaps in combination with an aminoglycoside to provide syn- ergy.4"Empirical therapy, according to Pallares and colleagues, should be based on the assessment of risk factors for infection with a penicillin resistant pneu- mococcusfor example, local incidence of penicillin resistance or likelihood of nosocomial infection (table 1).If no risk factors are present, and the probability of death appears low, then these patients can be treated with conventional regimens (benzyl penicillin, ampicillin or amoxicillin).However, if the patient is severely ill or has risk factors of penicillin resistance, they recommend the use of ceftriaxone or cefotaxime with erythromycin if an atypical pathogen cannot be ruled out.If high level cephalosporin resistance is present locally, then alternative regimens such as vancomycin or imipenem should be considered.4'For pneumococcal disease at other sites, particularly meningitis, it may not be possible to achieve sufficient local penicillin concentrations to treat pneumococci with intermediate resistance with penicillin.Treatment with a third generation cephalo- sporin such as ceftriaxone or cefotaxime may be neces- sary in this situation.In areas where cephalosporin resistant pneumococci are present, combination therapy with cefotaxime/ceftriaxone and vancomycin has been recommended.36"4   In the UK and other countries where the prevalence of antibiotic resistant pneumococci is low there is no reason to change the standard treatment for pneumo- coccal pneumonia at present, although it may be prudent to err on giving higher rather than lower doses of penicillin or amoxycillin to cover possible intermediate resistant strains.However, it is essential to continue careful surveillance of pneumococcal resistance throughout the country in order to detect an increase in prevalence which might necessitate a change in policy.Pneumococcal meningitis should be treated with large doses of cefotaxime (2 g every six hours) or ceftriaxone (4 g per day) until sensitivities are available (table 2).

VACCINES
Because of the many different pneumococcal serotypes it is not possible to protect against all pneumococcal infections with a single vaccine.This problem was partially solved by the development of polyvalent vac- cines containing initially 14 and, since 1984, 23 different pneumococcal serotypes (Pneumovax II).42The sero- types contained in the latter preparation cover 80-90% ofepisodes ofpneumococcal infection in most countries.The vaccine also includes most of the serotypes in which pneumococcal resistance is most commonly seen.34 Pneumovax is recommended for individuals with im- Table 1 Risk factors for infection with penicillin resistant Streptococcus pneumoniae335 munodeficiency states including hyposplenism and HIV infection; chronic lung, cardiac, hepatic and renal dis- ease; and diabetes mellitus.In the USA it is also recommended for all individuals over the age of 65. 4 The overall efficacy varies according to the patient group vaccinated and is estimated to be 56% overall, reaching 75% in the immunocompetent population."It appears to be less effective in patients with chronic renal failure and haematological malignancies.Uptake ofthe vaccine, at least in the USA, has been a problem with only 28% of the target population receiving it even after an awareness campaign.45Unfortunately the vaccine is not effective in children under two years of age because of immaturity of the immune system.In addition, the capsular polysaccharide antigens do not induce high level, high affinity antibodies or T cell memory as do the peptide-based or protein-based antigens.Thus, new conjugate vaccines are being developed using protein carriers attached to capsular polysaccharide in the hope ofimproving protection, as has been achieved for the Hib conjugate vaccine.The diversity of the pneumococcal polysaccharides makes this a much more complex task, and initial conjugate vaccines are likely to include only the seven most common serotypes."We consider the use and development of pneumococcal vaccines as an important means of prevention of resistant pneumo- coccal disease in at risk groups.

ANTIBIOTIC USAGE
As described above, the occurrence ofantibiotic resistant Streptococcus pneumoniae is frequently related to anti- biotic usage.Antibiotic prescribing has been shown to be inappropriate in many instances -for example, viral infections where no effect has been shown on either symptom duration or secondary bacterial infection.47As many as 50% of outpatient antibiotic prescriptions were considered unnecessary in one US study."In the UK antibiotic prescription rates have increased by nearly 50% between 1980 and 1993.49Although the reasons for this increase in antibiotic prescribing have not yet been investigated, it has been suggested that this is due to a gradual increase in the use of antibiotics for respiratory symptoms.In one recent study of 1089 adults who presented to their general practitioner with acute lower respiratory symptoms, three quarters re- ceived an antibiotic even though the GP felt antibiotics to be definitely indicated in less than a third of treated cases and not needed in a fifth.Factors such as patient pressure and GP work pressure were found to contribute to the prescribing of unnecessary antibiotics.50In some countries antibiotics can be obtained without pre- scription which may lead to inappropriate use and the development of resistance.The use of antibiotics in animal food stuffs and in veterinary practice is not well regulated in many countries and may lead to the emergence of resistance genes which may be passed from animal microbial flora to human pathogens.5151 More careful regulation of antibiotic use is necessary to limit the development, not only of antibiotic resistant pneumococci, but other resistant bacteria such as methicillin resistant Staphylococcus aureus and vancomycin resistant enterococci.Enterococci are fairly closely re- lated to streptococci and thus the potential exists for transfer of genetic material encoding vancomycin re- sistance from enterococci to pneumococci.Such an event would leave very few antibiotics effective against pneumococci.
LEARNING POINTS * The incidence of penicillin and cephalosporin resistant pneumococci is increasing.

Conclusion
There is evidence from many different centres throughout the world that the incidence of resistance in pneumococci, not only to penicillin but also to other antibiotics, is increasing rapidly.The evidence presented by Pallares and colleagues is somewhat reassuring in that, for the moment, many of these pneumococcal strains show only intermediate penicillin resistance and, at least in pneumonia, respond to high dose penicillin.However, high level resistance to penicillin and also to cephalosporins is becoming more common, and such strains may require alternative antibiotic regimens.Other strategies which may help to prevent disease due to resistant pneumococci include the increased use of existing pneumococcal vaccines and the development of improved conjugate vaccines.The problem of in- appropriate antibiotic use needs to be urgently addressed to control the development, not only of antibiotic re- sistant Streptococcus pneumoniae, but also many other species of resistant bacteria.

Figure 2
Figure 2 Schematic representation of penicillin resistance due to altered penicillin binding affinity.(A) Penicillin binding protein (PBP) catalyses cross linking of peptidogly%can chains essential for manufacture of cell wall.

Table 2
Suggested treatment for pneumococcal infections * Alternative regimen in parentheses.