THE JOURNAL qF I~FECTIqUS DISEASES • VOL. 134, SUPPLEMENT © 1976 by the University of Chicago. All rights reserved.
•
AUGUST 1976
Tobramycin Therapy of Infections Due to Pseudomonas aeruginosa in Patients with Cystic Fibrosis: Effect of Dosage and Concentration of Antibiotic in Sputum
w.
From the Royal Hospital for Sick Children, and the Department of Human Genetics, University of Edinburgh, Edinburgh, Scotland
Morrice McCrae, 1. A. Raeburn, and E. 1. Hanson
Classically, cystic fibrosis has been associated with staphylococcal infection of the lung, and there is some evidence that the recent improvement in the prognosis of this disease has coincided with the introduction of effective antistaphylococcal drugs [1]. The exact role of staphylococcal infection in the pathogenesis of cystic fibrosis remains in dispute [2]. It cannot be disputed, however, that infection with Pseudomonas species is an increasing problem in this disease. Wood has estimated that in the United States some 70%80% of all patients with cystic fibrosis are now colonized with this type of organism [3]. Although the incidence of pseudomonas infection in our patients is smaller (18 %) than the estimate for the rate of infection in the United States, this infection is nevertheless a considerable problem. As has been found by others, treatment with carbenicillin and gentamicin has proved disappointing [4, 5]. Since some degree of improvement has been reported after administration of tobram!cin iv in a dose of 5 mg/kg per day [6], we decided to treat all of our patients. who were actively infected with mucoid strains of Pseudomonas aeruginosa with this and also larger doses of tobramycin. We wish to acknowledge the support of Dista Products, Ltd., and the assistance of the staff of the Central Microbiology Laboratories, Edinburgh, Scotland. Please address requests for reprints to Dr. W. Morrice McCrae, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, Scotland.
S191
Materials and Methods
Seventeen patients (age, 11 months to 16 years and 10 months) were treated with tobramycin. All had troublesome symptoms including recurrent cough and production of sputum at least during postural drainage in the course of physiotherapy. The patients had shown recent weight loss, and, with two exceptions, all had elevated rates of erythrocyte sedimentation and increased white blood cell counts as further evidence of infection. As has been frequently observed during infections in patients with cystic fibrosis, pyrexia was uncommon. The sputum in every case gave a profuse growth of mucoid P. aeruginosa. Four patients were treated at each of the following dosage levels: 5, 6, 8, and 10 mg/kg per day. One patient was given 12 mg/kg per day. The antibiotic was given iv in three divided doses, and treatment was continued for two weeks. Every second day the serum level of antibiotic was measured 1 hr after an injection and again immediately before the next injection. Sputum was collected on the same days for estimation of the level of antibiotic as well as for bacteriological examination. Assays of serum or sputum concentrations of the drug were performed with a plate diffusion technique which has been described previously [7, 8]. The organism used in the assay was a strain of Pseudomonas (kindly supplied by Ms. Holland, Roussel Laboratories, Ltd., Swindon, U.K.), and it was seeded into diagnostic sensitiv-
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
~stablished .respiratory in~ections .with mucoid Pseudomonas aeruginosa in patients suffermg from cystic fibrosis were treated with conventional as well as l~rger doses of tobramycin. The infection was eradicated in four of the 17 patients treated, but the duration of follow-up study of one patient was short. ·It appeared that tr~atment was most successful in those patients in whom the highest peak concentrations of tobramycin in sputum were obtained. No side effects were noted, even when tobramycin was given in large doses for two weeks.
McCrae, Raeburn, and Hanson
Sl92
Results
Clinical results. After treatment, and on purely subjective grounds, some improvement might have been claimed in all cases. By comparison, the objective observations gave results that were not as satisfactory. Changes in white blood cell count and erythrocyte sedimentation rate often conflicted with the clinical impression of improvement. However, there was closer agreement between subjective judgments, weight gain, and changes in respiratory function (table 1). Levels of antibiotics. The variation in dose of tobramycin was reflected to some extent in the Table 1. Relation between dose of tobramycin administered iv to patients with cystic fibrosis and improvements in weight, erythrocyte sedimentation rate, white blood cell count, and respiratory function.
5 6 8 10 12
3/4 2/4 4/4 2/4 1/1
Dose Peak level of of drug tobramycin (mg/kg in serum per day) (rng/I) 5 6 8 10 12
5.7 4.5 4.9 6.8 8.7
Trough level of tobramycin in serum (rng/I)
± 1.9 ± 1.8
0.1 0.01 0.2 0.2 0.5
± 1.7 ± 2.2 ± 0.6
± 1.8 ± 1.8
± 0.2 ± 0.2 ± 0.2
Level of tobramycin in sputum (rng/I) 0.4 0.4 0.6 0.7 0.4
± ± ± ± ±
0.1 0.1 0.3 0.4 0.3
NOTE. Seventeen patients were treated; four patients in each group received 5, 6, 8, or 10 mg/kg per day, and one patient received 12 mg/kg per day. Data are means ± SE.
levels of antibiotic obtained in serum. The most interesting observation, however, was that concentrations of tobramycin exceeding the MIC for many species of Pseudomonas were achieved in the sputum (table 2). Bacteriology. P. aeruginosa was eradicated from the sputum in four cases, although the duration of follow-up study in one case was very short (table 3). After the two-week period of treatment, the patients were discharged from the hospital and were seen for follow-up study at monthly intervals. The patients from whom P. aeruginosa was apparently eradicated remained well without further treatment with tobramycin. These patients were all in a poor nutritional state at the beginning of treatment and had severe symptoms. Their ages varied from three years and eight months to 16 years and 10 months. The known period of colonization of these patients with mucoid P. aeruginosa varied from five months to two years and seven months. Table 3. Relation between dose of tobramycin administered iv to patients with cystic fibrosis and eradication of infection with Pseudomonas aeruginosa.
Improvement in Dose of drug (mg/kg per day) Weight
Table 2. Relation between levels of tobra-nycin in sputum and serum and dose of drug administered iv to patients with cystic fibrosis.
Erythrocyte sedimentation rate
White blood cell count
Respiratory function
0/4 1/4 1/4 2/4 0/1
1/4 2/4 2/4 3/4 1/1
2/4 4/4 3/4 3/4 1/1
NOTE. Data are given as number of patients with indicated improvement/number of patients treated.
Dose of drug (mg/kg per day) 5 6 8 10 12
No. of patients from whom infection was eradicated/no. of patients treated 0/4 1/4 1/4 1/4 1/1
* In
Duration of follow-up study (months) * 12 1 3 7
patients from whom infection was eradicated.
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
ity test agar (Oxoid, Ltd., London, U.K.) at pH 8.0. Standards were prepared in buffered saline at the same pH. The patients were weighed daily and a daily urinalysis was performed. Before treatment and at weekly intervals thereafter, the following tests were carried out: arterial blood gas analysis, counts of serum electrolytes and white blood cells, and determination of erythrocyte sedimentation rate. In patients old enough to cooperate, the following tests of respiratory function were also performed: fixed vital capacity, forced expiratory volume, and peak expiratory flow rates. Routine audiometry (as appropriate for age) had already been performed on all patients and was repeated after treatment. Throughout the period of treatment, the patients' usual nutritional management and twice daily physiotherapy were continued.
S193
Tobramycin and P. aeruginosa Infections
Discussion
It is not the purpose of this report to comment on
the relation between dose, route of administration, and distribution of tobramycin in tissue, although it is clear that factors other than dose must influence the level of antibiotic achieved in the sputum. It is highly probable that other factors, such as the degree of inflammatory reaction to the infection, are equally important. The number of patients treated in this series was small; therefore it would not be wise to attach undue importance to the apparent lack of side effects in this small number of patients treated with more-than the conventional dose of tobramycin. The possible risks that may accompany the use of large doses of tobramycin were thought to be justifiable because of the poor clinical condition and the poor prognosis of the patients. With use of unconventionally large doses of tobramycin, it was shown that pseudomonas infection could be eradicated in at least a small proportion of patients. To our knowledge, this result has not been previously reported. Although much more extensive clinical experience is required, it appears that the success of treatment with tobramycin does not relate absolutely to the dose of drug used but rather to
the peak levels of tobramycin achieved in sputum. The factors that determine the level of antibiotic in sputum require further study. Further clinical experience will also be required before it can be accepted that the use of large doses of tobramycin is free of adverse side effects. However, in view of the increasing incidence and disastrous outcome of infection with mucoid P. aeruginosa in patients with cystic fibrosis and the reported lack of success of treatment with other agents, even the limited success of tobramycin observed in this study is encouraging. References 1. Warick, W. J., Pogue, R E. Computer studies in cystic fibrosis. In D. Lawson [ed.], Proceedings of the Fifth International Cystic Fibrosis Conference. Cystic Fibrosis Research Trust, London, 1969, p. 320-330. 2. McCrae, W. M. Management of cystic fibrosis. In J. Apley [ed.]. Modern trends in pediatrics. Vol. 4. Butterworth, London, 1974, p. 157--179. 3. Wood, R. Pseudomonas in cystic fibrosis. In "Gap" Conference Reports. National Cystic Fibrosis Research Foundation, Atlanta, 1974, p. 4-6. 4. Marks, M. I., Prentice, R.,Swarson,R., Cotton, E. K., Eickhoff, T. C. Carbenicillin and gentamicin: pharmacological studies in patients with cystic fibrosis and. pseudomonas infections. J. Pediatr. 79:822-828, 1971. 5. Huang, N. N" Hiller, E. J.,Macri, C. M., Capitanio, M., Cundy, K. R Carbenicillin in patients with cystic fibrosis: clinical pharmacology and therapeutic evaluation. J. Pediatr. 78:338-345, 1971. 6. Hawley, H. B., Lewis, R M., Swartz, D. R., Gump, D. W. Tobramycin therapy of pumonary infections in patients with cystic fibrosis. Curr. Ther. Res. 16:414-423, 1974. 7. Raeburn, J. A., Devine, J. D. Clindamycin levels in sputum in a patient with purulent chest disease due to cystic fibrosis. Postgrad, Med.47:366-367, 1971. 8. Raeburn, J. A., Devine J. D. Pharmacological findings during azidocillin treatment of chest infections. Scand. J. Infect. Dis. 5: 135-139, 1973.
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
The mean levels of antibiotic in sputum achieved in patients from whom P. aeruginosa was eradicated did not differ significantly from the levels achieved in other patients who received the same dose. It may be of interest that three of these patients had the highest peak levels of tobramycin in sputum recorded during the study (0.88, 0.9, and 0.95 mg/I) . The patient who received 6 mg/kg per day did not at any time have a recorded level of antibiotic in sputum of > 0.65 mg/I. Side effects. No side effects attributable to treatment with tobramycin were noted during the trial or during the period of follow-up study.
•
AUGUST 1976
Tobramycin Therapy of Infections Due to Pseudomonas aeruginosa in Patients with Cystic Fibrosis: Effect of Dosage and Concentration of Antibiotic in Sputum
w.
From the Royal Hospital for Sick Children, and the Department of Human Genetics, University of Edinburgh, Edinburgh, Scotland
Morrice McCrae, 1. A. Raeburn, and E. 1. Hanson
Classically, cystic fibrosis has been associated with staphylococcal infection of the lung, and there is some evidence that the recent improvement in the prognosis of this disease has coincided with the introduction of effective antistaphylococcal drugs [1]. The exact role of staphylococcal infection in the pathogenesis of cystic fibrosis remains in dispute [2]. It cannot be disputed, however, that infection with Pseudomonas species is an increasing problem in this disease. Wood has estimated that in the United States some 70%80% of all patients with cystic fibrosis are now colonized with this type of organism [3]. Although the incidence of pseudomonas infection in our patients is smaller (18 %) than the estimate for the rate of infection in the United States, this infection is nevertheless a considerable problem. As has been found by others, treatment with carbenicillin and gentamicin has proved disappointing [4, 5]. Since some degree of improvement has been reported after administration of tobram!cin iv in a dose of 5 mg/kg per day [6], we decided to treat all of our patients. who were actively infected with mucoid strains of Pseudomonas aeruginosa with this and also larger doses of tobramycin. We wish to acknowledge the support of Dista Products, Ltd., and the assistance of the staff of the Central Microbiology Laboratories, Edinburgh, Scotland. Please address requests for reprints to Dr. W. Morrice McCrae, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, Scotland.
S191
Materials and Methods
Seventeen patients (age, 11 months to 16 years and 10 months) were treated with tobramycin. All had troublesome symptoms including recurrent cough and production of sputum at least during postural drainage in the course of physiotherapy. The patients had shown recent weight loss, and, with two exceptions, all had elevated rates of erythrocyte sedimentation and increased white blood cell counts as further evidence of infection. As has been frequently observed during infections in patients with cystic fibrosis, pyrexia was uncommon. The sputum in every case gave a profuse growth of mucoid P. aeruginosa. Four patients were treated at each of the following dosage levels: 5, 6, 8, and 10 mg/kg per day. One patient was given 12 mg/kg per day. The antibiotic was given iv in three divided doses, and treatment was continued for two weeks. Every second day the serum level of antibiotic was measured 1 hr after an injection and again immediately before the next injection. Sputum was collected on the same days for estimation of the level of antibiotic as well as for bacteriological examination. Assays of serum or sputum concentrations of the drug were performed with a plate diffusion technique which has been described previously [7, 8]. The organism used in the assay was a strain of Pseudomonas (kindly supplied by Ms. Holland, Roussel Laboratories, Ltd., Swindon, U.K.), and it was seeded into diagnostic sensitiv-
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
~stablished .respiratory in~ections .with mucoid Pseudomonas aeruginosa in patients suffermg from cystic fibrosis were treated with conventional as well as l~rger doses of tobramycin. The infection was eradicated in four of the 17 patients treated, but the duration of follow-up study of one patient was short. ·It appeared that tr~atment was most successful in those patients in whom the highest peak concentrations of tobramycin in sputum were obtained. No side effects were noted, even when tobramycin was given in large doses for two weeks.
McCrae, Raeburn, and Hanson
Sl92
Results
Clinical results. After treatment, and on purely subjective grounds, some improvement might have been claimed in all cases. By comparison, the objective observations gave results that were not as satisfactory. Changes in white blood cell count and erythrocyte sedimentation rate often conflicted with the clinical impression of improvement. However, there was closer agreement between subjective judgments, weight gain, and changes in respiratory function (table 1). Levels of antibiotics. The variation in dose of tobramycin was reflected to some extent in the Table 1. Relation between dose of tobramycin administered iv to patients with cystic fibrosis and improvements in weight, erythrocyte sedimentation rate, white blood cell count, and respiratory function.
5 6 8 10 12
3/4 2/4 4/4 2/4 1/1
Dose Peak level of of drug tobramycin (mg/kg in serum per day) (rng/I) 5 6 8 10 12
5.7 4.5 4.9 6.8 8.7
Trough level of tobramycin in serum (rng/I)
± 1.9 ± 1.8
0.1 0.01 0.2 0.2 0.5
± 1.7 ± 2.2 ± 0.6
± 1.8 ± 1.8
± 0.2 ± 0.2 ± 0.2
Level of tobramycin in sputum (rng/I) 0.4 0.4 0.6 0.7 0.4
± ± ± ± ±
0.1 0.1 0.3 0.4 0.3
NOTE. Seventeen patients were treated; four patients in each group received 5, 6, 8, or 10 mg/kg per day, and one patient received 12 mg/kg per day. Data are means ± SE.
levels of antibiotic obtained in serum. The most interesting observation, however, was that concentrations of tobramycin exceeding the MIC for many species of Pseudomonas were achieved in the sputum (table 2). Bacteriology. P. aeruginosa was eradicated from the sputum in four cases, although the duration of follow-up study in one case was very short (table 3). After the two-week period of treatment, the patients were discharged from the hospital and were seen for follow-up study at monthly intervals. The patients from whom P. aeruginosa was apparently eradicated remained well without further treatment with tobramycin. These patients were all in a poor nutritional state at the beginning of treatment and had severe symptoms. Their ages varied from three years and eight months to 16 years and 10 months. The known period of colonization of these patients with mucoid P. aeruginosa varied from five months to two years and seven months. Table 3. Relation between dose of tobramycin administered iv to patients with cystic fibrosis and eradication of infection with Pseudomonas aeruginosa.
Improvement in Dose of drug (mg/kg per day) Weight
Table 2. Relation between levels of tobra-nycin in sputum and serum and dose of drug administered iv to patients with cystic fibrosis.
Erythrocyte sedimentation rate
White blood cell count
Respiratory function
0/4 1/4 1/4 2/4 0/1
1/4 2/4 2/4 3/4 1/1
2/4 4/4 3/4 3/4 1/1
NOTE. Data are given as number of patients with indicated improvement/number of patients treated.
Dose of drug (mg/kg per day) 5 6 8 10 12
No. of patients from whom infection was eradicated/no. of patients treated 0/4 1/4 1/4 1/4 1/1
* In
Duration of follow-up study (months) * 12 1 3 7
patients from whom infection was eradicated.
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
ity test agar (Oxoid, Ltd., London, U.K.) at pH 8.0. Standards were prepared in buffered saline at the same pH. The patients were weighed daily and a daily urinalysis was performed. Before treatment and at weekly intervals thereafter, the following tests were carried out: arterial blood gas analysis, counts of serum electrolytes and white blood cells, and determination of erythrocyte sedimentation rate. In patients old enough to cooperate, the following tests of respiratory function were also performed: fixed vital capacity, forced expiratory volume, and peak expiratory flow rates. Routine audiometry (as appropriate for age) had already been performed on all patients and was repeated after treatment. Throughout the period of treatment, the patients' usual nutritional management and twice daily physiotherapy were continued.
S193
Tobramycin and P. aeruginosa Infections
Discussion
It is not the purpose of this report to comment on
the relation between dose, route of administration, and distribution of tobramycin in tissue, although it is clear that factors other than dose must influence the level of antibiotic achieved in the sputum. It is highly probable that other factors, such as the degree of inflammatory reaction to the infection, are equally important. The number of patients treated in this series was small; therefore it would not be wise to attach undue importance to the apparent lack of side effects in this small number of patients treated with more-than the conventional dose of tobramycin. The possible risks that may accompany the use of large doses of tobramycin were thought to be justifiable because of the poor clinical condition and the poor prognosis of the patients. With use of unconventionally large doses of tobramycin, it was shown that pseudomonas infection could be eradicated in at least a small proportion of patients. To our knowledge, this result has not been previously reported. Although much more extensive clinical experience is required, it appears that the success of treatment with tobramycin does not relate absolutely to the dose of drug used but rather to
the peak levels of tobramycin achieved in sputum. The factors that determine the level of antibiotic in sputum require further study. Further clinical experience will also be required before it can be accepted that the use of large doses of tobramycin is free of adverse side effects. However, in view of the increasing incidence and disastrous outcome of infection with mucoid P. aeruginosa in patients with cystic fibrosis and the reported lack of success of treatment with other agents, even the limited success of tobramycin observed in this study is encouraging. References 1. Warick, W. J., Pogue, R E. Computer studies in cystic fibrosis. In D. Lawson [ed.], Proceedings of the Fifth International Cystic Fibrosis Conference. Cystic Fibrosis Research Trust, London, 1969, p. 320-330. 2. McCrae, W. M. Management of cystic fibrosis. In J. Apley [ed.]. Modern trends in pediatrics. Vol. 4. Butterworth, London, 1974, p. 157--179. 3. Wood, R. Pseudomonas in cystic fibrosis. In "Gap" Conference Reports. National Cystic Fibrosis Research Foundation, Atlanta, 1974, p. 4-6. 4. Marks, M. I., Prentice, R.,Swarson,R., Cotton, E. K., Eickhoff, T. C. Carbenicillin and gentamicin: pharmacological studies in patients with cystic fibrosis and. pseudomonas infections. J. Pediatr. 79:822-828, 1971. 5. Huang, N. N" Hiller, E. J.,Macri, C. M., Capitanio, M., Cundy, K. R Carbenicillin in patients with cystic fibrosis: clinical pharmacology and therapeutic evaluation. J. Pediatr. 78:338-345, 1971. 6. Hawley, H. B., Lewis, R M., Swartz, D. R., Gump, D. W. Tobramycin therapy of pumonary infections in patients with cystic fibrosis. Curr. Ther. Res. 16:414-423, 1974. 7. Raeburn, J. A., Devine, J. D. Clindamycin levels in sputum in a patient with purulent chest disease due to cystic fibrosis. Postgrad, Med.47:366-367, 1971. 8. Raeburn, J. A., Devine J. D. Pharmacological findings during azidocillin treatment of chest infections. Scand. J. Infect. Dis. 5: 135-139, 1973.
Downloaded from http://jid.oxfordjournals.org/ at New York University on February 15, 2015
The mean levels of antibiotic in sputum achieved in patients from whom P. aeruginosa was eradicated did not differ significantly from the levels achieved in other patients who received the same dose. It may be of interest that three of these patients had the highest peak levels of tobramycin in sputum recorded during the study (0.88, 0.9, and 0.95 mg/I) . The patient who received 6 mg/kg per day did not at any time have a recorded level of antibiotic in sputum of > 0.65 mg/I. Side effects. No side effects attributable to treatment with tobramycin were noted during the trial or during the period of follow-up study.
