- Email: [email protected]
Antibiotic therapy in cystic fibrosis: Evaluation of clinical trials
Antibiotic therapy in cystic fibrosis: Evaluation of clinical trials Evaluation of antibiotic efficacy for infections in previously well individuals is based on eradication of the bacterium and resolution of the signs and symptoms of inflammation. In patients with cystic fibrosis, these criteria are less applicable: systemic signs of inflammation (fever, leukocytosis, and increased erythrocyte sedimentation rate) are variably present, and bacteria are present In the lower respiratory tract after clinical improvement. Administration of a variety of antibiotics produces resolution of subjective slgns and symptoms and improvement in pulmonary function tests. Because of the cost of therapy, the need to evaluate new and potentially toxic antibiotics, and the desire to provide optimum care, the evaluation of therapy needs to be objective. Controlled studies evaluating efficacy in a blinded fashion and assessing lung function and resolution of local pulmonary Inflammation may provide reliable data on antibiotic effectiveness in CF. (J PED!ATR1986;108(2):866-870) A r n o l d L. Smith, M.D. From the Division of infectious Disease, University of Washington, Children's Orthopedic Hospital and Medical Center, Seattle, Washington
Progressive pulmonary dysfunction in individuals with cystic fibrosis ultimately leads to death. Approximately 98% of the deaths among patients with CF who were older than 1 year of age are ascribed to pulmonary disease, and lung function is extremely compromised in the 3 months preceding death. In 10 men given treatment for 13 to 18 years, it was found that the vital capacity was 62% of that predicted for age and weight; and these men represent the survivors, inasmuch as one half of the C F population dies by 20 years of age. 1 Because of the almost uniform lethality of progressive pulmonary dysfunction in C F patients, medical intervention in this population has concentrated on the treatment of lung disease. Treatment consists of improving the pulmonary toilet, administration of antibiotics, and, occasionally, efforts to improve the strength of muscle groups used in respiration. ANTIBIOTIC
USAGE IN CF
Since their introduction into general medical usage, various antibiotics have been administered to individuals
with CF. Compared with other available forms of therapy for infectious diseases, such as immune serum, antibiotics were clearly efficacious. Because of the dramatic impact of antibiotics on clearly defined infectious diseases (e.g., pneumonia caused by Staphylococcus aureus), their effect in CF patients was not objectively evaluated. Initiation of antibiotic therapy on diagnosis of the disease correlated with an increased life span; thus, their activity was thought to be self-evident. Antibiotics h~ik,e been administered to C F patients for CF ESR
866
[
I
prophylaxis of lower airway colonization as well as for treatment of acute exacerbations. Although many of the chronic features of the disease are present during acute exacerbations, this article focuses on clinical trials examining treatment of acute exacerbations. TREATMENT
Reprint requests: Arnold L. Smith, M.D., Head, Division of Infectious Disease, Children's Orthopedic Hospital and Medical Center, 4800 Sand Point Way, N.E., Seattle, WA 98105.
Cystic fibrosis Erythrocyte sedimentation rate
OF ACUTE EXACERBATIONS
Patients with CF, during "well" periods, have chronic cough productive of variable amounts of sputum. An acute exacerbation is defined clinically as an exaggeration of
Volume 108 Number 5, Part 2
Antibiotic therapy in CF
867
Table I, Rate of eradication of Pseudomonas aeruginosa from sputum after specific antibiotic therapy Reference
Antibiotics administered
Eradication rate
Phair et al) Rabin et al.2 Michalsen and Bergan~2 Heilesen et al.4 McLaughlin et al. l~ Martin et al) 3
Carbenicillin and gentamicin Carbenicillin or ticarcillin and tobrarnycin Azlocillin and tobramycin Ceftazidime and tobramycin Azlocillin and tobramycin Carbenicillin or ticarcillin and tobrarnycin
0/13 11/19" 14/36 11/11 1/18 15/20t
*Studies were performedin onlyninepatients,but 36 treatmentcourses were reported. tTwenty treatmentcourseswere reported after studiesin 18 patients.
Table II. Variability of objective indices of infection in CF patients with acute exacerbation Patients with
ESR (mm/hr)
Reference
temperature >37.8* C
Mean
Phair et al) Parry et al.TM Parry and Neu 15 Prince and Neu t6 Heilesen et al:
11/13 30/42 12/13 NR NR
52.5 57 34 NR
WBC (I03/uI)
Range
Mean
Range
NR 8-142 18-128 1-98
15.0 12.9 12.2 13.2 15.4
9.0-28.0 4.9-25.5 6.4-18.3 10.7-17.5 4.4-24.7
NR, Not reported.pulmonary symptoms: dyspnea, increased cough, increased volume and changed appearance of sputum, and decreased appetite with occasional weight loss. It is not clear that a "trigger" causes the acute exacerbation. Air pollution, viral infections, and airborne pulmonary allergens have been suggested as precipitating agents. Therapy for acute exacerbations usually entails bed rest, antibiotic administration, and regular and intense chest physiotherapy. Other supportive care includes oxygen administration, increased attention to nutritional status, and maintenance of fluid and electrolyte balance. Chest physiotherapy seeks to supplement normal host defenses, removing bacteria and cell debris present in the airway and entrapped in sputum. Bacteria in mucus are swept to the central airways, from which they can be expectorated; chest physiotherapy augments this process. INFECTION IN ACUTE EXACERBATIONS Antibiotics are administered to patients with pulmonary exacerbation on the assumption that infection plays a role in the worsening of symptoms. Evidence of this role consists of the presence of bacteria in the normally sterile lower respiratory tract, the presence in sputum of polymorphonuclear leukocytes that are evident on Gram stain and may be grossly recognized because sputum is purulent, and the presence in sputum of serum proteins not present in pharmacologically induced sputum. The presence of these proteins implies capillary leakage secondary to inflammation. Despite the above-mentioned findings implicating bacte-
rial infection in acute exacerbation, considerable evidence exists to the contrary. 1. Bacteria often persist in the lower respiratory tract despite clinical improvement (Table I). Eradication of Pseudomonas aeruginosa from sputum depends on the susceptibility of the pathogen to the antibiotic and the dose and route of antibiotic administration. Rabin et al. 2 defined a sputum as "clear" of P. aeruginosa if no more than 10 colonies were found in 1 ml sputum. The presence of a mucoid capsule may also influence the rate of eradication of P. aeruginosa from sputum. One conclusion from the data in Table I is that eradication is variable. 2. Systemic manifestations Of infection, such as fever, are present in only one third of the patients. Similarly, the presence of peripheral leukocytosis is variable (Table II). Many reports contain only a passing comment regarding fever or leukocytosis or their resolution with treatment. Phair et al. 3 noted that of 13 children observed, 11 were febrile on admission, and the temperature decreased to <37.8~ in eight after antibiotic administration. In the same study, peripheral leukocyte count decreased in the eight patients clinically responsive to treatment: six nonresponsive children had "variable and inconsistent change in the WBC." In a Danish study4 in which all patients responded clinically, the mean peripheral leukocyte count decreased from 15,400 cells per microliter to 8,000 cells per microliter; however, in one patient the value had .increased in association with treatment and clinical improvement.
868
Smith
The Journal of Pediatrics May 1986
Table III. Comparison of antibiotic regimens for t r e a t m e n t of acute exacerbation in cystic fibrosis Outcome indicator
References
Dosage (mg/kg/ day)
Wientzen et al? 7
6
Beaudry et al. TM
200
Hyatt et al. 8
5 600 210
McLaughlin et al. 1~
210 400 280 300 6 300 6 300
Regimen Tobramycin vs Placebo Cloxacillin vs Gentamicin Carbenicillin Oxacillin vs Oxacillin Carbenicillin Sisomicin Ticarcillin Tobramycin vs Azlocillin Tobramycin vs Azlocillin
P. aeruginosa eradication (>2 log decrease)
Improved pulmonary function after treatment
Clinical response
11
3/7 1/8
4 0
11 7
10
11
0/11
FEV25-75 31.5 • 10.7
Score 3.7 + 0.5
10 14
11
3/11 0/6
35.8 • 10.7 FEV1 3.67 + 5.81 3.21 ___9.92
3.9 ___0.7 "'Failure" 7 3
VC 67 + 22
Duration (days)
No. of patients
7-14
14
9* 14
6/14
10
17
(Logs decrease)
10
18
2.5 2.0
71 +_ 24
Shwachman Score 69 + 11 71 • 13
10
16 2.0
69 • 11
68 • 13
FEV, Forced expiratory volume; VC, vital capacity. *Six patients were evaluated after nine courses.
Table IV. S p u t u m composition changes with respiratory i n f l a m m a t i o n Reference Burgi et al.9 Lopez-Vidriero and Reid" Boat and Matthews 19
Constituent
Value in normal sputum
DNA (mg/ml) LDH activity (U/L) Albumin (mg/dl) Transferrin (mol/ml) Chloride (mEq/L) Potassium (mEq/L)
1.10 ___0.80 0.17 _+ 0.14 26.2 _+ 8.0 0.9 + 0.2 162 ___60 13.2 + 5.4
Value in purulent sputum 0.17 1.80 122.8 1.6 75 28.0
+ 0.14 ___0.90 + 57.0 • 0.5 + 57 + 8.2
LDH, Lactate dehydrogenase. 3. Acute-phase r e a c t a n t s such as the E S R are variably increased in the s e r u m of patients with acute exacerbations (Table II). 4. T h e chest r o e n t g e n o g r a m m a y not change despite i m p r o v e m e n t in p u l m o n a r y status. Typical bronchial pneumonia (acute inflammation within the alveoli) is extremely rare. 5. P u l m o n a r y function appears to improve with hospitalization regardless of t h e types of antibiotics administered. Serial studies of p u l m o n a r y function in children with C F hospitalized for acute exacerbation show improvem e n t ? 7 T h e p u l m o n a r y function tests t h a t most closely reflected subjective clinical i m p r o v e m e n t were vital capacity, the forced expiratory volume in 1 second, and the ratio
of residual volume to total lung capacity. In one of these studies, 5 the arterial oxygen saturation increased; in another, 7 the exercise capacity improved. These data suggest t h a t lung f u n c t i o n per se a n d not test p e r f o r m a n c e is improved by hospital t r e a t m e n t . In all of these studies, antibiotics were administered; in one, 7 the dosages were not stated. Thus, the exact role of antibiotics in disease remission remains unclear. Trials of antibiotic therapy in individuals with C F have tended to evaluate outcome by subjective criteria. Few have sought to control for confounding variables, a n d flaws exist in each study. However, from the available data ( T a b l e III), antipseudomonal antibiotics a p p e a r to be beneficial for the t r e a t m e n t of acute exacerbation.
Volume 108 Number 5, Part 2 E V A L U A T I O N OF A N T I B I O T I C THERAPY Traditionally, efficacy of antibiotic administration for treatment of a bacterial infection has been defined as resolution of systemic and local signs of inflammation and eradication of the organism. Antibiotic treatment of acute exacerbation is associated with improvement in clinical status, but P. aeruginosa is variably eradicated (Table I). Similarly, systemic manifestations of infection, such as fever and leukocytosis, are also variably present in patients with an acute exacerbation (Table II). As a result, these clinical indicators cannot be reliably used as an index of resolution of the infection. Local inflammation has been assessed by sputum examination in some studies. However, the subjective nature of scoring sputum as purulent, mucoid, or mucopurulent leads to large interobserver errors and unreliable assessment. Direct measurement of inflammatory products in sputum might objectively define sputum as purulent. Data exist indicating that purulent sputum differs significantly in composition from normal sputum (Table IV). The DNA in sputum is derived almost exclusively from disintegrating polymorphonuclear leukocytes. Sloughing respiratory epithelial cells contribute a small amount; the contribution by the bacteria is negligible. Thus, measurement of sputum DNA may objectively indicate the magnitude of leukocyte infiltration or purulence.8 Capillary leakage of plasma proteins occurs in the sites of inflammation. Albumin concentration in sputum may indicate the magnitude of the capillary leakage associated with acute endobronchial inflammation2 Quantitative sputum cultures have been used to assess antibiotic therapy in CF. 1~11 This approach assumes that the pathogen is present in the infectious forms at densities > 105 bacteria per milliliter. This asstimption is true for urinary tract infections and in distinguishing P. aeruginosa colonization of burn wounds f r o m those infected. A decrease in the density of P. aeruginosa in sputum should occur if active antibiotic concentrations are achieved within the bronchial lumen. As has been published] ~ a decrease in sputum P. aeruginosa density is associated with antibiotic administration; the decrement is dependent on administration of antipseudomonal antibiotics) Thus, this technique holds promise as an additional objective way of evaluating antibiotic therapy in CF. CONCLUSION Antibiotic administration is associated with improvement in che quality of life and longer life expectancy in CF patients. Because of the unique features of endobronchial infection in CF, the usual indicators of resolution are not
Antibiotic therapy in CF
869
reliable. Subjective evaluation of outcome remains the primary standard by which antibiotics are compared. Performed in a blind fashion with appropriate controls, this approach can yield meaningful data. Precise statistical evaluation of outcome appears possible by quantitatively assessing infection, in terms of organism density, and the magnitude of the inflammatory response, in terms of sputum DNA and albumin content. Such an approach is necessary to define the potential benefit of new, expensive, and, in some cases, potentially toxic aotibiotics. REFERENCES 1. Wood RE, Boat TF, Doershuk CF. Cystic fibrosis. Am Rev Respir Dis 1976;113:833-878. 2. Rabin HR, Harley FL, Bryan LE, et al. Evaluation of a high dose tobramycin and ticareillin treatment protocol in cystic fibrosis based on improved susceptibility criteria and antibiotic pharmacokinetics. Proc Eighth Int Cystic Fibrosis Congress, Toronto, Canada, May 1980. 3. Phair JP, Tan JS, Watanakunakorn C, et al. Carbenicillin treatment of Pseudomonas pulmonary infection. Am J Dis Child 1970;120:22-25. 4. Heilesen AM, Permin H, Koch C, et al. Treatment of chronic Pseudomonas aeruginoas infection in cystic fibrosis patients with ceftazidime and tobramycin. Scand J Infect Dis 1983;15:271-276. 5. Strieder DJ, Khaw KT, Simpser M, et al. In-hospital treatment of chronic lung disease in cystic fibrosis: improved lung function. Seventh International Cystic Fibrosis Congress. Paris: Boehringer Mannheim France SA, 1978. 6. Redding GJ, Restuccia R, Cotton EK, et al. Serial changes in pulmonary functions in children hospitalized with cystic fibrosis. Am Rev Respir Dis 1982;126:31-36. 7. Cerny FJ, Cropp GJA, Bye MR. Hospital therapy improves exercise tolerance and lung function in cystic fibrosis. Am J Dis Child 1984;138:261-265. 8. Hyatt AC, Chipps BE, Kumor KM, et al. A double-blind controlled trial of anti-Pseudomonas chemotherapy of acute respiratory exacerbations in patients with cystic fibrosis. J PEDIATR1981;99:307-314. 9. Burgi H, Wiesmann U, Richterich R, et al. New objective criteria for inflammation in bronchial secretions. Br Med J 1968;2:654-656. 10. McLaughlin FJ, Matthews WJ Jr, Strieder DJ, et al. Clinical and bacteriological rsponses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo. J Infect Dis 1983;147:559-567. 11. Lopez-Vidriero MT, Reid L: Bronchial mucus in health and disease. Br Med Bull 1978;34:63-74. 12. Michalsen H, Bergan T. Azlocillin with and without an aminoglycosideagainst respiratory tract infectionsin children with cystic fibrosis. Scand J Infect Dis 1981;29(suppl):9297. 13. Martin AJ, Smally CA, George RH, et al. Gentamicin and tobramycin compared in the treatment of mucoid Pseudomonas lung infections in cystic fibrosis. Arch Dis Child 1980;55:604-607.
8 70
Smith
14. Parry MF, Neu HC, Merlino M, et al. Treatment of pulmonary infections in patients with cystic fibrosis: comparative study of ticarcillin and gentamicin. J PEDIATR 1977;90:144-148. 15. Parry MF, Neu HC. Tobramycin and ticarcillin therapy for exacerbations of pulmonary disease in patients with cystic fibrosis. J Infect Dis 1976;134(suppl):S194-S197. 16. Prince AS, Neu HC. Use of piperacillin, a semisynthetic penicillin, in the therapy of acute exacerbations of pulmonary d!sease in patients with cystic fibrosis. J PEDIATR 1980; 97-1-48-151.
The Journal of Pediatrics May 1986
17. Wientzen R, Prestidge CB, Kramer RI, et al. Acute pulmonary exacerbations in cystic fibrosis. Am J Dis Child 1980; t34:1134-1138. 18. Beaudry PH, Marks MI, McDougall D, et al. Is antiPseudomonas therapy warranted in acute respiratory exacerbations in children with cystic fibrosis? J PEDIATR 1~980; 97:144-147. 19. Boat T, Matthews LN. In: Dulfano M J, ed. Sputum fundamentals and clinical pathology. Springfield, II1.: Charles C Thomas, 1973;243-274.
Progressive pulmonary dysfunction in individuals with cystic fibrosis ultimately leads to death. Approximately 98% of the deaths among patients with CF who were older than 1 year of age are ascribed to pulmonary disease, and lung function is extremely compromised in the 3 months preceding death. In 10 men given treatment for 13 to 18 years, it was found that the vital capacity was 62% of that predicted for age and weight; and these men represent the survivors, inasmuch as one half of the C F population dies by 20 years of age. 1 Because of the almost uniform lethality of progressive pulmonary dysfunction in C F patients, medical intervention in this population has concentrated on the treatment of lung disease. Treatment consists of improving the pulmonary toilet, administration of antibiotics, and, occasionally, efforts to improve the strength of muscle groups used in respiration. ANTIBIOTIC
USAGE IN CF
Since their introduction into general medical usage, various antibiotics have been administered to individuals
with CF. Compared with other available forms of therapy for infectious diseases, such as immune serum, antibiotics were clearly efficacious. Because of the dramatic impact of antibiotics on clearly defined infectious diseases (e.g., pneumonia caused by Staphylococcus aureus), their effect in CF patients was not objectively evaluated. Initiation of antibiotic therapy on diagnosis of the disease correlated with an increased life span; thus, their activity was thought to be self-evident. Antibiotics h~ik,e been administered to C F patients for CF ESR
866
[
I
prophylaxis of lower airway colonization as well as for treatment of acute exacerbations. Although many of the chronic features of the disease are present during acute exacerbations, this article focuses on clinical trials examining treatment of acute exacerbations. TREATMENT
Reprint requests: Arnold L. Smith, M.D., Head, Division of Infectious Disease, Children's Orthopedic Hospital and Medical Center, 4800 Sand Point Way, N.E., Seattle, WA 98105.
Cystic fibrosis Erythrocyte sedimentation rate
OF ACUTE EXACERBATIONS
Patients with CF, during "well" periods, have chronic cough productive of variable amounts of sputum. An acute exacerbation is defined clinically as an exaggeration of
Volume 108 Number 5, Part 2
Antibiotic therapy in CF
867
Table I, Rate of eradication of Pseudomonas aeruginosa from sputum after specific antibiotic therapy Reference
Antibiotics administered
Eradication rate
Phair et al) Rabin et al.2 Michalsen and Bergan~2 Heilesen et al.4 McLaughlin et al. l~ Martin et al) 3
Carbenicillin and gentamicin Carbenicillin or ticarcillin and tobrarnycin Azlocillin and tobramycin Ceftazidime and tobramycin Azlocillin and tobramycin Carbenicillin or ticarcillin and tobrarnycin
0/13 11/19" 14/36 11/11 1/18 15/20t
*Studies were performedin onlyninepatients,but 36 treatmentcourses were reported. tTwenty treatmentcourseswere reported after studiesin 18 patients.
Table II. Variability of objective indices of infection in CF patients with acute exacerbation Patients with
ESR (mm/hr)
Reference
temperature >37.8* C
Mean
Phair et al) Parry et al.TM Parry and Neu 15 Prince and Neu t6 Heilesen et al:
11/13 30/42 12/13 NR NR
52.5 57 34 NR
WBC (I03/uI)
Range
Mean
Range
NR 8-142 18-128 1-98
15.0 12.9 12.2 13.2 15.4
9.0-28.0 4.9-25.5 6.4-18.3 10.7-17.5 4.4-24.7
NR, Not reported.pulmonary symptoms: dyspnea, increased cough, increased volume and changed appearance of sputum, and decreased appetite with occasional weight loss. It is not clear that a "trigger" causes the acute exacerbation. Air pollution, viral infections, and airborne pulmonary allergens have been suggested as precipitating agents. Therapy for acute exacerbations usually entails bed rest, antibiotic administration, and regular and intense chest physiotherapy. Other supportive care includes oxygen administration, increased attention to nutritional status, and maintenance of fluid and electrolyte balance. Chest physiotherapy seeks to supplement normal host defenses, removing bacteria and cell debris present in the airway and entrapped in sputum. Bacteria in mucus are swept to the central airways, from which they can be expectorated; chest physiotherapy augments this process. INFECTION IN ACUTE EXACERBATIONS Antibiotics are administered to patients with pulmonary exacerbation on the assumption that infection plays a role in the worsening of symptoms. Evidence of this role consists of the presence of bacteria in the normally sterile lower respiratory tract, the presence in sputum of polymorphonuclear leukocytes that are evident on Gram stain and may be grossly recognized because sputum is purulent, and the presence in sputum of serum proteins not present in pharmacologically induced sputum. The presence of these proteins implies capillary leakage secondary to inflammation. Despite the above-mentioned findings implicating bacte-
rial infection in acute exacerbation, considerable evidence exists to the contrary. 1. Bacteria often persist in the lower respiratory tract despite clinical improvement (Table I). Eradication of Pseudomonas aeruginosa from sputum depends on the susceptibility of the pathogen to the antibiotic and the dose and route of antibiotic administration. Rabin et al. 2 defined a sputum as "clear" of P. aeruginosa if no more than 10 colonies were found in 1 ml sputum. The presence of a mucoid capsule may also influence the rate of eradication of P. aeruginosa from sputum. One conclusion from the data in Table I is that eradication is variable. 2. Systemic manifestations Of infection, such as fever, are present in only one third of the patients. Similarly, the presence of peripheral leukocytosis is variable (Table II). Many reports contain only a passing comment regarding fever or leukocytosis or their resolution with treatment. Phair et al. 3 noted that of 13 children observed, 11 were febrile on admission, and the temperature decreased to <37.8~ in eight after antibiotic administration. In the same study, peripheral leukocyte count decreased in the eight patients clinically responsive to treatment: six nonresponsive children had "variable and inconsistent change in the WBC." In a Danish study4 in which all patients responded clinically, the mean peripheral leukocyte count decreased from 15,400 cells per microliter to 8,000 cells per microliter; however, in one patient the value had .increased in association with treatment and clinical improvement.
868
Smith
The Journal of Pediatrics May 1986
Table III. Comparison of antibiotic regimens for t r e a t m e n t of acute exacerbation in cystic fibrosis Outcome indicator
References
Dosage (mg/kg/ day)
Wientzen et al? 7
6
Beaudry et al. TM
200
Hyatt et al. 8
5 600 210
McLaughlin et al. 1~
210 400 280 300 6 300 6 300
Regimen Tobramycin vs Placebo Cloxacillin vs Gentamicin Carbenicillin Oxacillin vs Oxacillin Carbenicillin Sisomicin Ticarcillin Tobramycin vs Azlocillin Tobramycin vs Azlocillin
P. aeruginosa eradication (>2 log decrease)
Improved pulmonary function after treatment
Clinical response
11
3/7 1/8
4 0
11 7
10
11
0/11
FEV25-75 31.5 • 10.7
Score 3.7 + 0.5
10 14
11
3/11 0/6
35.8 • 10.7 FEV1 3.67 + 5.81 3.21 ___9.92
3.9 ___0.7 "'Failure" 7 3
VC 67 + 22
Duration (days)
No. of patients
7-14
14
9* 14
6/14
10
17
(Logs decrease)
10
18
2.5 2.0
71 +_ 24
Shwachman Score 69 + 11 71 • 13
10
16 2.0
69 • 11
68 • 13
FEV, Forced expiratory volume; VC, vital capacity. *Six patients were evaluated after nine courses.
Table IV. S p u t u m composition changes with respiratory i n f l a m m a t i o n Reference Burgi et al.9 Lopez-Vidriero and Reid" Boat and Matthews 19
Constituent
Value in normal sputum
DNA (mg/ml) LDH activity (U/L) Albumin (mg/dl) Transferrin (mol/ml) Chloride (mEq/L) Potassium (mEq/L)
1.10 ___0.80 0.17 _+ 0.14 26.2 _+ 8.0 0.9 + 0.2 162 ___60 13.2 + 5.4
Value in purulent sputum 0.17 1.80 122.8 1.6 75 28.0
+ 0.14 ___0.90 + 57.0 • 0.5 + 57 + 8.2
LDH, Lactate dehydrogenase. 3. Acute-phase r e a c t a n t s such as the E S R are variably increased in the s e r u m of patients with acute exacerbations (Table II). 4. T h e chest r o e n t g e n o g r a m m a y not change despite i m p r o v e m e n t in p u l m o n a r y status. Typical bronchial pneumonia (acute inflammation within the alveoli) is extremely rare. 5. P u l m o n a r y function appears to improve with hospitalization regardless of t h e types of antibiotics administered. Serial studies of p u l m o n a r y function in children with C F hospitalized for acute exacerbation show improvem e n t ? 7 T h e p u l m o n a r y function tests t h a t most closely reflected subjective clinical i m p r o v e m e n t were vital capacity, the forced expiratory volume in 1 second, and the ratio
of residual volume to total lung capacity. In one of these studies, 5 the arterial oxygen saturation increased; in another, 7 the exercise capacity improved. These data suggest t h a t lung f u n c t i o n per se a n d not test p e r f o r m a n c e is improved by hospital t r e a t m e n t . In all of these studies, antibiotics were administered; in one, 7 the dosages were not stated. Thus, the exact role of antibiotics in disease remission remains unclear. Trials of antibiotic therapy in individuals with C F have tended to evaluate outcome by subjective criteria. Few have sought to control for confounding variables, a n d flaws exist in each study. However, from the available data ( T a b l e III), antipseudomonal antibiotics a p p e a r to be beneficial for the t r e a t m e n t of acute exacerbation.
Volume 108 Number 5, Part 2 E V A L U A T I O N OF A N T I B I O T I C THERAPY Traditionally, efficacy of antibiotic administration for treatment of a bacterial infection has been defined as resolution of systemic and local signs of inflammation and eradication of the organism. Antibiotic treatment of acute exacerbation is associated with improvement in clinical status, but P. aeruginosa is variably eradicated (Table I). Similarly, systemic manifestations of infection, such as fever and leukocytosis, are also variably present in patients with an acute exacerbation (Table II). As a result, these clinical indicators cannot be reliably used as an index of resolution of the infection. Local inflammation has been assessed by sputum examination in some studies. However, the subjective nature of scoring sputum as purulent, mucoid, or mucopurulent leads to large interobserver errors and unreliable assessment. Direct measurement of inflammatory products in sputum might objectively define sputum as purulent. Data exist indicating that purulent sputum differs significantly in composition from normal sputum (Table IV). The DNA in sputum is derived almost exclusively from disintegrating polymorphonuclear leukocytes. Sloughing respiratory epithelial cells contribute a small amount; the contribution by the bacteria is negligible. Thus, measurement of sputum DNA may objectively indicate the magnitude of leukocyte infiltration or purulence.8 Capillary leakage of plasma proteins occurs in the sites of inflammation. Albumin concentration in sputum may indicate the magnitude of the capillary leakage associated with acute endobronchial inflammation2 Quantitative sputum cultures have been used to assess antibiotic therapy in CF. 1~11 This approach assumes that the pathogen is present in the infectious forms at densities > 105 bacteria per milliliter. This asstimption is true for urinary tract infections and in distinguishing P. aeruginosa colonization of burn wounds f r o m those infected. A decrease in the density of P. aeruginosa in sputum should occur if active antibiotic concentrations are achieved within the bronchial lumen. As has been published] ~ a decrease in sputum P. aeruginosa density is associated with antibiotic administration; the decrement is dependent on administration of antipseudomonal antibiotics) Thus, this technique holds promise as an additional objective way of evaluating antibiotic therapy in CF. CONCLUSION Antibiotic administration is associated with improvement in che quality of life and longer life expectancy in CF patients. Because of the unique features of endobronchial infection in CF, the usual indicators of resolution are not
Antibiotic therapy in CF
869
reliable. Subjective evaluation of outcome remains the primary standard by which antibiotics are compared. Performed in a blind fashion with appropriate controls, this approach can yield meaningful data. Precise statistical evaluation of outcome appears possible by quantitatively assessing infection, in terms of organism density, and the magnitude of the inflammatory response, in terms of sputum DNA and albumin content. Such an approach is necessary to define the potential benefit of new, expensive, and, in some cases, potentially toxic aotibiotics. REFERENCES 1. Wood RE, Boat TF, Doershuk CF. Cystic fibrosis. Am Rev Respir Dis 1976;113:833-878. 2. Rabin HR, Harley FL, Bryan LE, et al. Evaluation of a high dose tobramycin and ticareillin treatment protocol in cystic fibrosis based on improved susceptibility criteria and antibiotic pharmacokinetics. Proc Eighth Int Cystic Fibrosis Congress, Toronto, Canada, May 1980. 3. Phair JP, Tan JS, Watanakunakorn C, et al. Carbenicillin treatment of Pseudomonas pulmonary infection. Am J Dis Child 1970;120:22-25. 4. Heilesen AM, Permin H, Koch C, et al. Treatment of chronic Pseudomonas aeruginoas infection in cystic fibrosis patients with ceftazidime and tobramycin. Scand J Infect Dis 1983;15:271-276. 5. Strieder DJ, Khaw KT, Simpser M, et al. In-hospital treatment of chronic lung disease in cystic fibrosis: improved lung function. Seventh International Cystic Fibrosis Congress. Paris: Boehringer Mannheim France SA, 1978. 6. Redding GJ, Restuccia R, Cotton EK, et al. Serial changes in pulmonary functions in children hospitalized with cystic fibrosis. Am Rev Respir Dis 1982;126:31-36. 7. Cerny FJ, Cropp GJA, Bye MR. Hospital therapy improves exercise tolerance and lung function in cystic fibrosis. Am J Dis Child 1984;138:261-265. 8. Hyatt AC, Chipps BE, Kumor KM, et al. A double-blind controlled trial of anti-Pseudomonas chemotherapy of acute respiratory exacerbations in patients with cystic fibrosis. J PEDIATR1981;99:307-314. 9. Burgi H, Wiesmann U, Richterich R, et al. New objective criteria for inflammation in bronchial secretions. Br Med J 1968;2:654-656. 10. McLaughlin FJ, Matthews WJ Jr, Strieder DJ, et al. Clinical and bacteriological rsponses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo. J Infect Dis 1983;147:559-567. 11. Lopez-Vidriero MT, Reid L: Bronchial mucus in health and disease. Br Med Bull 1978;34:63-74. 12. Michalsen H, Bergan T. Azlocillin with and without an aminoglycosideagainst respiratory tract infectionsin children with cystic fibrosis. Scand J Infect Dis 1981;29(suppl):9297. 13. Martin AJ, Smally CA, George RH, et al. Gentamicin and tobramycin compared in the treatment of mucoid Pseudomonas lung infections in cystic fibrosis. Arch Dis Child 1980;55:604-607.
8 70
Smith
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