Background Penicillin-resistant strains of Streptococcus pneumoniaeare now found worldwide, and strains with resistance to cephalosporinare being reported. The appropriate antibiotic therapy for pneumococcalpneumonia due to resistant strains remains controversial.
Methods To examine the effect of resistance to penicillin andcephalosporin on mortality, we conducted a 10-year, prospectivestudy in Barcelona of 504 adults with culture-proved pneumococcalpneumonia.
Results Among the 504 patients, 145 (29 percent) had penicillin-resistantstrains of S. pneumoniae (minimal inhibitory concentration [MIC]of penicillin G, 0.12 to 4.0 µg per milliliter), and 31patients (6 percent) had cephalosporin-resistant strains (MICof ceftriaxone or cefotaxime, 1.0 to 4.0 µg per milliliter).Mortality was 38 percent in patients with penicillin-resistantstrains, as compared with 24 percent in patients with penicillin-sensitivestrains (P = 0.001). However, after the exclusion of patientswith polymicrobial pneumonia and adjustment for other predictorsof mortality, the odds ratio for mortality in patients withpenicillin-resistant strains was 1.0 (95 percent confidenceinterval, 0.5 to 1.9; P = 0.84). Among patients treated withpenicillin G or ampicillin, the mortality was 25 percent inthe 24 with penicillin-resistant strains and 19 percent in the126 with penicillin-sensitive strains (P = 0.51). Among patientstreated with ceftriaxone or cefotaxime, the mortality was 22percent in the 59 with penicillin-resistant strains and 25 percentin the 127 with penicillin-sensitive strains (P = 0.64).
The frequency of resistance to cephalosporin increased from2 percent in 1984–1988 to 9 percent in 1989–1993(P = 0.002). Mortality was 26 percent in patients with cephalosporin-resistantS. 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 with cephalosporin-resistantstrains and 24 percent in the 168 with cephalosporin-sensitiveorganisms (P = 0.64).
Conclusions Current levels of resistance to penicillin and cephalosporinby S. pneumoniae are not associated with increased mortalityin patients with pneumococcal pneumonia. Hence, these antibioticsremain the therapy of choice for this disease.
Since the first descriptions two decades ago of strains of Streptococcuspneumoniae with a decreased susceptibility to penicillin (minimalinhibitory concentration [MIC] of penicillin G, or the lowestconcentration that inhibits pneumococcal growth, >0.12 µgper milliliter),1,2 there have been increasing reports of infectionscaused by pneumococcal strains with high levels of resistanceto penicillin, to multiple antibiotics, and more recently tocephalosporin.3,4,5,6,7,8,9,10,11,12,13 The prognostic factorshave been studied,14,15 but the effect of resistance to penicillinand cephalosporin on mortality due to pneumococcal pneumoniain adults is not known.
Despite the decreased susceptibility of pneumococci to penicillinG, it is probable that penicillin, the time-honored treatmentfor pneumococcal infection, should remain the antibiotic ofchoice for some such infections. However, it is not clear whichtypes of pneumococcal infection may be treated successfullywith penicillin, and up to what MIC.
On the basis of reports by us and others,13,16 pneumococcalmeningitis due to strains against which the MIC of penicillinis 0.12 µg per milliliter or higher should not be treatedwith that drug. Instead, either a third-generation cephalosporinor vancomycin is recommended.13,16 Recently, cephalosporin therapyhas been reported to have failed in patients with pneumococcalmeningitis due to strains against which cefotaxime and ceftriaxonehave high MICs.17
On the other hand, preliminary data suggest that in some casespneumococcal pneumonia against which the MIC of penicillin isincreased may respond to penicillin or related -lactam antibiotics,18,19,20because the serum concentrations achieved with these drugs21are several times higher than the MICs. Nevertheless, the efficacyof penicillin is uncertain, and the role of extended-spectrumcephalosporins (ceftriaxone or cefotaxime) in treating resistantpneumococcal pneumonia is not well defined.
We sought to determine the factors influencing mortality inadults with severe pneumococcal pneumonia, as well as to assessthe effect of resistance to penicillin and cephalosporin onmortality in such patients. In addition, we evaluated the responseto therapy with penicillin or cephalosporin in relation to thedegree of resistance of the infecting strain.
Methods
Study Patients and Sources of Data
This 10-year, prospective study included patients with pneumoniaand no other focal disease, such as meningitis, for whom culturesof blood, pleural fluid, or specimens from the lower respiratorytract were positive for S. pneumoniae. The study was carriedout in the Hospital de Bellvitge "Princeps d'Espanya," a 1000-bedteaching institution in Barcelona, Spain, that serves an areawith a population of more than 1 million and admits only adultpatients.
From January 1984 through December 1993, a total of 494 isolatesof S. pneumoniae were identified from blood samples in our microbiologylaboratory; 412 of these strains were isolated from patientswith pneumonia, whereas the remainder were from patients withmeningitis (49 patients) or bacteremia (33 patients). In addition,138 patients whose blood cultures were negative had S. pneumoniaeisolated from cultures of pleural fluid (46 patients), culturesof specimens obtained by transthoracic needle aspiration (37patients), or cultures of bronchoscopic specimens obtained bybrushing that had more than 1000 colony-forming units (cfu)(55 patients). Thus, a total of 550 patients had diagnoses ofculture-proved pneumococcal pneumonia. At our institution, selectedpatients with severe pneumonia whose initial diagnoses wereunclear were included in a prospective protocol (approved bythe ethics committee of the hospital) in recent years to studythe efficacy of procedures to obtain bronchoscopic specimensby brushing and transthoracic needle aspiration.22 Studies ofsusceptibility to antibiotics were conducted for all the strainsobtained; several were included in previous reports.18,23
When pneumococci were isolated from blood or another specimen,the patient was evaluated by a staff member of the InfectiousDisease Service or the Pulmonary Disease Service. Most patientswere seen at outpatient clinics within one month after discharge.Data on mortality were obtained by following the patients duringhospitalization and reviewing the clinical records of the outpatientclinic and records of deaths.
We decided to include both patients with bacteremia and thosewithout bacteremia in the study, because no significant differencesin mortality were found between the two groups (28 percent and29 percent, respectively). This study design allowed us to enrollmore patients with strains resistant to penicillin and cephalosporin,so that more accurate statistical comparisons could be made.
Among the 550 patients, 504 completed the study protocol; theremaining 46 were excluded from the univariate and multivariateanalyses. The mortality rate among these 46 patients was 26percent, similar to the rate of 28 percent among the patientswho were included. The entire group of 550 patients was includedin the studies of susceptibility to antibiotics (Table 1).
Table 1. Susceptibility to Antibiotics in 550 Strains of Pneumococci Isolated from Patients with Pneumonia.
Definitions
A diagnosis of pneumococcal pneumonia was made if a patientwas found to have infection of the lower respiratory tract inthe clinical history and on physical examination, as well asa pulmonary infiltrate on chest radiography, and if S. pneumoniaewas isolated from cultures of one or more of the following typesof specimens: blood, pleural fluid, or specimens obtained bytransthoracic needle aspiration or bronchoscopic-specimen brushing.Patients who had only sputum cultures positive for pneumococciwere not included.
Mortality in the hospital was defined to include deaths withinone month after the diagnosis of pneumonia. Serious underlyingdisease was considered to be present if the patient had a confirmeddiagnosis of one of the following: cancer, systemic vasculitis,or cirrhosis of the liver; diabetes, if that disease had beendiagnosed and the patient was receiving hypoglycemic drugs;chronic renal failure, if the patient was undergoing dialysis;human immunodeficiency virus (HIV) infection, if the patienthad a positive enzyme-linked immunosorbent assay and Westernblot assay for HIV type 1 or type 2; heart failure, if the patienthad a history of congestive heart failure, evidence of heartfailure, or both at the time of admission; and chronic pulmonarydisease, if the patient had had chronic respiratory symptomsfor more than three months during the preceding two years. Nosocomiallyacquired pneumonia was defined by the presence of signs andsymptoms of lower respiratory tract infection that developedafter three days of hospitalization for an unrelated illness.Shock was defined as systolic blood pressure below 90 mm Hgtogether with hypoperfusion of the peripheral tissues. Multilobarinvolvement and pleural effusion were considered to be presentwhen more than one pulmonary lobe was involved and when therewas evidence of pleural fluid on a chest film, respectively.Leukopenia was diagnosed if the initial white-cell count wasbelow 5000 per cubic millimeter. Polymicrobial pneumonia wasconsidered to be present when S. pneumoniae and another microorganismwere isolated from cultures of blood or specimens obtained fromthe lower respiratory tract; monomicrobial pneumonia was consideredto be present when S. pneumoniae was the only microorganismisolated.
Antibiotic therapy was initially prescribed by the attendingphysician. When the results of the in vitro susceptibility testingwere known, the patient was evaluated by an infectious-diseasespecialist, and most patients continued to receive the drugsinitially prescribed, because their conditions were clearlyimproving. For the analysis, patients were divided into threegroups: the penicillin group (those treated with penicillinG or ampicillin); the cephalosporin group (those treated withceftriaxone or cefotaxime); and the group treated with otherantibiotics. In order to include more patients with penicillin-resistantdisease in each group, those treated with penicillin G and ampicillinwere grouped together, as were those treated with ceftriaxoneand cefotaxime, because the drugs in each pair have almost identicalMICs and produce similar clinical responses. Antibiotic therapyusually lasted from 7 to 14 days. The usual total intravenousdose of penicillin G was 2 million U every 4 hours; of ampicillin,2 g every 6 hours; of ceftriaxone, 1 to 2 g every 24 hours;and of cefotaxime, 1 to 2 g every 6 hours. The other antibioticswere administered according to standard criteria.21
Microbiologic Studies
Strains of S. pneumoniae were identified by standard methods.All strains were initially screened for susceptibility to antimicrobialagents by the disk-diffusion method, with Mueller–Hintonblood agar plates.24 A 1-µg oxacillin disk was used todetect all strains that had decreased sensitivity to penicillin.The MICs of the oxacillin-resistant strains were determinedby the microdilution method in cation-supplemented Mueller–Hintonbroth with 5 percent whole defibrinated horse blood, at theappropriate concentration of antibiotic. The wells of the microdilutionplates were inoculated to a volume of 100 µl with an inoculumcontaining 1 million cfu per milliliter. All pneumococcal strainswere stored frozen at -40°C in skim milk until their MICswere determined by the agar-dilution method. Two strains ofS. pneumoniae were used as controls: American Type Culture Collection(ATCC) 49619 (serotype 19) and ATCC 6303 (serotype 3). The MICwas defined as the lowest concentration of antibiotic that preventedgrowth visible without the microscope after an overnight incubationof plates at 35°C. The MICs of the antibiotics shown inTable 1 and elsewhere in this article were determined by theagar-dilution method. Resistance to antimicrobial agents wasdefined according to the criteria of the National Committeefor Clinical Laboratory Standards.25 Strains were serotypedat the Spanish Pneumococcal Reference Laboratory (Majadahonda,Madrid) with standard antiserum (Statens Serumsinstitut, Copenhagen,Denmark). A more detailed description of the microbiologic methodsused is given elsewhere.18,23
Statistical Analysis
To study trends in pneumococcal pneumonia and to avoid a selectionbias, we included only patients with bacteremic pneumonia inthe analysis, since blood cultures were performed routinely,whereas the other diagnostic methods were used selectively.We calculated the rates of infection acquired in the hospitalby subtracting three days from each hospital stay and summingthe residual durations of hospitalization.
The correlation of MICs for penicillin with those for cephalosporinwas determined by the Pearson correlation coefficient. The chi-squaretest was used to compare the proportions in samples with useof two-by-k contingency tables, where k was the number of categoriesof MICs studied.
The relation of covariates with mortality was initially assessedby univariate analysis, and odds ratios were then determinedwith a logistic-regression model. An adjusted analysis was performedwith models constructed by multiple logistic-regression analysis.26In this adjusted analysis, binary variables were coded as 0(absent) or 1 (present), and polychotomous variables were codedwith indicator variables. All variables that were significantin any of the models were included. Independent variables werechecked for collinearity.
Age was subdivided into three groups: 19 to 39 years, 40 to69 years, and 70 years or older. The categories of cancer, cirrhosis,systemic vasculitis, and disease necessitating splenectomy werecombined as serious underlying diseases, because they were allassociated with increased mortality, as shown in Table 2.
Table 2. Univariate Analysis of Factors Influencing Mortality in 504 Adult Patients with Pneumococcal Pneumonia.
We considered the possibility that if drug-resistant organismsare more virulent than susceptible ones, then some variablesrelated to the severity of infection might be intermediate variables,rather than predisposing factors requiring statistical control.When we compared the patients with penicillin-resistant strainsand those with susceptible strains, however, there were no statisticallysignificant differences in variables such as shock at admission(18 percent and 14 percent, respectively; P = 0.13) and multilobarinvolvement (26 percent and 29 percent, P = 0.47), suggestingthat resistant strains were not more virulent than susceptiblestrains, as has been reported.13,16
We included the entire cohort of 504 subjects for whom datawere complete in the univariate and multivariate analyses (Table 2and Table 3). Other models that involved only patients withmonomicrobial pneumonia (those in which S. pneumoniae was theonly microorganism isolated from cultures) and included thesame covariates are also shown (Table 3). To measure the effectof drug resistance on mortality while adjusting for other terms,we fitted the variable of resistance to penicillin into themodels, whether it was significant or not.
Table 3. Multivariate Analysis of Factors Influencing Mortality in the Entire Cohort of 504 Patients with Pneumococcal Pneumonia and among All Patients with Monomicrobial Pneumonia and Only Those with Bacteremia.
In assessing responses to antibiotic therapy, we studied onlypatients with monomicrobial pneumococcal pneumonia, comparingthe mortality of patients with resistant strains with that ofpatients with susceptible strains with regard to each antimicrobialagent (or group of agents) (Table 4). Because the study wasnot a randomized clinical trial, comparisons between groupsof antibiotics were avoided. P values of less than 0.05 wereconsidered to indicate statistical significance, and all reportedP values are two-tailed.
Table 4. Mortality among 456 Patients with Monomicrobial Pneumococcal Pneumonia, According to Type of Antibiotic Therapy and Degree of Resistance of the Infecting Strain.
Results
Of the 504 adults with severe pneumococcal pneumonia, 145 (29percent) had penicillin-resistant strains and 31 (6 percent)had cephalosporin-resistant strains. During the study period,we observed a significant increase in resistance to penicillin,cephalosporin, imipenem, and erythromycin (Table 1). The distributionof serotypes is shown in the first footnote to Table 1.
Trends in Bacteremic Pneumococcal Pneumonia
The incidence of community-acquired bacteremic pneumococcalpneumonia increased during the study period (Figure 1). Thisincrease was due mainly to the inclusion of the patients withHIV (who accounted for 4 episodes of pneumonia in 1984–1988and 34 episodes in 1989–1993). The incidence of bacteremicpneumococcal pneumonia acquired in the hospital did not increasesignificantly (in 1984–1988 there were 0.019 and in 1989–19930.030 episodes per 1000 patient-days).
Figure 1. Trends in Community-Acquired BacteremicPneumococcal Pneumonia.
Analysis of Mortality
Overall mortality was 28 percent (140 of 504), and most deathsoccurred within seven days after diagnosis (Figure 2). The factorsinfluencing mortality in the univariate analysis are shown inTable 2. Patients with HIV had lower mortality than those withoutHIV, but after we controlled for age (the patients with HIVbeing younger than those without HIV) the risk of death didnot differ significantly (adjusted odds ratio for the patientswith HIV, 0.7; 95 percent confidence interval, 0.2 to 1.9; P= 0.51).
Figure 2. Cumulative Mortality among 504 Patients with Severe Pneumococcal Pneumonia.
In the multivariate analysis, the independent prognostic factorsfor mortality were age of 70 years or above, serious underlyingdisease, heart failure, shock, multilobar involvement, leukopenia(<5000 cells per cubic millimeter), nosocomially acquiredpneumonia, and polymicrobial pneumonia (Table 3). The typesof microorganisms recovered in the patients with polymicrobialpneumonia are shown in the third footnote to Table 2.
Overall, the mortality rate among the patients with penicillin-resistantstrains was 38 percent, and among those with susceptible strainsit was 24 percent (P = 0.001) (Table 2), but after we controlledfor other predictors of mortality the odds ratios for thosewith resistant strains were 1.3 (95 percent confidence interval,0.7 to 2.2; P = 0.32) in the entire cohort and 1.0 (95 percentconfidence interval, 0.5 to 1.9; P = 0.84) among the patientswith monomicrobial pneumococcal pneumonia. Similar results wereobtained for the patients with bacteremia (Table 3).
When conditions that resulted from the infection, such as shockat the time of admission and multilobar involvement, were notincluded in the model for the entire cohort, and after we adjustedthat analysis for the other terms shown in Table 3, resistanceto penicillin was still not significantly associated with mortality(adjusted odds ratio, 1.1; 95 percent confidence interval, 0.6to 1.8; P = 0.62). Similar results were obtained when the samecovariates were studied in the model for the patients with monomicrobialpneumonia (data not shown).
Response to Antibiotic Therapy
As Table 4 shows, among the patients with monomicrobial pneumococcalpneumonia who were treated with penicillin G or ampicillin,the mortality rates among the 24 patients with penicillin-resistantstrains and the 126 patients with susceptible strains were 25percent and 19 percent, respectively (odds ratio, 1.4; 95 percentconfidence interval, 0.5 to 3.9; P = 0.51). After adjustment,the odds ratio was 0.9 (95 percent confidence interval, 0.3to 2.8; P = 0.90). It is important to note that eight of thenine patients with MICs of 2 µg per milliliter recoveredand that the only patient with an MIC of 4 µg per milliliter(a patient with severe underlying disease) died.
Among the patients treated with ceftriaxone or cefotaxime, themortality rates among the 59 patients with penicillin-resistantstrains and the 127 patients with susceptible strains were 22percent and 25 percent, respectively (odds ratio, 0.8; 95 percentconfidence interval, 0.4 to 1.7; P = 0.64). After adjustment,the odds ratio was 0.4 (95 percent confidence interval, 0.2to 1.1; P = 0.10).
Among the patients treated with other antibiotics, the mortalityrates among the 33 with penicillin-resistant strains and the87 with susceptible strains were 42 percent and 21 percent,respectively (odds ratio, 2.8; 95 percent confidence interval,1.2 to 6.6; P = 0.02), but this difference was not significantafter adjustment (adjusted odds ratio, 1.4; 95 percent confidenceinterval, 0.4 to 4.1; P = 0.54).
Emergence of Resistance to Cephalosporins
Strains with decreased susceptibility to cephalosporin (MICof ceftriaxone or cefotaxime, >1.0 µg per milliliter)were found in 2 percent of patients in 1984–1988 and in9 percent in 1989–1993 (P = 0.002) (Table 1). There wasa close correlation between the MICs of the cephalosporins andthat of penicillin (r = 0.85, P<0.001).
During the first years of the study, the MICs of ceftriaxoneand cefotaxime were usually two to four times smaller than thatof penicillin G, but in the more recent years they were usuallyone to two times smaller. Moreover, we observed five instancesof resistance in which the MICs of the cephalosporins were equalto that of penicillin G, and one instance in which the MIC ofceftriaxone or cefotaxime was 4 µg per milliliter andthat of penicillin G was 0.5 µg per milliliter (the patientrecovered with penicillin therapy).
Overall, the mortality rate among the patients with cephalosporin-resistantpneumococcal strains was similar to that among the patientswith cephalosporin-susceptible strains (26 percent vs. 28 percent;odds ratio, 0.9; 95 percent confidence interval, 0.4 to 2.1;P = 0.89) (Table 2). Among the patients treated with ceftriaxoneor cefotaxime, the mortality rates among the 18 with cephalosporin-resistantstrains and the 168 with susceptible strains were 22 percentand 24 percent, respectively (odds ratio, 0.8; 95 percent confidenceinterval, 0.4 to 1.7; P = 0.64) (Table 4).
Discussion
Over the past two decades, pneumococci have become increasinglyresistant to penicillin and other antibiotics.8,9,10,27,28 Themore recent identification of cephalosporin-resistant strainsis a cause for additional concern.13,29 At our institution,we have seen an increase in the frequency of infections dueto pneumococci resistant to penicillin, cephalosporin, and erythromycin,the antibiotics used most commonly to treat pneumonia (Table 1).
During the study period, we found an increasing trend towardcommunity-acquired bacteremic pneumococcal pneumonia (Figure 1).This was at least partly due to the greater numbers of HIV-infectedpatients, who are at higher risk for pneumococcal infections.30,31The incidence of bacteremic pneumococcal pneumonia acquiredin the hospital did not increase significantly. Although outbreaksof pneumococcal pneumonia have been reported in hospitals andprisons,18,32 no outbreaks were detected in the present study.
The overall mortality reported in patients with pneumococcalbacteremia (and usually with pneumonia) has remained unchangedat about 25 percent over the past four decades14,15,33,34,35,36,37and is close to the 28 percent mortality in our study. The factorsassociated with increased mortality in this study (Table 3)are clinically consistent and similar to those reported previously.14,15The increased mortality from nosocomially acquired infection38probably reflects the greater severity of underlying diseasein these patients. There was also higher mortality among ourpatients with polymicrobial pneumonia, who had other seriouspathogens in addition to pneumococci. On the other hand, theHIV-infected patients had lower mortality, probably becauseof their relative youth. In other reports HIV infection wasnot found to affect mortality from pneumococcal pneumonia significantly.30,31
In our study, the patients with penicillin-resistant pneumococcalstrains had higher mortality than those with penicillin-susceptiblestrains in the univariate analysis. However, after adjustmentfor other variables, resistance to penicillin was not associatedwith increased mortality. The patients with penicillin-resistantstrains had more serious underlying conditions than the patientswith penicillin-susceptible strains.18 Similarly, the case fatalityrate of South African children with penicillin-resistant pneumococcalinfections did not differ significantly from that of childrenwith penicillin-susceptible infections.6 In our study, resistanceto cephalosporin was also not associated with increased mortality.
Our study was not designed to compare the efficacy of variousantibiotics, and it was not a randomized clinical trial. Therefore,the response to antibiotic therapy was analyzed by comparingmortality in patients with resistant strains and patients withsusceptible strains with regard to each antimicrobial agent(or group of agents) (Table 4).
Our data suggest that high-dose intravenous penicillin G (150,000to 200,000 U per kilogram of body weight per day) may be effectivein patients with pneumococcal pneumonia due to strains for whichthe MIC of penicillin ranges from 0.12 to 2 µg per milliliter.Ceftriaxone or cefotaxime may be a good alternative when theMIC of penicillin is higher and those of ceftriaxone and cefotaximeare 2 µg per milliliter or less. It is not known whetherpneumonia due to strains for which the MIC of penicillin was4 µg per milliliter or higher would respond to penicillintherapy, or whether infections for which the MICs of ceftriaxoneand cefotaxime were 4 µg per milliliter or higher wouldrespond to cephalosporin therapy.
Careful selection of an effective antibiotic for the initialempirical therapy requires an awareness of patterns of susceptibilityin the patient's geographic area. We think that identifyingpatients at greater risk of dying (Table 3) or of having a resistantstrain18,39 may help in choosing the appropriate therapy. Forexample, patients with a low probability of death and no riskfactors for penicillin-resistant strains could be given initialempirical treatment with high-dose intravenous penicillin G,ampicillin, or amoxicillin. In patients with a higher risk ofdeath or with risk factors for pneumococci with a high levelof resistance to penicillin, it would be prudent to start empiricaltreatment with an alternative antibiotic. In these cases, ceftriaxoneor cefotaxime may be given, together with erythromycin whenthe presence of legionella or another atypical pathogen cannotreasonably be ruled out. Other alternatives, such as imipenemor vancomycin, ought to be considered in regions where a highlevel of resistance to cephalosporins has become prevalent.
In summary, our study suggests that the current levels of resistanceto penicillin and cephalosporin do not appear to increase mortalityin patients with pneumococcal pneumonia. High-dose intravenouspenicillin may be effective for infections in which the MICof penicillin is up to 2 µg per milliliter, and ceftriaxoneor cefotaxime may be effective when the MIC of penicillin ishigher. However, the emergence of high levels of resistanceto cephalosporin is an alarming problem. It is to be hoped thatadministering the existing pneumococcal vaccine to adults atan earlier age as well as developing a new vaccine suitablefor children will help to prevent these difficult-to-treat infectionsin the future.40
Supported by a grant (FIS 92/1057) from the Fondo de InvestigacionesSanitarias, National Health Service, Madrid.
We are indebted to the members of the medical staffs of theInfectious Disease, Respiratory Disease, and Internal Medicineservices, who provided care to many of the patients includedin this study, and to the staff members of the MicrobiologyService who performed the studies of susceptibility to antibiotics.
Source Information
From the Infectious Disease (R.P., C.C., P.F.V., F.G.), Microbiology (J.L., R.M.), Internal Medicine (M.V.), and Pulmonary Disease (F.M.) Services, Hospital de Bellvitge "Princeps d'Espanya" and the University of Barcelona — both in Barcelona, Spain.
Address reprint requests to Dr. Pallares at the Infectious Disease Service, Hospital de Bellvitge "Princeps d'Espanya," 08907 L'Hospitalet, Barcelona, Spain.
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(1999). Use of an Oxacillin Disk Screening Test for Detection of Penicillin- and Ceftriaxone-Resistant Pneumococci. J. Clin. Microbiol.
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[Abstract][Full Text]
Campbell, G. D. Jr.
(1999). Commentary on the 1993 American Thoracic Society Guidelines for the Treatment of Community-Acquired Pneumonia. Chest
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[Abstract][Full Text]
A correction has been published: N Engl J Med 1995;333(24):1655.
-lactam antibiotics,18,19,20 because the serum concentrations achieved with these drugs21 are several times higher than the MICs. Nevertheless, the efficacy of penicillin is uncertain, and the role of extended-spectrum cephalosporins (ceftriaxone or cefotaxime) in treating resistant pneumococcal pneumonia is not well defined. 
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