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Antibiotic prophylaxis in cystic fibrosis: Inhaled cephaloridine as an adjunct to oral cloxacillin
626
October 1982 The Journai o f P E D I A T R I C S
Antibiotic prophylaxis in cystic fibrosis: Inhaled cephaloridine as an adjunct to oral cloxacillin The effect of prophylactic antibiotics on bacterial colonization of the respiratory tract and on general progression of cystic fibrosis was studied in a two-year prospective study of 47 mildly to moderately affected patients. One group of patients received inhale d cephaloridine and the other received no inhaled antibiotic," both groups received cloxacil!in orally. Carriage of Haemophilus influenzae was greater in the group not receiving inhaled antibiotic (55 % vs 20%). Rates of carriage of Staphylococcus aureus (23%), Pseudomonas aeruginosa (>90%), Pseudomonas cepacia (45%), and other organisms were similar in both groups. There were no significant differences between the two groups in incidence of respiratory tract infections or hospital admissions, clinical scores, radiologic scores, or rate of change of pulmonary function. Although continuous antistaphylococcal antibiotic prophylaxis may be successful in suppressing colonization with S. aureus, it may also contribute to the high rates of carriage of Ps. aeruginosa and Ps. cepacia observed in patients with cystic fibrosis.
G. Nolan, P. McIvor, H. Levison,* P. C. Fleming, M. Corey, and R. Gold, T o r o n t o , Ont., C a n a d a
RECURRENT BACTERIAL INFECTIONS are thought to play a critical role in the progression of pulmonary disease in cystic fibrosis?-4 Survival and morbidity have improved since antibiotics were introduced for treatment of acute exacerbations of respiratory symptoms. 4:7 However, the value of continuous prophylactic antibiotic therapy in suppressing or eliminating colonization of the respiratory tract by bacteria is still controversial?, 4,8-i2Staphylococcus aureus has been assumed to play a unique and destructive role in cystic fibrosis, and continuous antibiotic prophylaxis is advocated as a means to prevent progressive lung damage? The CF Clinic at the Hospital for Sick Children has been a strong proponent of continuous prophylactic treatment with antistaphylococcal antibiotics delivered in combination by both the oral and inhaled routes, T h e standard regimen at the CF clinic has consisted of c!oxacillin or cephalexin orally ptus inhaled cephaloridine. The latter antibiotic was employed because Of a lack of
From the Department of Pediatrics, The Hospital for Sick Children, Toronto, and Faculty of Medicine, University of Toronto. *Reprint address: The Hospital fi?r Sick Children, 555 University Ave., Toronto, Ont., Canada M5G 1X8
1Iol. 101, No. 4, pp. 626-630
significant absorption (P.C. Fleming, personal communication), and because of a high frequency of hypersensitivity reactions in patients and family members when inhaled methicillin was used. Because of the marked reluctance0f patients and parents to alter any aspect of therapy perAbbreviations used CF: cystic fibrosis FEF25.75: forced expiratory flow at 25 to 75% of viial capacity FVC: forced vital capacity FEVt: forced expiratory volume in one second PFR: peak flow rate TLC: total lung capacity RV: residual volume Pao2: partial pressure of oxygen Paco2: partial pressure of carbon dioxide PEA: phenyl-ethyl agar ceived to be effective without strong scientific evidence supporting change, a prospective study was undertaken to determine the effect of discontinuation of the inhalant component of standard antibiotic prophylaxis. MATERIALS
AND METHODS
Patient selection. All patients attending the CF clinic, 7 years of age and older, with mild-to-moderate lung disease
0022-3476/82/100626+05500.50/0
9 1982 The C. V. Mosby Co.
Volume 101 Number 4 and living in the metro Toronto area were considered eligible for the study. Baseline sputum culture results were available for at least two years prior to entry. An explanatory letter from the clinic director providing background information and physician approval was sent to the 110 suitable patients, who were all subsequently contacted by the clinical fellow (G. N.) or nurse coordinator (P. McI). This study was approved by the Human Experimentation Committee of the Hospital for Sick Children. Suitable patients were stratified into groups based on sex, age (in five-year groupings), and pulmonary function (FEF25_75 greater than 80% or between 40 to 80% of predicted for sex and height). The FEFzs_75 (forced expiratory flow at 25-75% of vital capacity) was used because it is a sensitive indicator of pulmonary disease in CF? ~ ~3.~aIn each stratum, the first patient, for whom written, informed consent was obtained, was randomly allocated to treatment or control group and subsequent patients in that stratum were allocated alternatively to treatment or control. Forty-nine patients agreed to participate and the process of allocation resulted in well-balanced groups; 24 patients (12 male and 12 female) discontinued inhaled antibiotic ( O F F group); 25 patients (t2 male, 13 female) continued nebulized cephaloridine, 500 mg, two to three times/day (ON group). Both groups received cloxaciUin 50 m g / kg/day by mouth and other routine medications. At this dose of cloxacillin, the peak serum concentration ranged between 5 to 15 #/ml, 10 to 30 times the MIC ofS. aureus (R. Gold and H. Levis0n, unpublished data). In both groups, physiotherapy was performed two to three times per day following inhalation therapy with a bronchodilator (salbutamol in a buffered nebulizing solution). Cephaloridine was added to the nebulizing sotution in the ON group. No placebo was available for cephaloridine so it was not possible for the study to be blind. Patient assessment, The patients were seen in the clinic every two months or more frequently if necessary. Sputum for quantitative culture was collected and the history of respiratory tract infections, physical examination, height, weight, blood pressure, and Shwachman scores were recorded at each clinic visit. Chest roentgenograms and pulmonary function tests were performed at the start of the study and at six monthly intervals thereafter. Home visits were made by the research nurse every other month to collect sputum for quantitative culture, to assess compliance, and to obtain interval history of respiratory infections. Compliance was assessed by determining the quantity of antibiotics remaining in vials at each visit. Respiratory tract infections were defined as increased cough and sputum production with or without radiographic changes, hemoptysis, fever, anorexia, weight loss, or other manifestations of infection. If intervention was
Antibiotic prophylaxis in cystic fibrosis
627
required, a seven- to ten-day course of broad-spectrum antibiotic (ampicillin or trimethoprin-sulfamethoxazole) was used orally. When symptoms warranted, patients were admitted to hospital for two weeks of intravenous therapy with ticarcillin (300 m g / k g / d a y ) and tobramycin (10 mg/kg/day) combined with physiotherapy. Laboratory investigations. Bacteriology. Expectorated samples of sputum were obtained, if possible, after the first physiotherapy of the day or after deep coughing. If no sputum was produced, a specimen was obtained by deep pharyngeal suction at the clinic. Samples were almost always obtained at least four hours after a dose of cephaloridine, making it unlikely that culture results would be significantly affected by residual drug in this sputum. The sputum was examined microscopically and purulent portions washed with sterile saline and then homogenized in 2% N-acetyl cysteine at pH 7.2, a procedure which has no apparent effect on growth of bacteria in sputum. 12 Serial tenfold dilutions were prepared and inoculated on to blood agar, bile salt agar, phenyl-ethyl agar, PEA with 0.5 gg penicillin, PEA with 4 #g methicillin and Levinthal agar. Organisms were identified and enumerated by standard methods. A culture was considered positive when the colony count for a given bacterium was equal to or greater than 104/ml. Carriage was considered to be chronic if more than 75% of cultures were positive; intermittent if 25 to 75% were positive; and transient if fewer than 25% were positive. Sputum cultures for two years prior to entry into the study were reviewed to obtain a baseline for each child. Pulmonary function. Pulmonary function tests were performed every six months during the study. The forced vital capacity, forced .expiratory volume in one second, forced expiratory flow rate 25% to 75% of vital capacity were measured with a water-filled spirometer (Collins). The peak flow rate was recorded with a Wright peak flow mater. Total lung capacity, residual volume, and R V / T L C were measured in a body plethysmograph and by helium dilution. Blood gases were taken from arterialized capillary samples. The technician was blind as to the treatment group of each patient. Chest roentgenograms. The chest films were scored using a modification of the method of Brasfield and Hicks zs in which a maximum score is 25 and points are deducted for air trapping, linear markings, nodular and cystic lesions, large lesions, and general severity. All scoring was clone by a single observer (G. N.) in blinded fashion, This radiologic score was incorporated into the Shwachman score. 7 Statistical analysis. Individual linear regression equations with time were computed for the following variables:
628
Nolan et al.
The Journal of Pediatrics October 1982
CARRIAGE OF BACTERIA DURING THE STUDY 100-
9 ON 80Z m
60-
Table I. Comparison of annual rates of change of pulmonary function, clinical scores, radiographic scores, and weight in patients with cystic fibrosis receiving prophylactic oral cloxacillin therapy with or without inhaled cephaloridine
~ 40N
Treatment groups
20-
Test
Figure. Bacteria present in sputum cultures during the study. The ON group is represented by the shaded areas, the OFF group by the clear areas.
percent of predicted FVC, FEV~, FEF2s_75 PFR, RV/ TLC%, Pao2, Paco2, percent of ideal weight for height, and radiologic and Shwachman scores. The slope of the linear regression was used as the individual's annual rate of change for each variable, thus minimizing the effects of random or temporary fluctuations. Initial mean values of all the above variables and age were compared between the ON and OFF groups using the Student t test for independent samples. T tests were also used to compare the mean slopes in the two groups for each of the variables. Chi square tests were used to compare the number of patients in each group with respiratory tract infections, hospital admissions, and carriage of bacteria. RESULTS Two patients dropped out early in the study, both females in the OFF group. One girl with mild disease, age 14, changed her mind about participating; another girl, age 9, died with a fulminant pulmonary infection after two months of study. Pseudomonas cepacia was cultured from her sputum, blood, and lung at postmortem. The data from these two patients are not included in any of the analyses. Forty-seven patients continued in the study. One 14year-old girl (ON group) died after 11 months of study and one 16-year-old boy (OFF group) declined to continue for a second year. The data were analyzed with and without inclusion of these two patients. As none of the study results was altered, the data we present here have all the available data from the 47 patients. There were no differences between the two treatment groups in mean age (12.6 + 0.9 vs 13.2 _+ 0.8 years), or Shwachman or radiologic scores. The percent of ideal weight for height, a variable not included in the stratification, showed a small, but statistically significant
FVC FEVt FEF25.75 PFR Pco2 Po2 RV TLC RV/TLC Shwachman score Radiograph Weight for height
OFF
-2.5 -2.8 -1.3 -2.4 +0.2 -2.0 +29.7 +3.4 +4.7 -0.7 -0.8 -0.7
+ 1.0 _+ 1.3 _+ 2.9 4- 1.5 _+ 0.3 + 1.1 + 8.8 + 1.8 + 1.3 + 0.8 _+ 0.2 _+ 0.8
ON
-2.0 _+ 4.7 -3.7 __+1.3 -6.0 +_ 2.4 -0.7 4-_ 1.9 +0.6 +_ 0.2 -0.7 _+ 1.0 15.7 + 54 +0.5 _+ 1.1 +3.0 _+ 1.0 +0.02 _+ 1.0 -0.7 + 0.2 -0.8 _+ 0.7
Results expressed as slope (mean + SE) of linear regression line.
(P < 0.05) difference in favor of the O F F group. The initial mean pulmonary function variables were almost identical in the two groups. The results of pulmonary function testing, Shwachman scores, radiologic scores, and percent of ideal weight for height over the two years of follow-up, expressed as the mean slope of linear regression + its standard error for each variable, showed no significant differences between the two groups for any of the variables (Table I). Review of sputum cultures obtained prior to entry into the study revealed that the OFF group had a significantly (P < 0.02) higher carriage rate of Proteus sp. in their sputum (31.8% of patients) compared to the ON group (4.0% of patients); there were no significant differences in the sputum carriage rates of other organisms. Data obtained prior to the study are not strictly comparable to those of the study because (1) more intensive efforts were made to obtain good sputum specimens rather than saliva, and (2) specimens were evaluated more intensively in the laboratory. There were 903 sputums collected during the study at routine visits from the 47 patients. There were no chronic carriers of S. aureus in either group; the proportion of transient and intermittent carriers were 63 and 37%, respectively (Figure). Three of the five carriers in the ON group acquired S. aureus during the study, i.e., sputum cultures had been negative for the two years prior to the study. The two patients previously colonized continued to carry the organism. Three of six carriers in the OFF group acquired S. aureus and three patients had continued
Volume 101 Number 4
Antibiotic prophylaxis in cystic fibrosis
629
Table lI. Incidence of reported respiratory tract infections (RTI), RTI requiring supplemental antibiotic treatment, and hospital admissions in patients with cystic fibrosis receiving prophylactic cloxacillin with (ON group) or without (OFF group) inhaled cephaloridine Annual incidence Treatment group
ON
OFF
Sex
Number
Reported RTI
Male Female Total
12
13 25
Male Female Total
12 10 22
carriage. Thus, there was no statistical difference between the two groups for rates of acquisition or continued carriage of S. aureus. Pseudomonas aeruginosa was the most common organism cultured either alone or in combination with other bacteria. Over 90% of the patients carried this organism; over half of these were chronic carriers. Pseudomonas cepacia was cultured in the sputum of over 40%. No significant differences in carrier or acquisition rates of P. aeruginosa, P. cepacia, Escherichia coli, or Klebsiella sp. were observed between the 2 groups. The high carrier rate ofP. cepacia was not unique to the study group; it has been observed in the entire population of the CF Clinic. Carriage of H. influenzae was significantly more common in the OFF than in the ON group (64% vs 24%, P < 0.01). The rate of acquisition of H. influenzae in children previously negative in the two years prior to the study was also significantly greater in the OFF group (55% vs 20%, P < 0.025). Carriage of Proteus sp. was also more common in the OFF group, but patients in this group were significantly more likely to be carriers at the time of entry into the study. There was no difference in new acquisitions of Proteus. Other bacteria, including Serratia marcescens, Ps. maltophilia, and Enterobacter sp. were infrequently isolated. All strains of S. aureus and H. influenzae recovered during the course of the study were sensitive to cloxacillin and cephaloridine, respectively, by disc sensitivities. Clinical progress of patients in the two groups was compared by analysis of the incidences of reported respiratory tract infections, respiratory infections requiring additional antibiotics, and hospitalization for exacerbations of pulmonary symptoms (Table II). The differences were not statistically significant either for total respiratory infections (x 2 = 3.06, P > 0.05) or hospitalization (x 2 -- 1.53, P > 0.1). None of these pulmonary exacerbations was
Treated R TI
Hospital admissions
2.4
1.7
3.5 3.0
3.0 2.4
0.21 0.35 0.28
3.2 4.2 3.6
2.8 3.6 3.1
0.21 0.70 0.43
associated with acquisition of S. aureus or H. influenzae. All of the hospitalized patients were colonized with P. aeruginosa and 11 of the 15 patients were also colonized with P. cepacia. Adverse effects of daily oral cloxacillin therapy or inhaled cephaloridine were minimal. No patient discontinued or changed medications because of side effects. DISCUSSION Since the early reports of CF 2,6 S. aureus has been the asual initial pathogen isolated from the sputum of patients early in the disease. ~~ Damage to the lung by this organism is assumed to increase susceptibility to infection by other organisms. Antibiotic treatment directed against S. aureus has been advocated as one of the main reasons for the improvement in morbidity and mortality over the last three decades). 4,7.~0Coincidental with intensive antibiotic treatment of infections, the frequency of colonization with S. aureus has been decreasing while there has been a concomitant increase in colonization with P. aeruginosa. 17-19 Whether the replacement of S. aureus by Pseudomonas species is the result of antibiotic prophylaxis n or is part of the natural history of the disease, regardless of therapy, remains to be determined. In this study, we examined the effect of an inhaled antibiotic, cephaloridine, in addition to oral prophylaxis with cloxacillin. The patients we studied were over 7 years of age and had mild-to-moderate pulmonary disease. There was a similar rate of progression of the disease over the two years of study in the patients who discontinued compared to those who continued inhaled cephaloridine therapy. The incidence of respiratory tract symptoms and of hospitalization were similar in the two groups. No significant differences in clinical scores, radiographic scores, or pulmonary function tests were observed between the two groups over the two-year period of study.
630
Nolan et al.
Eleven patients (23%) acquired S. aureus during the study with equal rates in the two groups. The majority (64%) of these patients carried the organism transiently. There was no increase in respiratory symptoms in any of these patients in association with acquisition of S. aureus. Inhaled cephaloridine may have decreased the acquisition and carriage of H. influenzae. Loening-Baucke et a112 showed a similar effect on carriage of H. influenzae with oral cephalexin therapy; however, no change in clinical status was associated with carriage or acquisition of this organism. Pseudomonas aeruginosa was found in over 90% of patients. Most patients were chronic carriers. In addition, 45% of patients in this study were colonized in Ps. cepacia, which appears to colonize the respiratory tract in some patients without altering the clinical course; in others, infection is associated with rapid progression to respiratory failure and death. Such a course was observed in both patients who died during the study period. The ten other patients colonized with Ps. cepacia who required hospital admission had clinical and radiologic improvement despite no reduction in the colony count of Ps. cepacia. In summary, no h a r m has been demonstrated by discontinuing inhaled cephaloridine while continuing to administer cloxacillin orally in a group of children with C F and mild to moderately severe pulmonary disease. Whether or not routine, continuous oral prophylaxis with antistaphylococcal antibiotics is of any benefit remains to be determined. The use of inhaled cephaloridine has been discontinued in all children attending the C F Clinic at the Hospital for Sick Children without any detectable alteration in clinical status and with a total annual saving of over $250,000. The recent report demonstrating benefit of inhaled gentamicin and carbenMllin in C F patients with severe pulmonary disease is very exciting. 2~A prospective, doubleblind trial of such therapy in children with mild to moderately severe pulmonary disease is being undertaken to determine whether the claimed benefits can be confirmed. Careful, properly designed trials of antibiotic therapy of patients with cystic fibrosis are remarkable by their rarity and are urgently needed before yet another unproven form of therapy becomes widely used in cystic fibrosis.
The authors acknowledge Miss Shelley Gelber for her assistance with the preparation of this manuscript,
The Journal of Pediatrics October 1982 REFERENCES 1. Marks MI: The pathogenesis and treatment of pulmonary infections in patients with cystic fibrosis, J PED1ATR98:173, 1981. 2. Shwachman H, Kulczycki LL, and Khaw KT: Studies in cystic fibrosis: A report on sixty-five patients over 17 years of age, Pediatrics 36:689, 1965. 3. Wood RE, Boat TF, and Doershuk CF: Cystic fibrosis, Am Rev Respir Dis 113:833, 1976. 4. Shwachman H, Redmond A, and Khaw KT: Studies in cystic fibrosis, Pediatrics 46:335, 1970. 5. Doershuk CF, Matthews LW, Tucker AS, Nudelman H, Eddy G, Wise M, and Spector S: A 5 year clinical evaluation of a therapeutic program for patients with cystic fibrosis, J PED1ATR 65:677, 1964. 6. di Sant'Agnese PA, and Andersen DH: Celiac syndrome(IV), Am J Dis Child 72:17, 1946. 7. Shwachman H, and Kulczycki LL: Long-term study of one hundred and five patients with cystic fibrosis, Am J Dis Child 96:6, i958. 8. Lawson D: Cystic fibrosis--assessing the effects of treatment, Arch Dis Child 47:1, 1972. 9. Field P: Cystic fibrosis: A review of clinic patients, Aust Paediatr J 14:91, 1978. 10. di Sant'Agnese PA, and Davis PB: Cystic fibrosis in adults: 75 cases and a review of 232 cases in the literature, Am J Med 66:121, 1979. 11. Phelan PD: Editorial comments: Management of cystic fibrosis, Aust Paediatr J 14:61, 1978. 12. Loening-Baucke VA, Mischler E, and Myers MG: A placebocontrolled trial of cephalexin therapy in the ambulatory management of patients with cystic fibrosis, J PEDIATR 95:630, 1979. 13. Corey M, Levison H, and Crozier D: Five- to seven-year course of pulmonary function in cystic fibrosis, Am Rev Respir Dis 114:1085, 1976. 14. Gurwitz D, Corey M, Francis P J, Crozier D, and Levison H: Perspectives in cystic fibrosis, Pediatr Clin North Am 26:603, 1979. 15. Brasfield D, Hicks G, Soong S J, and Tiller RE: The chest roentgenogram in cystic fibrosis: A new scoring system, Pediatrics 63:24, 1979. 16. May JR, Herrick NC, and Thompson D: Bacterial infection in cystic fibrosis, Arch Dis Child 47:908, 1972. 17. Huang NN, Van Loon EL, and Sheng KT: The flora of the respiratory tract of patients with cystic fibrosis of the pancreas, J PEDIATR59:512, 1961. 18. Mearns MB, Hunt GH, and Rushworth R: Bacterial flora of respiratory tract in patients with cystic fibrosis, 1950-1971, Arch Dis Child 47:902, 1972. 19. lacocca VF, Sibbinga MS, and Barbero G J: Respiratory tract bacteriology in cystic fibrosis, Am J Dis Child 106:315, 1963. 20. Hodson ME, Penketh ARL, and Batten JC: Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis, Lancet 2:1137, 1981.
October 1982 The Journai o f P E D I A T R I C S
Antibiotic prophylaxis in cystic fibrosis: Inhaled cephaloridine as an adjunct to oral cloxacillin The effect of prophylactic antibiotics on bacterial colonization of the respiratory tract and on general progression of cystic fibrosis was studied in a two-year prospective study of 47 mildly to moderately affected patients. One group of patients received inhale d cephaloridine and the other received no inhaled antibiotic," both groups received cloxacil!in orally. Carriage of Haemophilus influenzae was greater in the group not receiving inhaled antibiotic (55 % vs 20%). Rates of carriage of Staphylococcus aureus (23%), Pseudomonas aeruginosa (>90%), Pseudomonas cepacia (45%), and other organisms were similar in both groups. There were no significant differences between the two groups in incidence of respiratory tract infections or hospital admissions, clinical scores, radiologic scores, or rate of change of pulmonary function. Although continuous antistaphylococcal antibiotic prophylaxis may be successful in suppressing colonization with S. aureus, it may also contribute to the high rates of carriage of Ps. aeruginosa and Ps. cepacia observed in patients with cystic fibrosis.
G. Nolan, P. McIvor, H. Levison,* P. C. Fleming, M. Corey, and R. Gold, T o r o n t o , Ont., C a n a d a
RECURRENT BACTERIAL INFECTIONS are thought to play a critical role in the progression of pulmonary disease in cystic fibrosis?-4 Survival and morbidity have improved since antibiotics were introduced for treatment of acute exacerbations of respiratory symptoms. 4:7 However, the value of continuous prophylactic antibiotic therapy in suppressing or eliminating colonization of the respiratory tract by bacteria is still controversial?, 4,8-i2Staphylococcus aureus has been assumed to play a unique and destructive role in cystic fibrosis, and continuous antibiotic prophylaxis is advocated as a means to prevent progressive lung damage? The CF Clinic at the Hospital for Sick Children has been a strong proponent of continuous prophylactic treatment with antistaphylococcal antibiotics delivered in combination by both the oral and inhaled routes, T h e standard regimen at the CF clinic has consisted of c!oxacillin or cephalexin orally ptus inhaled cephaloridine. The latter antibiotic was employed because Of a lack of
From the Department of Pediatrics, The Hospital for Sick Children, Toronto, and Faculty of Medicine, University of Toronto. *Reprint address: The Hospital fi?r Sick Children, 555 University Ave., Toronto, Ont., Canada M5G 1X8
1Iol. 101, No. 4, pp. 626-630
significant absorption (P.C. Fleming, personal communication), and because of a high frequency of hypersensitivity reactions in patients and family members when inhaled methicillin was used. Because of the marked reluctance0f patients and parents to alter any aspect of therapy perAbbreviations used CF: cystic fibrosis FEF25.75: forced expiratory flow at 25 to 75% of viial capacity FVC: forced vital capacity FEVt: forced expiratory volume in one second PFR: peak flow rate TLC: total lung capacity RV: residual volume Pao2: partial pressure of oxygen Paco2: partial pressure of carbon dioxide PEA: phenyl-ethyl agar ceived to be effective without strong scientific evidence supporting change, a prospective study was undertaken to determine the effect of discontinuation of the inhalant component of standard antibiotic prophylaxis. MATERIALS
AND METHODS
Patient selection. All patients attending the CF clinic, 7 years of age and older, with mild-to-moderate lung disease
0022-3476/82/100626+05500.50/0
9 1982 The C. V. Mosby Co.
Volume 101 Number 4 and living in the metro Toronto area were considered eligible for the study. Baseline sputum culture results were available for at least two years prior to entry. An explanatory letter from the clinic director providing background information and physician approval was sent to the 110 suitable patients, who were all subsequently contacted by the clinical fellow (G. N.) or nurse coordinator (P. McI). This study was approved by the Human Experimentation Committee of the Hospital for Sick Children. Suitable patients were stratified into groups based on sex, age (in five-year groupings), and pulmonary function (FEF25_75 greater than 80% or between 40 to 80% of predicted for sex and height). The FEFzs_75 (forced expiratory flow at 25-75% of vital capacity) was used because it is a sensitive indicator of pulmonary disease in CF? ~ ~3.~aIn each stratum, the first patient, for whom written, informed consent was obtained, was randomly allocated to treatment or control group and subsequent patients in that stratum were allocated alternatively to treatment or control. Forty-nine patients agreed to participate and the process of allocation resulted in well-balanced groups; 24 patients (12 male and 12 female) discontinued inhaled antibiotic ( O F F group); 25 patients (t2 male, 13 female) continued nebulized cephaloridine, 500 mg, two to three times/day (ON group). Both groups received cloxaciUin 50 m g / kg/day by mouth and other routine medications. At this dose of cloxacillin, the peak serum concentration ranged between 5 to 15 #/ml, 10 to 30 times the MIC ofS. aureus (R. Gold and H. Levis0n, unpublished data). In both groups, physiotherapy was performed two to three times per day following inhalation therapy with a bronchodilator (salbutamol in a buffered nebulizing solution). Cephaloridine was added to the nebulizing sotution in the ON group. No placebo was available for cephaloridine so it was not possible for the study to be blind. Patient assessment, The patients were seen in the clinic every two months or more frequently if necessary. Sputum for quantitative culture was collected and the history of respiratory tract infections, physical examination, height, weight, blood pressure, and Shwachman scores were recorded at each clinic visit. Chest roentgenograms and pulmonary function tests were performed at the start of the study and at six monthly intervals thereafter. Home visits were made by the research nurse every other month to collect sputum for quantitative culture, to assess compliance, and to obtain interval history of respiratory infections. Compliance was assessed by determining the quantity of antibiotics remaining in vials at each visit. Respiratory tract infections were defined as increased cough and sputum production with or without radiographic changes, hemoptysis, fever, anorexia, weight loss, or other manifestations of infection. If intervention was
Antibiotic prophylaxis in cystic fibrosis
627
required, a seven- to ten-day course of broad-spectrum antibiotic (ampicillin or trimethoprin-sulfamethoxazole) was used orally. When symptoms warranted, patients were admitted to hospital for two weeks of intravenous therapy with ticarcillin (300 m g / k g / d a y ) and tobramycin (10 mg/kg/day) combined with physiotherapy. Laboratory investigations. Bacteriology. Expectorated samples of sputum were obtained, if possible, after the first physiotherapy of the day or after deep coughing. If no sputum was produced, a specimen was obtained by deep pharyngeal suction at the clinic. Samples were almost always obtained at least four hours after a dose of cephaloridine, making it unlikely that culture results would be significantly affected by residual drug in this sputum. The sputum was examined microscopically and purulent portions washed with sterile saline and then homogenized in 2% N-acetyl cysteine at pH 7.2, a procedure which has no apparent effect on growth of bacteria in sputum. 12 Serial tenfold dilutions were prepared and inoculated on to blood agar, bile salt agar, phenyl-ethyl agar, PEA with 0.5 gg penicillin, PEA with 4 #g methicillin and Levinthal agar. Organisms were identified and enumerated by standard methods. A culture was considered positive when the colony count for a given bacterium was equal to or greater than 104/ml. Carriage was considered to be chronic if more than 75% of cultures were positive; intermittent if 25 to 75% were positive; and transient if fewer than 25% were positive. Sputum cultures for two years prior to entry into the study were reviewed to obtain a baseline for each child. Pulmonary function. Pulmonary function tests were performed every six months during the study. The forced vital capacity, forced .expiratory volume in one second, forced expiratory flow rate 25% to 75% of vital capacity were measured with a water-filled spirometer (Collins). The peak flow rate was recorded with a Wright peak flow mater. Total lung capacity, residual volume, and R V / T L C were measured in a body plethysmograph and by helium dilution. Blood gases were taken from arterialized capillary samples. The technician was blind as to the treatment group of each patient. Chest roentgenograms. The chest films were scored using a modification of the method of Brasfield and Hicks zs in which a maximum score is 25 and points are deducted for air trapping, linear markings, nodular and cystic lesions, large lesions, and general severity. All scoring was clone by a single observer (G. N.) in blinded fashion, This radiologic score was incorporated into the Shwachman score. 7 Statistical analysis. Individual linear regression equations with time were computed for the following variables:
628
Nolan et al.
The Journal of Pediatrics October 1982
CARRIAGE OF BACTERIA DURING THE STUDY 100-
9 ON 80Z m
60-
Table I. Comparison of annual rates of change of pulmonary function, clinical scores, radiographic scores, and weight in patients with cystic fibrosis receiving prophylactic oral cloxacillin therapy with or without inhaled cephaloridine
~ 40N
Treatment groups
20-
Test
Figure. Bacteria present in sputum cultures during the study. The ON group is represented by the shaded areas, the OFF group by the clear areas.
percent of predicted FVC, FEV~, FEF2s_75 PFR, RV/ TLC%, Pao2, Paco2, percent of ideal weight for height, and radiologic and Shwachman scores. The slope of the linear regression was used as the individual's annual rate of change for each variable, thus minimizing the effects of random or temporary fluctuations. Initial mean values of all the above variables and age were compared between the ON and OFF groups using the Student t test for independent samples. T tests were also used to compare the mean slopes in the two groups for each of the variables. Chi square tests were used to compare the number of patients in each group with respiratory tract infections, hospital admissions, and carriage of bacteria. RESULTS Two patients dropped out early in the study, both females in the OFF group. One girl with mild disease, age 14, changed her mind about participating; another girl, age 9, died with a fulminant pulmonary infection after two months of study. Pseudomonas cepacia was cultured from her sputum, blood, and lung at postmortem. The data from these two patients are not included in any of the analyses. Forty-seven patients continued in the study. One 14year-old girl (ON group) died after 11 months of study and one 16-year-old boy (OFF group) declined to continue for a second year. The data were analyzed with and without inclusion of these two patients. As none of the study results was altered, the data we present here have all the available data from the 47 patients. There were no differences between the two treatment groups in mean age (12.6 + 0.9 vs 13.2 _+ 0.8 years), or Shwachman or radiologic scores. The percent of ideal weight for height, a variable not included in the stratification, showed a small, but statistically significant
FVC FEVt FEF25.75 PFR Pco2 Po2 RV TLC RV/TLC Shwachman score Radiograph Weight for height
OFF
-2.5 -2.8 -1.3 -2.4 +0.2 -2.0 +29.7 +3.4 +4.7 -0.7 -0.8 -0.7
+ 1.0 _+ 1.3 _+ 2.9 4- 1.5 _+ 0.3 + 1.1 + 8.8 + 1.8 + 1.3 + 0.8 _+ 0.2 _+ 0.8
ON
-2.0 _+ 4.7 -3.7 __+1.3 -6.0 +_ 2.4 -0.7 4-_ 1.9 +0.6 +_ 0.2 -0.7 _+ 1.0 15.7 + 54 +0.5 _+ 1.1 +3.0 _+ 1.0 +0.02 _+ 1.0 -0.7 + 0.2 -0.8 _+ 0.7
Results expressed as slope (mean + SE) of linear regression line.
(P < 0.05) difference in favor of the O F F group. The initial mean pulmonary function variables were almost identical in the two groups. The results of pulmonary function testing, Shwachman scores, radiologic scores, and percent of ideal weight for height over the two years of follow-up, expressed as the mean slope of linear regression + its standard error for each variable, showed no significant differences between the two groups for any of the variables (Table I). Review of sputum cultures obtained prior to entry into the study revealed that the OFF group had a significantly (P < 0.02) higher carriage rate of Proteus sp. in their sputum (31.8% of patients) compared to the ON group (4.0% of patients); there were no significant differences in the sputum carriage rates of other organisms. Data obtained prior to the study are not strictly comparable to those of the study because (1) more intensive efforts were made to obtain good sputum specimens rather than saliva, and (2) specimens were evaluated more intensively in the laboratory. There were 903 sputums collected during the study at routine visits from the 47 patients. There were no chronic carriers of S. aureus in either group; the proportion of transient and intermittent carriers were 63 and 37%, respectively (Figure). Three of the five carriers in the ON group acquired S. aureus during the study, i.e., sputum cultures had been negative for the two years prior to the study. The two patients previously colonized continued to carry the organism. Three of six carriers in the OFF group acquired S. aureus and three patients had continued
Volume 101 Number 4
Antibiotic prophylaxis in cystic fibrosis
629
Table lI. Incidence of reported respiratory tract infections (RTI), RTI requiring supplemental antibiotic treatment, and hospital admissions in patients with cystic fibrosis receiving prophylactic cloxacillin with (ON group) or without (OFF group) inhaled cephaloridine Annual incidence Treatment group
ON
OFF
Sex
Number
Reported RTI
Male Female Total
12
13 25
Male Female Total
12 10 22
carriage. Thus, there was no statistical difference between the two groups for rates of acquisition or continued carriage of S. aureus. Pseudomonas aeruginosa was the most common organism cultured either alone or in combination with other bacteria. Over 90% of the patients carried this organism; over half of these were chronic carriers. Pseudomonas cepacia was cultured in the sputum of over 40%. No significant differences in carrier or acquisition rates of P. aeruginosa, P. cepacia, Escherichia coli, or Klebsiella sp. were observed between the 2 groups. The high carrier rate ofP. cepacia was not unique to the study group; it has been observed in the entire population of the CF Clinic. Carriage of H. influenzae was significantly more common in the OFF than in the ON group (64% vs 24%, P < 0.01). The rate of acquisition of H. influenzae in children previously negative in the two years prior to the study was also significantly greater in the OFF group (55% vs 20%, P < 0.025). Carriage of Proteus sp. was also more common in the OFF group, but patients in this group were significantly more likely to be carriers at the time of entry into the study. There was no difference in new acquisitions of Proteus. Other bacteria, including Serratia marcescens, Ps. maltophilia, and Enterobacter sp. were infrequently isolated. All strains of S. aureus and H. influenzae recovered during the course of the study were sensitive to cloxacillin and cephaloridine, respectively, by disc sensitivities. Clinical progress of patients in the two groups was compared by analysis of the incidences of reported respiratory tract infections, respiratory infections requiring additional antibiotics, and hospitalization for exacerbations of pulmonary symptoms (Table II). The differences were not statistically significant either for total respiratory infections (x 2 = 3.06, P > 0.05) or hospitalization (x 2 -- 1.53, P > 0.1). None of these pulmonary exacerbations was
Treated R TI
Hospital admissions
2.4
1.7
3.5 3.0
3.0 2.4
0.21 0.35 0.28
3.2 4.2 3.6
2.8 3.6 3.1
0.21 0.70 0.43
associated with acquisition of S. aureus or H. influenzae. All of the hospitalized patients were colonized with P. aeruginosa and 11 of the 15 patients were also colonized with P. cepacia. Adverse effects of daily oral cloxacillin therapy or inhaled cephaloridine were minimal. No patient discontinued or changed medications because of side effects. DISCUSSION Since the early reports of CF 2,6 S. aureus has been the asual initial pathogen isolated from the sputum of patients early in the disease. ~~ Damage to the lung by this organism is assumed to increase susceptibility to infection by other organisms. Antibiotic treatment directed against S. aureus has been advocated as one of the main reasons for the improvement in morbidity and mortality over the last three decades). 4,7.~0Coincidental with intensive antibiotic treatment of infections, the frequency of colonization with S. aureus has been decreasing while there has been a concomitant increase in colonization with P. aeruginosa. 17-19 Whether the replacement of S. aureus by Pseudomonas species is the result of antibiotic prophylaxis n or is part of the natural history of the disease, regardless of therapy, remains to be determined. In this study, we examined the effect of an inhaled antibiotic, cephaloridine, in addition to oral prophylaxis with cloxacillin. The patients we studied were over 7 years of age and had mild-to-moderate pulmonary disease. There was a similar rate of progression of the disease over the two years of study in the patients who discontinued compared to those who continued inhaled cephaloridine therapy. The incidence of respiratory tract symptoms and of hospitalization were similar in the two groups. No significant differences in clinical scores, radiographic scores, or pulmonary function tests were observed between the two groups over the two-year period of study.
630
Nolan et al.
Eleven patients (23%) acquired S. aureus during the study with equal rates in the two groups. The majority (64%) of these patients carried the organism transiently. There was no increase in respiratory symptoms in any of these patients in association with acquisition of S. aureus. Inhaled cephaloridine may have decreased the acquisition and carriage of H. influenzae. Loening-Baucke et a112 showed a similar effect on carriage of H. influenzae with oral cephalexin therapy; however, no change in clinical status was associated with carriage or acquisition of this organism. Pseudomonas aeruginosa was found in over 90% of patients. Most patients were chronic carriers. In addition, 45% of patients in this study were colonized in Ps. cepacia, which appears to colonize the respiratory tract in some patients without altering the clinical course; in others, infection is associated with rapid progression to respiratory failure and death. Such a course was observed in both patients who died during the study period. The ten other patients colonized with Ps. cepacia who required hospital admission had clinical and radiologic improvement despite no reduction in the colony count of Ps. cepacia. In summary, no h a r m has been demonstrated by discontinuing inhaled cephaloridine while continuing to administer cloxacillin orally in a group of children with C F and mild to moderately severe pulmonary disease. Whether or not routine, continuous oral prophylaxis with antistaphylococcal antibiotics is of any benefit remains to be determined. The use of inhaled cephaloridine has been discontinued in all children attending the C F Clinic at the Hospital for Sick Children without any detectable alteration in clinical status and with a total annual saving of over $250,000. The recent report demonstrating benefit of inhaled gentamicin and carbenMllin in C F patients with severe pulmonary disease is very exciting. 2~A prospective, doubleblind trial of such therapy in children with mild to moderately severe pulmonary disease is being undertaken to determine whether the claimed benefits can be confirmed. Careful, properly designed trials of antibiotic therapy of patients with cystic fibrosis are remarkable by their rarity and are urgently needed before yet another unproven form of therapy becomes widely used in cystic fibrosis.
The authors acknowledge Miss Shelley Gelber for her assistance with the preparation of this manuscript,
The Journal of Pediatrics October 1982 REFERENCES 1. Marks MI: The pathogenesis and treatment of pulmonary infections in patients with cystic fibrosis, J PED1ATR98:173, 1981. 2. Shwachman H, Kulczycki LL, and Khaw KT: Studies in cystic fibrosis: A report on sixty-five patients over 17 years of age, Pediatrics 36:689, 1965. 3. Wood RE, Boat TF, and Doershuk CF: Cystic fibrosis, Am Rev Respir Dis 113:833, 1976. 4. Shwachman H, Redmond A, and Khaw KT: Studies in cystic fibrosis, Pediatrics 46:335, 1970. 5. Doershuk CF, Matthews LW, Tucker AS, Nudelman H, Eddy G, Wise M, and Spector S: A 5 year clinical evaluation of a therapeutic program for patients with cystic fibrosis, J PED1ATR 65:677, 1964. 6. di Sant'Agnese PA, and Andersen DH: Celiac syndrome(IV), Am J Dis Child 72:17, 1946. 7. Shwachman H, and Kulczycki LL: Long-term study of one hundred and five patients with cystic fibrosis, Am J Dis Child 96:6, i958. 8. Lawson D: Cystic fibrosis--assessing the effects of treatment, Arch Dis Child 47:1, 1972. 9. Field P: Cystic fibrosis: A review of clinic patients, Aust Paediatr J 14:91, 1978. 10. di Sant'Agnese PA, and Davis PB: Cystic fibrosis in adults: 75 cases and a review of 232 cases in the literature, Am J Med 66:121, 1979. 11. Phelan PD: Editorial comments: Management of cystic fibrosis, Aust Paediatr J 14:61, 1978. 12. Loening-Baucke VA, Mischler E, and Myers MG: A placebocontrolled trial of cephalexin therapy in the ambulatory management of patients with cystic fibrosis, J PEDIATR 95:630, 1979. 13. Corey M, Levison H, and Crozier D: Five- to seven-year course of pulmonary function in cystic fibrosis, Am Rev Respir Dis 114:1085, 1976. 14. Gurwitz D, Corey M, Francis P J, Crozier D, and Levison H: Perspectives in cystic fibrosis, Pediatr Clin North Am 26:603, 1979. 15. Brasfield D, Hicks G, Soong S J, and Tiller RE: The chest roentgenogram in cystic fibrosis: A new scoring system, Pediatrics 63:24, 1979. 16. May JR, Herrick NC, and Thompson D: Bacterial infection in cystic fibrosis, Arch Dis Child 47:908, 1972. 17. Huang NN, Van Loon EL, and Sheng KT: The flora of the respiratory tract of patients with cystic fibrosis of the pancreas, J PEDIATR59:512, 1961. 18. Mearns MB, Hunt GH, and Rushworth R: Bacterial flora of respiratory tract in patients with cystic fibrosis, 1950-1971, Arch Dis Child 47:902, 1972. 19. lacocca VF, Sibbinga MS, and Barbero G J: Respiratory tract bacteriology in cystic fibrosis, Am J Dis Child 106:315, 1963. 20. Hodson ME, Penketh ARL, and Batten JC: Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis, Lancet 2:1137, 1981.