quantitative assessment of chest radiographs to evaluate the efficacy of ceftazidime versus...

VOL. 62, No. 5, MAY 2001

Quantitative Assessment of Chest Radiographs to Evaluate the Efficacy of Ceftazidime versus Ceftriaxone in a Randomized, Double-Blind Study in Adults with Community-Acquired Pneumonia Roberto Dal Negro, MD, FCCP,’ Giancarlo Pomari, MD,’ and Monica Larosa, PhD2

‘Pulmonary Department, Bussolengo General Hospital, and *Clinical and Healthcare Research Department, Glaxo Welcome S.p.A., Verona, ltaly

ABSTRACT Background: The therapeutic strategy for antibiotic treatment of community-

acquired pneumonia (CAP) and assessments of the efficacy of such treatments are usually based on microbiologic, clinical, and chest radiographic findings. However, all these techniques have several limitations, particularly evaluation of pulmonary lesions on chest radiographs (CXRs), which is still based only on semiquantitative criteria.

Ob]ectiwe: The aim of the present study was to use a novel computerized mathematical-statistical method of digital imaging for the quantitative evaluation of standard CXRs as an additional tool to assess and compare the efficacy of different antimicrobial treatments in patients with CAP.

Methods: In this prospective, multicenter (10 centers), randomized, double- blind trial, hospitalized patients with CAP received intramuscularly either ceftazidime 1 g BID for 7 days or ceftriaxone 1 g QD (plus an injection of an inert solution every 12 hours to maintain the double-blind provision) for 7 days. CXRs were obtained before, during, and at the end of treatment in both groups. The computerized digital imaging of CXRs and their consequent mathematical- statistical analyses were performed at a central institute. The clinical outcome was also evaluated by the treating physicians using a semiquantitative, Clevel scale at baseline, in the interim, and 1 to 3 days after the end of treatment.

Results: Sixtyeight patients were enrolled; 33 patients received ceftazidime and 35 received ceftriaxone. The standardized analysis of CXR digital imaging showed a significantly faster regression of the original pulmonary lesions (P = 0.024) in the ceftazidime group, although no differences were observed in clinical outcome between the 2 treatment groups.

Conclusions: Some quantitative and reproducible indices that enable a comparison of the radiologic outcome in 2 treatment arms of a clinical study can be

Accepted for publication February 28, 200 1. Printed in the USA. Reproduction in whole or part is not permitted. 0011-393x/01 /$19.00

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obtained with this new method. The findings indicate that this method can be used as a tool to decrease the variability in radiographic findings during antibiotic treatment for CAP.

Key words: community-acquired pneumonia, chest radiograph, digital imaging, ceftazidime, ceftriaxone. (Cur-r Ther Res Clin Exp. 2001;62:372-385)

INTRODUCTION The incidence of community-acquired pneumonia (CAP) is rather high, with 2 to 15 cases per 1000 persons per year.’ Bacterial pneumonia has an overall estimated incidence in the United States of 4 million cases per year.* Strepto- coccus pneumoniae is the most commonly identified pathogen in CAP, with a reported incidence of 27% to 46%; other common extracellular pathogens often associated with lower respiratory tract infection include Moraxella catarrhalis, Haemophilus influenzae, and Klebsiella pneumoniae. l-4

The clinical presentation of CAP is usually characterized by the production of sputum, leukocytosis, cough, chest pain, dyspnea, elevated body temperature, and radiographic evidence of pulmonary infiltration. The choice of antimicrobial therapy is frequently made on an empiric basis.‘,3*5

In clinical trials, the efficacy of antibiotic treatments for lower respiratory tract infections is still based on clinical, microbiologic, and radiographic assessments. However, these evaluation criteria have several limitations. Micro- biologic evaluations are time consuming and are rarely effective in identifying the causative pathogens. Clinical evaluation is generally based on qualitative criteria and semiquantitative scores, which depend in part on patients’ perception and the physicians’ judgment. Radiographic assessments also have a limi- tation in that they depend on both the judgment criteria and the perception of the examiner.’ Thus, studies of the efficacy of antibiotic treatments for CAP might be hampered by the variability in the pretreatment and posttreatment quantitative radiographic assessments of the extent of pulmonary lesions. Moreover, this problem might be amplified in clinical studies aimed at evalu- ating the performance of different drugs belonging to the same pharmacologic class but characterized by different spectrum activities and/or different pharmacokinetic profiles,5*6 as in the case of ceftazidime and ceftriaxone, both third- generation cephalosporins that are widely used in the treatment of CAP.7-10 These molecules differ in their antibacterial spectrum (unlike ceftriaxone, ceftazidime is also effective against Pseudomonas aeruginosa), serum half-life (ceftriaxone can be administered once daily whereas ceftazidime must be administered twice daily), serum protein binding (ceftazidime is only 10% protein- bound, whereas ceftriaxone is 90% protein-bound), and route of excretion (90% renal for ceftazidime versus 56% renal and 44% biliary for ceftriaxone).g,”

The aim of the present study was to use a novel computerized mathematical- statistical method of digital imaging for the quantitative evaluation of standard

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chest radiographs (CXRs) as an additional tool to assess and compare the efficacy of different antimicrobial treatments in patients with CAP.

PATIENTS AND METHODS

Patients Patients were consecutively enrolled in a multicenter, prospective, double- blind, randomized trial. Ten pneumology institutes participated in the study. The inclusion criteria were age ~18 years; clinical evidence of lower respiratory tract infection, defined as radiographic evidence of parenchymal involvement; and written informed consent. Exclusion criteria were known or supposed sen- sitization to beta-lactam antibiotics, creatinine clearance ~30 mL/min, concomi- tant treatment with other antibiotics, lung cancer, coma, absence of cough reflex, pregnancy, and breastfeeding.

Treatment Patients were randomized to 1 of 2 treatment regimens: ceftazidime 1 g intramuscularly twice daily for 7 days or ceftriaxone 1 g intramuscularly once daily (plus an injection of an inert solution after 12 hours to ensure the double-blind provision of the study) for 7 days. Drugs were administered by professional nurses who were not involved in the patients’ clinical management to ensure the blinding of study physicians. The time of drug administration was recorded daily. Any violation of the treatment protocol was recorded and explained on the case-report form.

All patients underwent radiologic examination at baseline (at the time of entering the study), during treatment (between day 3 and day 5 of treatment), and at the end of treatment (between day 7 and day 9 after onset of treatment). Clinical evaluations were made at baseline, between day 3 and day 5 of treatment, and 1 to 3 days after the end of treatment (between day 8 and day 10 after onset of treatment). A complete set of clinical laboratory and serum chemistry tests, as well as a microbiologic evaluation, was planned at baseline and posttreatment.

Radiologic Evaluation Posteroanterior and lateral CXRs were taken for each patient at baseline, during treatment, and at the end of treatment. The technical parameters for x-ray determination were similar for all equipment of the participating pneumology institutes. In all participating institutes, a CXR was determined to be a “sufficient- quality” CXR if it fulfilled the image-quality’ criteria for posteroanterior and lateral CXR proposed by European Union Experts12 and the Italian Radiological Guidelines.13 These criteria are a revised and simplified application of the European Guidelines on Quality Criteria for Diagnostic Radiographic lmages.14

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All CXRs were collected by the pulmonary department of the Bussolengo General Hospital, Verona, Italy, for digital imaging processing and mathematical- statistical analysis. The digital imaging was performed according to the method described by Dal Negro and Girelli-Bruni. 6 X-ray images were scanned at 150 dots per inch using a VXR-S film digitizer (Vidar Systems Corporation, Herndon, Virginia) and digitally processed with an MIP software system for Windows 98 (Metrika, Verona, Italy) that produces a compressed TIFF file for each CXR image.6 The processing software program standardizes the gray tones (scale: O-255) and the size of the lung lesion to be compared.

The region of interest (ROI) was defined as the most appropriate and suitable portion of the CXR image that could be selected to circumscribe the chest region containing the pathologic lesion being measured.‘j ROIs were selected from the digitized image obtained at baseline and were reproduced automatically on the images obtained during treatment and at the end of treatment.

The mean level of gray tones obtained after digitization and standardization of CXR images, which represents an index of the severity of the lung lesion, was the primary indicator of the efficacy of treatment. Therefore, the parenchymal lesions on the CXR images could be expressed as histograms that shift toward the light gray-white side of the gray tone distribution range (mean, 2 to 255) indicating disease, or toward the dark gray-black side of the range (0 to mean 2) indicating normal tissue (Figures 1A and B). After the standardization pro cedures, the extent of the shift in the distribution of gray tones of the CXR image from baseline to the end of treatment indicates the extent of changes occurring as a result of antibiotic treatment. These calculations and comparisons can be represented by index 1, which is the ratio of the 2 areas under histograms in the gray tone range between 0 and mean 2, where mean 2 is the mean value of the distribution of gray tones obtained on day 7. This ratio can be expressed as:

Index 1 = Area under the histogram of the ROI associated with the CXR on day 7 (area 2)

Area under the histogram of the ROI associated with the baseline CXR (area 1)

This index gives a measure of the extent to which the histogram of the ROI associated with the baseline CXR has shifted toward the black area after 7 days of antibiotic treatment (Figure 1C). Similarly we calculated index 2, the ratio between the 2 areas under histograms in the range between mean 2 and 255, as follows:

Index 2 = Area under the histogram of the ROI associated with the baseline CXR (area 1)

Area under the histogram of the ROI associated with CXR on day 7 (area 2)

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CURRENTTHERAPEUTIC RESEARCH@

Gray Level Gray Level

0 Mean 2

Gray Level

255

Figure 1. (A) Example of a histogram of the region of interest (ROI) obtained from baseline chest radiographs (CXRs), in which lighter gray tones predominate, indicating a disease condition. (B) Histogram of ROI obtained at the end of treatment with ceftazidime, with a notable shift from the light gray-white side of the gray tone distribution range (correspond- ing to the higher parenchymal density of lung lesion) toward the dark gray-black side of the range, indicating regression of the pulmonary lesion. (C) Baseline and end-of-treatment time histograms in relation to index 1 (area Z/area 1 > 1). Index 1 provides a quantitative measure of the extent of the shift toward 0 tones of end-of-treatment values versus baseline values. Mean 2 is the mean value of the distribution of gray tones obtained on day 7.

Index 2 measures the extent to which the histogram obtained from the CXR at the end of treatment has shifted from the lighter gray tone.6

This analysis was performed by radiologists and physicians unaware of the antibiotic treatment administered to the patient and unaware of the patient’s name, clinical course, and the time at which the CXR was obtained.

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Microbiologic Evaluation Samples (expectorated sputum and bronchoalveolar lavage when available) were collected at baseline and after treatment, and were processed for bacte rial testing using routine culture methods.

Clinical Evaluation At baseline, during treatment, and after treatment, the treating physicians assessed the clinical outcome using a semiquantitative, 41evel scale based on the total symptom score resulting from the sum of points assigned to each sign and symptom. The signs and symptoms recorded were body temperature, cough, quantity and quality of expectorated sputum, chest pain, and findings on chest examination. The clinical outcome was classified as a success if the temperature reduced to <37.3”C and there was a ~50% reduction in baseline symptom score; a partial success if there was a drop in temperature but the fever per- sisted and there was a reduction of 20% to 50% in baseline symptom score; no change/worsened if the symptom score was >80% of the baseline score and there was evidence of bacterial resistance in culture; and not evaluable if treatment had to be discontinued before day 4 of administration or there were relevant violations of the study protocol. The overall qualitative clinical evaluation (ie, success, no change/worsened, etc) was based on the temperature profile, improvement in total baseline symptom score, and microbiologic findings.

Drug tolerance during and after treatment was monitored from the results of laboratory tests, vital signs measurements, and the occurrence of adverse events. Complete blood count and renal function serologic tests were performed at baseline and after treatment.

Statistical Procedures The primary end point was the extent of lesion regression, as measured by the decrease in mean gray level, on the CXR images obtained at the intermediate time point and at the end of treatment compared with baseline. The number of patients to be enrolled in the study was planned assuming a between-treatment difference of 20 points with a residual standard deviation of ~25 points. Ac- cordingly, 80 patients would have guaranteed the study had a power approxi- mating 95%. A 2-tailed test with OL = 0.05 was used for treatment comparisons. The mean levels of gray obtained at each examination were evaluated with a covariance analysis. In addition, index 1 and index 2 (secondary evaluation end points) were used for the analysis of variance comparison of the 2 treatments. The correlation between the decrease in the mean levels of gray obtained after treatment and index 1 was also investigated. Calculations were made with SAS@ for Windows version 6.12 (SAS lnc, Cary, North Carolina) using the MEANS, GLM, FREQ, NPARlWAY, and UNIVARlATE procedures. According to the study protocol, the analysis of clinical findings had to be made on the intent-to-treat (ITT) population, that is, all enrolled patients who received ~1 drug dose. The patients for whom a clinical evaluation could not be obtained were initially

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considered treatment failures. A second analysis of the clinical response to treatment was limited to the clinically evaluable population, that is, all patients for whom a clinical judgment could be expressed during and after treatment. The Mantel-Haenszel test was used to determine the percentage of clinical successes in the 2 treatment groups (stratified by center).15 The comparison of the total symptom score and of the single symptom scores between the 2 treatment groups was performed with the Van Eleteren test (Wilcoxon test stratified by center).16 Using the baseline data we investigated whether the mean gray level extrapolated from the CXR images was correlated with total symptom score. Drug tolerance was evaluated in the ITT population.

Patients A total of 68 patients (45 men and 23 women; mean age, 59.54 f 20.19 years) were enrolled in the study and randomized to 1 of 2 treatment groups in the time allowed for recruitment: 33 patients (19 men and 14 women; mean age, 56.67 f 20.85 years) were assigned to the ceftazidime group and 35 patients (26 men and 9 women; mean age, 62.26 f 19.45 years) were assigned to the ceftriaxone group. On the basis of the hypothesis previously described (between-treatment difference = 20, residual SD = 25) the number of patients enrolled ensured a study power ~80%. Demographic characteristics were com- parable in the 2 treatment groups, although the number of male patients and the mean age of patients was slightly higher in the ceftriaxone group (Table I). All patients were hospitalized at the time of enrollment.

Two patients, 1 in each group, did not complete the study because of severe adverse events. A third severe adverse event was detected by the treating physician 5 days after the start of treatment with ceftriaxone but did not result in withdrawal from the study. We did not define a per-protocol population since there were no major violations of the protocol.

Radiologic Evaluation The radiologic evaluation at baseline, during treatment, and at the end of treatment was performed in all patients whose CXR images were considered of sufficient quality according to the defined quality criteria (radiographically evaluable population; Table II), and it was adjusted for baseline value, sex, age, and study site (sites were grouped in 2 geographic clusters). The mean gray level was the only primary variable; therefore, no adjustment for multi- plicity was performed. The adjusted means of the gray levels were used to compare the effect of the 2 drugs and to calculate the relative confidence intervals.

Baseline, intermediate, and end-of-treatment CXRs were assessable for 57 patients; baseline and end-of-treatment CXRs were assessable for 58 pa-

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R. Dal Negro et al.

Table I. Demographic characteristics of the study population.

Ceftazidime 1 g BID Ceftriaxone 1 g QD (n = 33) (n = 35)

Sex, no. (O/6) Male Female

Age, Y Mean (SD) Range

Body weight, kg Males, no.

Mean (SD) Range

Females, no. Mean (SD) Range

Height, cm Males, no.

Mean (SD) Range

Females, no. Mean (SD) Range

19 (58) 14 (42)

56.67 (20.85) 16-94

19 25 68.68 (10.56) 75.56 (13.80)

52-90 46-l 03 14 9

57.29 (9.23) 58.56 (7.49) 45-74 45-70

19 167.60 (6.71)

155-l 79 14

159.80 (7.42) 145-l 69

26 (74)

9 (26)

62.26 (19.45) 30-97

25 170.60 (6.10)

156-l 82 8

161 .OO (5.48) 152-l 68

tients. Ten patients were not radiologically assessable because CXRs were not available (7 cases) or were not of sufficient quality (3 cases).

An improvement in pulmonary lesions in the ceftazidime group and not in the ceftriaxone group was observed on the CXRs at the intermediate evaluation, although the difference between the 2 groups was not significant (f’ = 0.262) (Table ll). At the end-of-treatment evaluation, however, the differences between the 2 groups in improvement in pulmonary lesions became significant (P = 0.024) (Table 11 and Figure 2).

The analysis of the lesion regression based on index 1 and index 2 was conducted in the range from 0 to mean 2 gray tones, and from mean 2 to 255 gray tones, respectively. Baseline value, age, sex, and clinic center cluster were also included in the analysis of variance model. At the intermediate evaluation, radiologic findings were essentially unchanged in the 2 groups, whereas at the end of treatment, a slight improvement was detected in both groups. For simplicity, we report only index 1 data (Table 1lI).

The relationship between index 1 and the shift in mean gray levels calculated at baseline and end of treatment is not linear (Figure 3). The ratios, in fact, were not particularly high in the 5 cases (all in the ceftazidime group) with the highest decrease in mean gray levels.

379

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ray

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ly

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op

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ID

En

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ine

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ent

Cef

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xon

e 1

g Q

D

En

d o

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asel

ine

Tre

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ent

No

. o

f p

atie

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nte

rmed

iate

C

XR

M

ean

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vel

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D

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just

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ean

*

Mea

n d

iffe

ren

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ray

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l (c

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ime

vs c

eftr

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ne)

* 95

%

Cl

Ad

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t

No

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h

bas

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nd

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ster

.

30

27

153.

80

149.

23

151.

33

156.

63

38.9

4 44

.41

43.8

5 47

.43

1 so

.92

161.

43

- 10

.51

(-29

.1

to

-8.0

9)

0.26

2 30

28

15

3.80

13

1.67

15

3.14

14

8.21

38

.94

40.3

8 44

.08

41.7

4 13

3.85

15

3.31

-

19.4

6 (-

36.2

to

-2

.7)

0.02

4

R. Dal Negro et al.

250 -

225 -

200 -

175 -

150 -

125 -

lOO-

75 -

50 I I I I I I Before After Before After

Ceftazidime Ceftriaxone

Figure 2. Mean gray level at baseline and at end of treatment in the ceftazidime and ceftriaxone groups. Solid lines indicate chest radiograph (CXR) images showing a decrease in mean gray level of 220 tones. A total of 14 CXR images in the ceftazidime group and 7 in the ceftriaxone group showed a mean gray level decrease of 220 tones.

Microbiologic Evaluation The microbiologic response to treatment was not assessed because the base line identification of the causative pathogen was possible only in 13 patients.

Clinical Evaluation

Toxicity Nine adverse events were reported in 7 patients (2 in the ceftazidime group and 5 in the ceftriaxone group). Three of these events were severe-2 in the ceftazidime group (thoracic empyema and an adenocarcinoma, both diagnosed after the enrollment) and 1 in the ceftriaxone group (fatal event related to a con- comitant lung cancer, diagnosed only after the study enrollment). None of these events was considered by the treating physicians to be related to the study drugs.

Efficacy At the posttreatment evaluation, a high rate of clinical success was observed in both treatment groups, both in the ITT population (Table IV) and in the clinically assessable population (data not shown). A weak correlation between the mean gray level and the symptom score was demonstrated only at baseline (Spearman’s rank test: r = 0.276; P = 0.04) (data not shown).

DISCUSSION In clinical trials, the efficacy of antibiotic treat%ents for lower respiratory tract infections is usually assessed based on microbiologic, clinical, and CXR evalu-

381


Table III. Index 1 in the radiographically evaluable population.*

Ceftazidime Ceftriaxone 1 g BID 1 g QD

No. of evaluable patients with baseline and intermediate CXR

Index 1 Geometric mean Range Adjusted meant

Between-treatment comparison Ceftazidime/ceftriaxone ratio 95% Cl Adjusted Pt

No. of evaluable patients with baseline and end-of-treatment CXR

Index 1 Geometric mean Range Adjusted meant

Between-treatment comparison Ceftazidimekeftriaxone ratio 95% Cl Adjusted Pt

30 27

1.05 1 .oo 0.5-2.3 0.4-2.8

1 .Ol 0.99

1.02 0.75-l .39

0.883

30

1.26 1.24 0.4-2.5 0.4-2.2

1.20 1.17

28

1.02 0.78-l .34

0.857

CXR = chest radiograph. *Index 1 is the area Z/area 1 ratio in the interval from 0 gray tones to the posttreatment mean gray level (mean 2).

+Adjusted for baseline, age, sex, and treatment center cluster.

ations. Since CXR assessment is still largely subjective and dependent on the examiner’s skill and perception, our aim in this study was to implement an objective method to quantitatively evaluate the extent of pulmonary lesions seen on radiographs before, during, and at the end of antibiotic treatment and to use it to assess and compare more exactly the different therapeutic strate gies to treat CAP in adults.

Histograms from the selected ROIs were reproducible and allowed the quantitative comparison of radiographic changes observed at the intermediate evaluation and at the end of treatment. The shift toward gray tones was an indicator of the extent of the changes observed in the original pulmonary lesion.

At the end of treatment, the difference between the 2 groups in improvement in the pulmonary lesion seen on the CXR became significant, although both treatments were equivalent in terms of routine clinical outcome when assessed posttreatment.

Ceftazidime is characterized &y lower serum protein binding than ceftriaxone (10% vs 90%) and by a higher microbiologically active concentration of the

382

R. Dal Negro et al.

2.5 -

2.0 -

1.5 -

1.0 -

0.5 - o -0 0

0

.

o Ceftazidime 0 Ceftriaxone

.

.

. .

0 I I I I I

-75 -25 25 75 125

Shift in Mean Gray Level (Before Treatment - After Treatment)

Figure 3. Relationship between difference in mean gray levels and index 1 obtained at baseline and at end of treatment.

unbound drug. These different pharmacokinetic characteristics may explain the faster regression of pulmonary lesions detected by the digital analysis of CXRs in the ceftazidime group.

This novel method can be particularly useful when an objective and quantitative comparison between different antiobiotic treatments must be made, as in clinical studies aimed at assessing the pharmaceutical profile and cost- benefit ratio of antibiotic treatments.17*18

However, the present standardized digital method of CXR analysis still has some sources of variability. We could detect a faster regression of pulmonary lesions on the CXRs in the ceftazidime group, but only when the mean gray level was used as a parameter; no differences in pulmonary lesion regression were observed when the other 2 indicators were used. These discordant results may be explained by the nonlinear relationship between index 1 and the shift in mean gray level at baseline and at the end of treatment. Moreover, this novel method, even though sufficiently reproducible and standardized, is still partly influenced by the intrinsic variability of the CXR procedure per se.

CONCLUSIONS The results of the present study show that the novel mathematical-statistical analysis for digital imaging of standard CXR can be used to detect differences in radiologic response to different antimicrobial treatments for CAP. These differences may be a result of the different pharmacokinetic profiles of the

383


Table IV. Posttreatment clinical response (assessed using symptoms score) in the intent- to-treat population.

Ceftazidime 1 g BID Ceftriaxone 1 g QD (n = 33) (n = 35)

Success, no. (%) 95% Cl Partial success, no. (%) No change/worsened, no. (%) Not evaluable, no. (%) Difference in success rate (95% Cl) Mantel-Haenszel test* Test/x* df = 1 P

30 (91) 33 (94) 75.7-98.1 80.8-99.3

2 (6) 0 (0) 0 (0) 1 (3) 1 (3) 1 (3)

- 3.4 (- 15.8 to 9.1) 0.26

0.608

Success = temperature reduced to <37.3”C and ~50% reduction in baseline symptom score; partial success = drop in temperature but persistence of fever and reduction of 20% to 50% in baseline symptom score; no change/worsened = symptom score >80% of baseline and bacterial resistance in culture; not evaluable = treatment discontinuation before day 4 of administration or relevant violations of the study protocol. *Adjusted for treatment center cluster.

antimicrobial agents being studied and are independent of the differences in the semiquantitative clinical routine outcome.

Additional studies are needed to investigate the reasons for this discrepancy and to assess the actual sensitivity of the method. These preliminary results indicate that this novel method may help decrease the variability and subjec- tivity in radiologic assessment of patients with CAP, but further studies are needed to confirm these results.

ACKNOWLEDGMENTS We thank the King’s Associate Consultants, Sacile, Italy, for expert assistance in the preparation of the manuscript.

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Address correspondence to: Dr. Roberto Dal Negro Director of the Pulmonary Department Ospedale di Bussolengo U.L.S.S. 22 Regione Veneto 37012 Bussolengo (Verona), Italy

Bartlett JG, Breiman RF, Mandell LA, File TM. Community-acquired pneumonia in adults: Guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis. 1998;26:81 l-838. Dal Negro R, Girelli-Bruni E. Lower respiratory tract infections: Digital processing and standardization of chest X-ray to assess quantitative indices for image comparison. Farmacia Terapia. 1999;16:29-35. Cars 0. Efficacy of beta-lactam antibiotics: Integration of pharmacokinetics and pharmacodynamics. Diagn Microbial Infect Dis. 1997;27:29-33. Craig WA. Outpatient parenteral antibiotic therapy. Management of serious infections. Part I: Medical, socioeconomic, and legal issues. Selecting the antibiotic. Hosp B-act. 1993;28(Suppl 1):16-20. Halls GA. The management of infections and antibiotic therapy: A European survey. J Antimicrob Chemother. 1993;31:985-1000. Cazzola M, Dal Negro R. Confront0 fra Ceftazidima 1 g i.m daily, Ceftazidima 500 mg i.m. twice daily e Ceftriaxone 1 g i.m. once daily nelle riacutizzazioni della bronchite cronica. Farmacia Terapia. 1998;15:60-68. Cazzola M, Diamare F, Vinciguerra A, et al. La penetrazione polmonare degli antibi- otici ed il suo impatto clinico. Rass Pat App Respir. 1996;11:134-147. Vano E, Guibelalde E, Morillo A, et al. Evaluation of the European image quality criteria for chest examinations. Br J Radiof. 1995;68:1349-1355. Rossetti G. 11 controllo de1 prodotto. In: Rossetti G, ed. Gestione Manageriale de1 Servizio di Radiologia. Criteri Guida. Naples, Italy: ldelson by Gnocchi; 1995:129-151. Commission of the European Community. Quality criteria for diagnostic images. 2nd ed. Brussels: CEC; 1990. Working Document X11/173/90. To be published as European Guidelines on Quality Criteria for Diagnostic Radiographic Images, EUR 16260. Mantel N. Chisquare tests with one-degree of freedom: Extensions of the Mantel- Haenszel procedure. J Am Statist Assoc. 1963;58:690-700. Hollander M, Wolfe DA. Nonparametric Statistical Methods. New York: John Wiley & Sons; 1973:138-150. Thomas PD, Daly S, Steele T, Dollman C. Comparison of the efficacy and adverse effect profile of cefotaxime, 3 g/day, and ceftriaxone, 2 g/day, in the treatment of nosocomial lower respiratory tract infections in ICU patients. Eur Respir Rev. 1994; 4:321328.

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