Thorax 1996; 51(Suppl 2):S45-S50

Antibiotic resistant Streptococcuspneumoniae

E J Minton, J T Macfarlane*

Department of Infectious Diseases and *Department of Respiratory Medicine,

Nottingham City Hospital, Nottingham, UK

Introductory article

Resistance to penicillin and cephalosporin and mortality from severe pneumococcalpneumonia in Barcelona, Spain

R Pallares, J Linares, M Vadillo, C Cabellos, F Manresa, P F Viladrich, R Martin, F Gudiol

Background. Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, andstrains with resistance to cephalosporin are being reported. The appropriate antibiotic forpneumococcalpneumonia due to resistant strains remains controversial. Methods. To examine the effect of resistanceto penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelonaof 504 adults with culture-proved pneumococcal pneumonia. Results. Among the 504 patients, 145 (29percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] ofpenicillin 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 patientswith 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 forother predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strainswas 1.0 (95 percent confidence interval, 0.5 to 1 9: P= 0*84). Among patients treated with penicillin Gor ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent inthe 126 with penicillin-sensitive strains (P= 0.51). Among patients treated with ceftriaxone or cefotaxime,the mortality was 22 percent in the 59 with penicillin-resistant strains and 25 percent in the 127 withpenicillin-sensitive strains (P=0*64). The frequency of resistance to cephalosporin increased from 2percent in 1984-1988 to 9 percent in 1989-1993 (P=0.002). Mortality was 26 percent in patients withcephalosporin-resistant S. pneumoniae and 28 percent in patients with susceptible organisms (P= 0-89).Among patients treated with ceftriaxone or cefotaxime, mortality was 22 percent in the 18 withcephalosporin-resistant strains and 24 percent in the 168 with cephalosporin-sensitive organisms (P=0-64). Condusions. Current levels of resistance to penicillin and cephalosporin by S. pneumoniae arenot associated with increased mortality in patients with pneumococcal pneumonia. Hence, theseantibiotics remain the therapy of choice for this disease. (N Engl J Med 1 995;333:474-80)

For many years penicillin provided very effective treat-ment for pneumococcal infections. However, the lasttwo decades have seen the emergence of pneumococcalstrains with resistance not only to penicillin, but also toother antibiotics.' This has contributed to treatmentfailure, at least in pneumococcal meningitis.2 In spiteof this, it has been suggested that penicillin may still bean effective treatment for pneumococcal pneumonia asvery high tissue concentrations of antibiotic can beachieved.3 In August 1995 Pallares and colleagues,working in Barcelona where the incidence of penicillinresistance in pneumococci is particulary high, publisheda study comparing mortality from pneumonia due topenicillin sensitive pneumococci with that due to peni-cillin resistant strains.4 Their results suggest that there

may be little difference in mortality between the twogroups after correction for an increased incidence ofpoor prognostic factors amongst those patients withresistant infections.

In this review we will provide a general introductionto the topic of antibiotic resistant pneumococci, discussthe paper by Pallares et al in more detail, and finallymake our own suggestions on how to deal with thedifficult clinical problem of increasing antibiotic re-sistance in pneumococci.

Pneumococcal infection and the development ofantibiotic resistancePNEUMOCOCCAL PNEUMONIA: THE SIZE OF THE PROBLEMPneumococcal infection remains the commonest cause

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of community acquired pneumonia in the UK (76%of adult hospital admissions for community acquiredpneumonia in Nottingham in 19825). In the USA thereare approximately half a million episodes of pneumo-coccal pneumonia each year with 40 000 deaths.67 Indeveloping countries over a million children under theage of five years die annually from pneumonia, mostcommonly due to Streptococcus pneumoniae.8 Pneumoniadue to pneumococci is commoner in the elderly,9 inthose with underlying disease particularly immuno-suppression such as hyposplenism and HIV disease,o101and in alcoholics and vagrants.'2 There is a markedseasonal variation with peak incidence in the wintermonths.'2 13

PATHOGENISIS OF PNEUMOCOCCAL PNEUMONIAStreptococcus pneumoniae is found as normal naso-pharyngeal and oropharyngeal flora in approximately15% of children and 5% of adults.'4 It is thought to bepassed from person to person via respiratory secretionsand aerosols. Impairment of host defence mechanismswithin the bronchial tree such as ciliary movement,cough and secretory immunoglobulin (for example, inchronic lung disease or an acute viral infection) mayallow pneumococci to gain access to the lower res-piratory tract. The organisms are surrounded by a cap-sule composed ofpolysaccharide antigens (used in straintyping) which inhibits phagocytosis. Antibodies to thepolysaccharide capsule are protective, suggesting thatthis is an important virulence factor. Other virulencefactors include pneumolysin 0, a toxin which causescell lysis, and a neuraminidase which degrades host cellsurface structures. Components of the pneumococcalcell wall are able to interact with C-reactive proteinresulting in the activation of host non-specific immuneresponses. 14

DEVELOPMENT OF TREATMENT FOR PNEUMOCOCCALINFECTIONAt the beginning of this century the mortality frompneumococcal pneumonia approached 75%.15 Initialtreatment was optochin, a drug related to quinine which,although effective, had to be abandoned for clinical usebecause of ocular toxicity.'6 (It is still used for theidentification of pneumococci in the laboratory today.)Pneumococcal antisera and sulphonamides both im-proved the survival from pneumococcal disease, but theintroduction of pencillin reduced the overall mortalityrate to approximately 25%,'7 which has remained con-stant for many years in spite ofdevelopment of intensivecare techniques including positive pressure ventilation.'8

APPEARANCE OF PENICILLIN RESISTANT PNEUMOCOCCINot long after the introduction of penicillin in 1940 thefirst penicillin resistant pneumococcus was produced invitro,'9 but the first clinical isolate did not appear until20 years later in Boston, USA.20 In the late 1960s anumber of penicillin resistant strains were isolated inAustralia and New Guinea, possibly related to a trial ofprophylactic oral penicillin in an attempt to reduce theincidence of pneumococcal disease.2122 In the 1970san epidemic of penicillin and later multidrug resistantpneumococci was seen in paediatric wards in SouthAfrica and in Europe, particularly Spain and Hungary(fig 1).1 23-25

Figure 1 Worldwide prevalence and distribution ofpenicillin resistance of Streptococcus pneumoniae. Datacompiled from references 1, 23-25, 33, 36, 53-57.

DIAGNOSIS AND DEFINITION OF PENICILLIN RESISTANTPNEUMOCOCCAL INFECTIONPneumococci may be identified by Gram staining ofspecimens such as respiratory secretions, followed byconventional culture techniques, looking for char-acteristic colonial morphology, oc-haemolysis and op-tochin sensitivity, plus specific reactions with antiserato capsular polysaccharides.14 Penicillin sensitivity isscreened for by disc diffusion techniques. Filter paperdiscs containing a standardised amount of antibiotic areapplied to an agar plate inoculated with the bacterialisolate. After incubation a zone of growth inhibition ispresent around the disc if the isolate is sensitive to theantibiotic. More sensitive isolates have larger inhibitionzones which may be quantified approximately by com-parison with a previously characterised strain. In orderto quantify accurately the minimum inhibitory con-centration of antibiotic (MIC) for a particular isolate,more time consuming microdilution techniques arenecessary. A pneumococcal isolate is considered to besensitive to penicillin if the MIC is <06g,g/ml. Anisolate with intermediate resistance has an MIC of0 6-1 ,ug/ml, while the term "high level resistance" isused to describe isolates with MICs of > 2 gig/ml. TheE-test, a strip of paper impregnated with increasingconcentrations of an antibiotic, is a newer less laboriousmethod based on antibiotic diffusion techniques whichallows an approximate estimate of the MIC.26

MECHANISMS OF ANTIBIOTIC RESISTANCEPenicillins work by binding to a number of proteins(usually enzymes) essential for the synthesis of thebacterial cell wall and inhibiting their function. Penicillinresistant pneumococci have been shown to have peni-cillin binding proteins (PBPs) with much reducedaffinity for penicillin, so that the presence of penicillindoes not interfere with bacterial wall synthesis (fig 2).27There are thought to be at least two mechanismswhereby low affinity PBPs are acquired by pneumococci.Other bacteria, particularly viridans streptococci, maytransfer genetic material encoding low affinity PBP genesto pneumococci." Both types ofbacteria may be carriedin the oropharynx so that they may come into closeproximity. In addition, the presence of penicillin exertsa selective pressure on pneumococci favouring pointmutations causing a reduction in PBP affinity and thusan increase in MIC.29 Cephalosporin resistance is alsomediated by changes in PBP affinity, but fewer geneticchanges are required for resistance to occur.30 The genesfor antibiotic resistance may be spread amongst differentpneumococcal clones or serotypes by exchange of gen-etic information.31 In addition, a resistant strain can bespread geographically by colonisation of new hosts, as

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Antibiotic resistant Streptococcus pneumoniae

A

PenicillinXbinding site PBP type

C

B

p

p

Figure 2 Schematic representation of penicillin resistancedue to altered penicillin binding affinity. (A) Penicillinbinding protein (PBP) catalyses cross linking ofpeptidogly%can chains essential for manufacture of cell wall.(B) Penici lin (P) inhibits cross linking of peptidoglycanchains. (C) Penicillin is unable to interact with alteredbinding site and therefore cannot inhibit cross linking.

seen in Iceland when penicillin resistant pneumococciwere isolated of a type similar to that initially observed inSpain. Presumably the strain was acquired by Icelanderswhile on holiday in Spain and then transported home.32

EPIDEMIOLOGY OF ANTIBIOTIC RESISTANT

PNEUMOCOCCAL INFECTIONThe prevalence of penicillin resistant pneumococci var-

ies throughout the world and is particularly high inSouth Africa, Spain, Hungary, Israel, and the USA (fig1).' In the UK the level of penicillin resistance is fairlylow (1-7% of isolates in 1993).33 However, the pre-valence can vary markedly between districts of one

country - for example, in Hungary penicillin resistancein clinical isolates of pneumococci ranges from 3% toover 60% according to region.25 In the USA the rate ofpenicillin resistance reaches 25% in some areas - forexample, Atlanta where 9% ofpneumococcal isolates ina recent study were also resistant to extended spectrumcephalosporins.34 This study also noted that, while theoverall incidence of invasive pneumococcal disease wasmore common in blacks than whites, antibiotic resistantStreptococcus pneumoniae were more readily isolated fromwhite children living in suburban areas than from blackchildren living in an urban setting. Thus, although lowersocioeconomic status may predispose to pneumococcaldisease, access to medical care and prior exposure toantibiotics may be a more important predisposing factorfor infection with antibiotic resistant pneumococci.Some of the first isolates of penicillin resistant pneu-mococci were found in a village in New Guinea afterprophylactic penicillin had been used in an attempt toreduce the incidence of pneumococcal disease.22 Thisobservation also suggests that exposure to antibioticsincreases the likelihood of infection with a resistantrather than a susceptible strain of pneumococci. Re-sistant pneumococci are again more readily isolatedfrom patients who are already in hospital or who havebeen in hospital within the previous few months.3 Often

they have serious underlying disease such as cancer orrenal insufficiency.35 Such patients are also more likelyto have received antibiotics and perhaps to have comeinto contact with other patients already colonised withresistant bacteria. In South Africa the rate of spread ofresistant pneumococcal isolates was found to be relatedto the degree of overcrowding on paediatric wards,suggesting that the pneumococcus is readily spread bycontact with colonised individuals.23 Penicillin re-sistance may be found in any of the different pneumo-coccal serotypes but 80-90% consist of strainscovered by the current pneumococcal vaccine Pneumo-vax II. Just four serotypes (6B, 14, 19A, and 23F)have so far been associated with multidrug resistance.36

Introductory article by Pallares et al4STUDY DESIGNPallares and colleagues have carried out a large pro-spective survey over 10 years of patients with definitebacteriological diagnoses of pneumococcal pneumoniabased on isolation of pneumococci from blood or lowerrespiratory tract secretions, together with clinical andradiographic evidence of pneumonia. Patients were ad-mitted under the care ofan attending (general) physicianwho decided on the initial antibiotic regime. Onceculture and sensitivity results were available they werereviewed by respiratory or infectious disease physicianswho advised on subsequent antibiotic prescribing. Theinvestigators collected data on factors thought likely toinfluence the outcome, including clinical factors suchas age, presence of shock, underlying disease, andwhether the infection was acquired in hospital or in thecommunity. Laboratory data collected included whitecell counts, multilobar appearance on the chest radio-graph, and whether the infection was polymicrobial.The sole outcome examined was mortality with 28days of diagnosis which was analysed in relation to theantibiotic sensitivity of the pneumococcal isolate andthe antibiotic used to treat the infection. Both univariateand multivariate analyses were applied to the data.

TRENDS IN PNEUMOCOCCAL INFECTION OVER THE STUDYPERIODThe overall incidence of pneumococcal pneumonia in-creased, probably because of larger numbers of in-fections seen in HIV patients in the latter part of thestudy. Such patients have previously been shown to bemore susceptible than immunocompetent individualsto bacterial pneumonia, especially pneumococcalinfection.01'1 The proportion of resistant pneumococcalisolates increased, not only to penicillin but also tocephalosporins, erythromycin, and to second line agentssuch as imipenem. The number of patients with highlevel penicillin resistant isolates also increased from 6%to 15%. Cephalosporin resistance was usually found inassociation with resistance to penicillin. No vancomycinresistance was seen.

MORTALITYOverall mortality was significantly greater for thosepatients infected with penicillin resistant pneumococcalstrains (38%) than penicillin susceptible strains (24%).However, multivariate analysis revealed a number ofindependent predictors of poor prognosis including age>70, shock, and multilobar, nosocomial and poly-microbial infections. These factors occurred with greaterfrequency in the group of patients infected with penicillin

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resistant pneumococci. Once such poor prognostic fac-tors were taken into account there was no significantdifference in mortality between the penicillin resistantand penicillin susceptible groups. Thus, the isolation ofpenicillin resistant pneumococci from a patient may bea marker for poor prognosis, as has been observed forvancomycin resistant enterococci.37 No difference inseverity of infection at presentation was found betweenthe two groups, which suggests that the presence ofpenicillin resistance has no effect on pneumococcalvirulence. No difference in mortality (uncorrected) was

found between patients infected with cephalosporinsensitive in comparison to cephalosporin reistant strains.The patients who were HIV positive had a lower overallmortality, perhaps because these patients were younger

than the study group as a whole.

RESPONSE TO ANTIBIOTIC THERAPYThis study was not carried out as a randomised con-

trolled trial, so only limited conclusions can be drawnabout the effectiveness of different antibiotic strategies.In addition, the antibiotic treatment of patients was

reviewed and sometimes changed in the light of cultureresults, but this has not been taken into account in thedata analysis. In such cases it is not clear whether thedata were analysed with regard to initial or final choiceof antibiotic. With these caveats, there was no significantdifference in mortality rates for patients treated withpenicillin or ampicillin regardless of whether they were

infected with a penicillin sensitive or resistant pneu-

mococcal strain. This was so for both overall mortalityrates, and mortality rates adjusted for the presence ofpoor prognostic factors. Likewise, penicillin resistancedid not appear to have any effect on the outcome ofpatients treated with ceftriaxone or cefotaxime, or withother antibiotic regimes. The authors point out thateight ofnine patients receiving penicillin for isolates withMICs of > 2 ig/ml (high level resistance) recovered. Inaddition, of eight patients who received cephalosporinsfor high level penicillin resistant isolates all but one

patient survived. However, the numbers of patientswith high level penicillin resistance were small so thattreatment failures here might not be apparent.For those patients with cephalosporin resistance the

number of patients (n = 5) treated with cephalosporinwas too small to judge whether cephalosporins are

effective despite the presence of resistance. Nonetheless,there was little difference in overall mortality forcephalosporin resistant isolates regardless of the anti-biotic treatment regimen used.

Approaches to the management ofpneumococcal antibiotic resistanceTREATMENT OF ANTIBIOTIC RESISTANT STREPTOCOCCUS

PNEUMONIAEApart from the study by Pallares and colleagues, thereis other evidence that P-lactam antibiotics are effectiveagainst pneumococci with intermediate penicillin resist-ance. A study of South African children with pneumo-coccal pneumonia showed no significant difference inmortality between those with fully sensitive pneumo-coccal strains (11 %) and those with intermediate resist-ant strains (14%) when both received ,B-lactamantibiotics.38 Studies in Spain and in Houston similarlyfailed to show any difference in outcome.339 Thus, as

suggested by Pallares et al, high dose penicillin remainsthe 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 havebeen isolated, failure ofpenicillin has been documented,particulary in subjects with underlying disease.340 In thissituation high dose third generation cephalosporins,vancomycin or imipenem may be used, perhaps incombination with an aminoglycoside to provide syn-

ergy.4" Empirical therapy, according to Pallares andcolleagues, should be based on the assessment of riskfactors for infection with a penicillin resistant pneu-

mococcus - for example, local incidence of penicillinresistance or likelihood of nosocomial infection (table1). If no risk factors are present, and the probability ofdeath appears low, then these patients can be treatedwith conventional regimens (benzyl penicillin, ampicillinor amoxicillin). However, if the patient is severely ill or

has risk factors of penicillin resistance, they recommendthe use of ceftriaxone or cefotaxime with erythromycinif an atypical pathogen cannot be ruled out. If highlevel cephalosporin resistance is present locally, thenalternative regimens such as vancomycin or imipenem

should be considered.4' For pneumococcal disease atother sites, particularly meningitis, it may not be possibleto achieve sufficient local penicillin concentrations totreat pneumococci with intermediate resistance withpenicillin. Treatment with a third generation cephalo-sporin such as ceftriaxone or cefotaxime may be neces-

sary in this situation. In areas where cephalosporinresistant pneumococci are present, combination therapywith cefotaxime/ceftriaxone and vancomycin has beenrecommended.36"4

In the UK and other countries where the prevalenceof antibiotic resistant pneumococci is low there is no

reason to change the standard treatment for pneumo-coccal pneumonia at present, although it may be prudentto err on giving higher rather than lower doses ofpenicillin or amoxycillin to cover possible intermediateresistant strains. However, it is essential to continuecareful surveillance of pneumococcal resistancethroughout the country in order to detect an increasein prevalence which might necessitate a change in policy.Pneumococcal meningitis should be treated with largedoses 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 serotypesit is not possible to protect against all pneumococcalinfections with a single vaccine. This problem was

partially solved by the development of polyvalent vac-

cines containing initially 14 and, since 1984, 23 differentpneumococcal serotypes (Pneumovax II).42 The 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 whichpneumococcal resistance is most commonly seen.34Pneumovax is recommended for individuals with im-

Table 1 Risk factors for infection with penicillinresistant Streptococcus pneumoniae335

High local prevalence of penicillin resistant pneumococciExposure to ,Blactam antibiotics within previous 3 monthsAdmission to hospital within previous 3 monthsUnderlying immunosuppressive diseaseEpisodes of pneumonia within the previous yearInitial critical condition*

* Defined as two or more of the following: (1) severe underlyinadisease, (2) age of 75 or more, (3) leukopenia, (4) shock, (5)multilobar involvement.

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Antibiotic resistant Streptococcus pneumoniae

munodeficiency states including hyposplenism and HIVinfection; chronic lung, cardiac, hepatic and renal dis-ease; and diabetes mellitus. In the USA it is also re-

commended for all individuals over the age of 65.4 Theoverall efficacy varies according to the patient groupvaccinated and is estimated to be 56% overall, reaching75% in the immunocompetent population." It appearsto be less effective in patients with chronic renal failureand haematological malignancies. Uptake ofthe vaccine,at least in the USA, has been a problem with only28% of the target population receiving it even after an

awareness campaign.45 Unfortunately the vaccine is noteffective in children under two years of age because ofimmaturity of the immune system. In addition, thecapsular polysaccharide antigens do not induce highlevel, high affinity antibodies or T cell memory as dothe peptide-based or protein-based antigens. Thus, newconjugate vaccines are being developed using proteincarriers attached to capsular polysaccharide in the hopeofimproving protection, as has been achieved for the Hibconjugate vaccine. The diversity of the pneumococcalpolysaccharides makes this a much more complex task,and initial conjugate vaccines are likely to include onlythe seven most common serotypes." We consider theuse 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 resistantStreptococcus pneumoniae is frequently related to anti-biotic usage. Antibiotic prescribing has been shown tobe inappropriate in many instances - for example, viral

infections where no effect has been shown on eithersymptom duration or secondary bacterial infection.47 Asmany as 50% of outpatient antibiotic prescriptions wereconsidered unnecessary in one US study." In the UKantibiotic prescription rates have increased by nearly50% between 1980 and 1993.49 Although the reasons

for this increase in antibiotic prescribing have not yetbeen investigated, it has been suggested that this isdue to a gradual increase in the use of antibiotics forrespiratory symptoms. In one recent study of 1089adults who presented to their general practitioner withacute lower respiratory symptoms, three quarters re-

ceived an antibiotic even though the GP felt antibioticsto be definitely indicated in less than a third of treatedcases and not needed in a fifth. Factors such as patientpressure and GP work pressure were found to contributeto the prescribing of unnecessary antibiotics.50 In some

countries antibiotics can be obtained without pre-scription which may lead to inappropriate use and thedevelopment of resistance. The use of antibiotics inanimal food stuffs and in veterinary practice is notwell regulated in many countries and may lead to theemergence of resistance genes which may be passedfrom animal microbial flora to human pathogens.5151More careful regulation of antibiotic use is necessary tolimit the development, not only of antibiotic resistantpneumococci, but other resistant bacteria such as methi-cillin resistant Staphylococcus aureus and vancomycinresistant enterococci. Enterococci are fairly closely re-

lated to streptococci and thus the potential exists fortransfer of genetic material encoding vancomycin re-

sistance from enterococci to pneumococci. Such an

event would leave very few antibiotics effective againstpneumococci.

LEARNING POINTS* The incidence of penicillin and cephalosporin resistant pneumococci is increasing.* High dose penicillin is still effective in intermediate resistant pneumococcal bacteraemiaand pneumonia, but probably not in meningitis.

* Alternative antibiotic regimens are required for pneumococci with high level penicillinresistance; surveillance of local antibiotic resistance is critical for selection of appropriateempirical therapy.

* Pneumococcal vaccines protect against most pneumococcal serotypes with antibiotic re-

sistance and should be given more frequently, especially in areas where antibiotic resistantpneumococci are common.

* Antibiotic usage should be more carefully regulated to limit the emergence of antibioticresistant bacteria.

Table 2 Suggested treatment for pneumococcal infections

Site of infection Type of resistance

Fully sensitive Intermediate penicillin High level penicillin High level penicillin andresistance resistance cephalosporin resistance

Pneumonia and/or Benzyl penicillin High dose benzyl Cefotaxime Vancomycin 1 12 hourlysepticaemia 1-2g 6 hourly penicillin 2-4g 4 hourly 1-2g 6 hourly +aminoglycos,de

(ampicillin/amoxycillin)* (ampicillin/amoxycillin) (imipenem+aminoglycoside)Meningitis Benzyl penicillin Cefotaxime Cefotaxime Vancomycin 1 12 hourly

2-4 g 4hourly 2 g 6 hourly 2 g 6 hourly +aminoglycoside(ceftriaxone) (ceftriaxone)

* Alternative regimen in parentheses.

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ConclusionThere is evidence from many different centres through-out the world that the incidence of resistance inpneumococci, not only to penicillin but also to otherantibiotics, is increasing rapidly. The evidence presentedby Pallares and colleagues is somewhat reassuring inthat, for the moment, many of these pneumococcalstrains show only intermediate penicillin resistance and,at least in pneumonia, respond to high dose penicillin.However, high level resistance to penicillin and also tocephalosporins is becoming more common, and suchstrains may require alternative antibiotic regimens.Other strategies which may help to prevent disease dueto resistant pneumococci include the increased use ofexisting pneumococcal vaccines and the developmentof improved conjugate vaccines. The problem of in-appropriate antibiotic use needs to be urgently addressedto control the development, not only of antibiotic re-

sistant Streptococcus pneumoniae, but also many otherspecies of resistant bacteria.

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