Endotracheal Antibiotics for the Prevention of Tracheobronchial Infections in Tracheotomized Unconscious Patients*

Endotracheal Antibiotics for the Prevention of Tracheobronchial Infections in Tracheotomized Unconscious Patients* A Comparative Study of and Aminosidin 8 Combination Jean Klastersky, M.D.; Colette Hensgens, M.D.; Jacques Noternum, M.D.; Emile Mouau;ad, M.D.;t Francoise Meunier-Carpentier, M.D. Endotracheal administration of gentamicin has been compared to the endotracheal administration of aminosidin plus polymyxin B as a preventive measure against tracheobronchial infections in 25 and tracheotomized patients respectively who had been admitted to a neurosurgical unit. Both series were comparable as far as underlying disease, duration of hospitalization, surgical therapy. Both regimens were similarly effective from the bacteriologic and clinical points of view. Both regimens were similarly effective in preventing colonization of bronchial secre- tions by potential pathogens and were associated with a similar frequency of infectious episodes (eight in each group). The use of aminosidin-polymyxin B combination was associated with a lower incidence of emergence of gentamicin resistant strains, but the endotracheal administration of gentamicin was better tolerated than that of the combination. It is concluded that the combination of aminosidin-polymyxin is a useful alternative to gentamicin for the prevention of bronchopulmonary infections In unconscious tracheotomized patients. } n earlier studies from this laboratory, we have shown that gentamicin administered endotracheally to patients with serious neurologic diseases prevented a significant number of tracheobronchial infections. 1 The tolerance of this antimicrobial regimen has been satisfactory, but emergence of gentamicin-resistant strains, namely Providence, Pseudomonas and Klebsiella has been observed in the patients receiving endotracheal gentamicin.l2 This is why we have attempted to prevent colonization and superinfection of the tracheobronchial tree in tracheotomized patients with a combination of aminosidin-a new aminoglycoside antibiotic, the antimicrobial spectrum and pharmacologic properties of which are similar to those of kanamycin 3 -and polymyxin B in order to limit the emergence of gentamicin-resistant strains in our hospital. B has been used previously for the prevention of the colonization of the upper respiratory tract by nosocomial gram-negative micro- 0 Service de Medecine et Laboratoire d'investigation Clinique (Section des Maladies Infectieuses), Institut Jules Bordet, Brussels, Belgium. 0 Ciinique Neurochirurgicale, Universite Libre de Bmxelles. tservice d' Anesthesiologie, lnstitut Jules Bordet. Manuscript received November 13; revision accepted January 27. Reprint requests: Dr. KlaYtersky, Institut jules Bordet, 1 rue Jleger-Bordet, 1000 Brussels, Belgium 302 KLASTERSKY ET AL organisms, but the drug was given as an aerosol. 3.4 Limited clinical experience with endobronchial polymyxin in chronic bronchitis has also been reported.5 In addition, the preventive administration of polymyxin combined with an aminoglycoside has been used successfully to prevent the colonization of the urinary tract of patients with indwelling bladder catheters. 6 It will be shown here that the use of the aminosidin-polymyxin B combination and that of gentamicin resulted in a similar clinical effectiveness in the prevention of tracheobronchial infections in unconscious tracheotomized patients. MATERIAL AND METHODS All patients in this series were consecutively hospitalized in the intensive care neurosurgical unit at the lnstitut Jules Bordet; all were admitted to the study commencing on the day of the tracheostomy. Patients who died within 48 hours of their admission to the study, and those who were infected at the time of the admission and/ or were receiving systemic antibiotics were excluded. or the combination aminosiclin-polymyxin was allocated to the consecutive patients a ~ detennined by a preavailable random choice. The dosage of gentamicin w a 80 ~ mg tid and that for the combination was aminosidin : 250 mg plus pol}lllyxin 50 mg tid. The endotracheal treatment w a administered ~ as follows : a plastic catheter was introduced deeply into the trachea and

~ o. Table 1--Characteri tic of the Patient Studied patients No. men Mean age (years) Age range (years) Underlying disease Trauma Hemorrhage Tumor Other Previous or associated therapy Craniotomy Corticosteroids Antibiotics Respirator Follow-up Cumulative No. days Duration of hospitalization mean range Cumulative No. cultures of sputum Cumulative No. cultures of urine Cumulative No. x-ray films, chest Cumulative No. WBC counts 25 17 39.5 9-65 6 1 12 19 5 7 441 17.6 6-32 109 (4.3) 117 (4.7) 61 (2.4) 128 (5.1) Aminosidin + 44.2 18-76 2 I 3 11 18 4 7 353.0 6-27 96 (4.3) 94 (4.3) 54 (2.4) 118 (5.4) one patient with coma caused by barbiturate intoxication in the gentamicin group; 2 patients with carotid artery thrombosis and 1 patient with encephalomyelitis in the aminosidin-polymyxin group. Numbers in brackets indicate means for individual patients the antibiotics, dissolved in a total volume of 10 ml of saline solution, were injected slowly. Injections were performed three times daily, once with the patient lying in left lateral decubitus, once in right lateral decubitus and onoe in dorsal decubitus position. Apart from the endotracheal injections, the patients were managed routinely; frequent aspirations of bronchial secretions were performed in all. Systemic antibiotics were administered only when a bacterial infection was extremely likely on the basis of fever, leukocytosis and other clinical signs and symptoms. In these cases, systemic antibiotics were discontinued 48 hours after clinical improvement had occurred. Most patients in this series had an indwelling bladder catheter with a continuous rinse with sterile saline solution containing 0.25 percent of acetic acid through a three-way catheter. The effect of the endotracheal treatment on the respiratory flora was assessed by twice weekly cultures of the tracheal aspirates. Serum and blood samples were also obtained twice a week for the determination of urea, creatinine and white blood cell levels. Urine was cultured twice weekly and chest x-rays films were taken for most patients before and after therapy. The identification of all microorganisms isolated from the patients in this series was performed by routine methods. Sputum was inoculated semiquantitatively on blood agar and eosin methylene blue plates. Positive tracheal aspirates were those containing 1,000 colony-forming units per mi. For each sample, we considered the predominant aerobic microorganism only. Anaerobic cultures of the bronchial secretions were performed by the gas-pack system and blood-agar plates with and without gentamicin. Minimum inhibitory concentrations ( MIC) of gentamicin, polymyxin B and aminosidin were determined by the inoculareplicating methods using an inoculum containing approximately 104 to 1()5 viable organisms per mi. Mueller-Hinton medium ( BBL) was used throughout. Samples of bronchial secretions and sera for the determination of the antibacterial activity were collected several times from most p a t i eon n l ~ various days of therapy. They were obtained one hour after the endotracheal administration. The spntmn samples were prepared for assay by adding 1/ 3 vohune of saline to I vohune of spuhun. The mixture was homogenized and centrih ged at 1,500 rpm for 10 minutes. The supernatant, as well as the samples of serum were kept at -20 C until used. The estimation of the antibacterial activity of the samples of serum and sputum was performed by a standard tube dilution method using trypticase soy broth ( BBL) as a diluent and a strain of Ps aeruginosa and Staph aureus whose MIC for gentamicin, aminosidin and polymyxin B were respectively >S0-0.3, >50-0.3 and 0.002->SO 1-'g/ml. All the determinations were done in triplicate. Serum and sputum samples were held for 30 min at 56 C before the assay to destroy nonspecific bacteriostatic activity. REsULTS As indicated in Table 1, the two groups of patients studied here were comparable. Age and sex were similarly distributed in both groups, as well as the underlying neurologic diseases. A similar proportion of the patients in both groups underwent craniotomy, received assisted respiration, high doses of dexamethasone or were treated with antibiotics (usually penicillin or ampicillin) during the week preceding their admission to the study. The total duration of the study was 441 and 353 No. patients Cultures of sputum Purulent sputa Positive sputa Table 2-Bacteriologic and Clinical Re ult Mean value (and range) 4.3 (1-9) 3.6 (1-9) 2.1 (0-9) Culture of urine 4.7 (1-12) Purulent urine 3.1 (1-12) Positive urine 1.2 (0-6) WBC counts 5.1 (1-9) WBC counts> 10,000/ mm 1 3.9 (1-7) Chest x-ray films 2.4 (1-7) Abnormal chest x-ray findings 0.8 (0-6) Cumulative results(% ) 25 109 92 (84.4) 52 (47.7) 117 78 (66.6) 32 (27.3) 128 97 (75.7) 61 20 (32.7) Aminosidin + Mean value (and range) 4.3 (1-10) 3.0 (1-9) 2.3 (1-7) 4.3 (1-14) 3.0 (1-10) 1.5 (0-5) 5.4 (1-10) 4.4 (1-6) 2.4 (1-8) 1.2 (0-4) Cumulative results(% ) 96 66 (68.7) 51 (53.1) 94 68 (72.3) 34 (36.1) 118 98 (83.0) 54 28 (51.8) PREVENTION OF TRACHEOBRONCHIAL INFECTIONS 303

Table 3--Bacteriologic Finding in th-e Bronchial Secretion of the Treated Patient :\'o. po::;itive cultures ~ o n e l 2 3 4 5 and more than 5 Endotraeheal therapy No. patients 6 5 7 5 1 4 8 4 1 1 2 3 Aminosidin Microorganisms in sputum No. positive cultures (%) E coli 1 (1.9) HPrrat ia-klebsiella-enterobacter 15 (28.8) 3 (5.9) l'roteus-providence Ps aeruginosa Staph aureus Pneumococcus Htn ptococcus ({3 hemolytic) H inj/uenzae Y1 asts 2 (3.8) 18 (34.6) 2 (3.8) 7 (13.4) 8 (15.4} l (1.9) (43.1) 3 (5.9) 11 (21.5) l (1.9) 9 (17.6) + days for the gentamicin-treated and aminosidin/ polymyxin treated groups, respectively. Similar numbers of cultures of sputum and urine per patient were obtained in the two groups; similar numbers of white blood cell counts and chest x-ray films were performed for each patient in the two groups studied. The mean duration of the study and its range was similar in the two groups. In the present study, bacteriologic data will be presented as cumulative results for all the patients rather than means for individual patients. The number of specimens taken on each patient varied a great deal as a result of the duration of the patient's stay in the hospital. However, the distribution of the duration of the hospitalization was similar in both groups. Table 2 indicates that the frequency with which purulent or bacteriologically positive sputum and urine were found in the two groups was similar. Although positive sputum and urine were found more often in the patients who received aminosidin plus polymyxin endotracheally, the differences between the two groups were not significant at the 0.05 level (chi square test analysis). The frequency with which positive cultures of the bronchial secretions were obtained here for gentamicin-treated and aminosidin/polymyxin-treated patients, 47.7 percent and 53.1 percent respectively, are similar to the figures obtained in gentamicin-treated patients treated earlier in his hospital ( 56.5 percent). Positive cultures of the bronchial secretions in tracheotomized patients who received normal saline solution without antibiotics were found in 79.3 percent and 80.0 percent of the patients. 1 7 A high 304 KLASTERSKY ET AL ( < 10,000/ mm 3 ) white blood cell count was also found with a similar frequency in the two series of patients, but abnormal chest x-ray film findings were significantly more frequent ( l = 4.28; P<0.05) in the patients who received aminosidin plus polymyxin endotracheally. However, abnormal chest x ray film findings, ie a film indicating the presence of a pulmonary infiltrate, is not per se an adequate indication of pulmonary infection in the patients studied here. It has been shown that in patients with cranial injuries, a wide variety of pulmonary lesions may occur, a small number of which are infectious in origin. 8 Table 3 shows the similarity of distribution of patients in both groups with multiple positive cultures. A striking difference, however, was observed with respect to the nature of the offending microorganism recovered from the sputum in the two groups. Klebsiella was recovered in 28.8 percent of the specimens obtained from patients who received gentamicin and in only 5.9 percent of those from Table 4--Clinical Re ull6 Obtained with the Endotracheal Regimena No. patients 25 Cumulative No. days 441 Cumulative No. days on antihiotics 353 Aminosidin + 94 (21.3/100 days) 76 (21.5/ 100 days) No. episodes of antibiotic therapy (3.6/100 days) 12 (3.4 / 100 days) No. provpd infections 8 ~ 8# ~ o. pulmonary infections 5 6t No. urinary infections 2 0 ~ o. other infections u 2 No. suspected infections 6 4 No. pulmonary infections 2 2 No. deaths 9 6 No. deaths from infection 2 2 Serratia:!; Pneumococcus:!; Klebsiella:l (was associated with septicemia); Ps aeruginosa :2 E coli :l; Enterococcus:! ttj hemolytic Streptococcus : 1 ; Pneumococcus :3; Ps aeruginosa :2 tsepticemia caused by Streptococcus rrirulans (? Pndocarditis) Septicemia caused by Herellea (source unknown) and mpningitis + septicemia due to Ps aeruginosa ~ bacteremias: 2 Streptococcus ~ i r i < : il ; aklchsiella:l n s #2 bacteremias: Herellea:l; Ps aeruginosa:l ~ a n in d each # : group, one patient not included in this series was admitted with bacteremia caused by Ps aeruginosa and died within 48 hours after admission

aminosidin-polymyxin treated patients. This difference is statistically significant (/ = 9.41; P<0.01 ). On the other hand, Ps aeruginosa, the most frequent isolate in both groups, and pneumococci were found more frequently in the patients who received aminosidin plus polymyxin. The difference between the two groups was not statistically significant. Many of the strains, including 13 of the 15 Klebsiella strains isolated in gentamicin-treated patients were relatively resistant to gentamicin (MIC ~ 6 p.gjml). The mean MIC of gentamicin for the enterobacteriacae and Ps aeruginosa was 6.0 p.g/ml in the bacteria from gentamicin-treated patients and 1.5 J.Lgl ml in the other group. Positive isolates from the bronchial secretions were found more often as the duration of the hospital stay increased. No difference in this respect could be found between the patients who received the combination or gentamicin. Anaerobic microorganisms, most often Bacteroides, were found in patients in each series; in most instances these bacteria were found to be associated with aerobic microorganisms and their clinical significance was thus difficult to evaluate. Systemic antibiotics were given with similar frequency and for similar periods of time in both groups (Table 4). The number of bacteriologicallyproved infections, namely pulmonary infections, was identical in both groups. All these infections, in the gentamicin-treated group, were caused by gentamicin-resistant strains (MIC ~ 6 1-'-g/ml). Resistance to aminosidin or polymyxin B was not always present in the strains that were responsible for the infections in the aminosidin-polymyxin group. Death which could be attributed to infection occurred in two patients in each series. Significant antibacterial activity could be demonstrated in the bronchial secretions of the treated patients (Table 5). That some of the antibiotics were absorbed systemically from the endotracheal Table 5--Antibacterial Actimt:r in Serum and Sputum* SERCM Genta- Amino- Poly- sidin t myxin Bt micin 8 4 2 64 SPCTFM Amino- Polysidin t myxin Bt 8 ( <2-8) ( <2-8) ( <2-) (2-1024) (2-128) ( <2-256) As tested by the antibacterial activity against test-organisms and expressed as reciprocal of the maximum inhibitory dilution t:sing Staphylococcus aureus which MIC for gentamicin was 0.3.ug/ ml tt:sing Staphylococcus aureus which MIC for aminosidin was 0.3.ug/ ml tttsing Ps aeruginosa which MIC for polymyxin B was 0.003.ug/ ml administration is indicated by the antibacterial activity found in the serum. However, this latter activity was considerably lower than that observed in the bronchial secretions. Determinations of urea and creatinine were performed in all the patients in this series. No difference between the two groups could be detected. In no case was there any nephrotoxicity observed that could be related to the use of the endotracheal antibiotics. Tests for cochlear and vestibular dysfunction were not performed for obvious reasons in these comatose patients. However, in no patient who could be evaluated a posteriori was there any suggestion of acoustic or vestibular dysfunction that could have been attributed to the administration of gentamicin. The administration of aminosidin-polymyxin B mixture was associated in some patients with irritative cough which usually lasted for a few minutes. Recent studies in our hospital have indicated that polymyxin B alone was responsible. DISCUSSION It has been shown that gentamicin administered endotracheally to comatose tracheotomized patients can prevent the colonization in the respiratory tract of gram-negative bacilli and that it reduces the frequency of serious gram-negative tracheobronchial infections and their attached morbidity and mortality. t." 4 7 The bacteriologic and clinical results obtained here with endotracheal gentamicin are similar to those obtained under similar clinical conditions earlier in this hospital. t. 7 The use of a combination of aminosidin plus polymyxin B was associated with effectiveness similar to that of gentamicin from the clinical and bacteriologic points of view. The favorable response obtained with the aminosidin-polymyxin combination suggests that it might be used in the prevention of serious tracheobronchial infections in comatose tracheotomized patients; however, the endotracheal administration of polymyxin may cause a mild tracheobronchial irritation and coughing in some patients. The major reason to use endotracheally aminosidin plus polymyxin instead of gentamicin for the prevention of tracheobronchial infections in tracheotomized patients is the fear of the emergence of gentamicin-resistant strains. That the use of endotracheal gentamicin probably increased the frequency of isolation of gentamicin-resistant organisms is suggested by the finding of gentamicin-resistant Providence in our neurosurgical unit in the past. 2 It is difficult to determine whether the frequency of isolation of gentamicin-resistant strains is a continuing contamination of the patients admitted to our unit by these strains. It should be stressed, however, that the Prov- PREVENTION OF TRACHEOBRONCHIAL INFECTIONS 305

idence bacilli had disappeared from the unit and were replaced by gentamicin-resistant Klebsiella for unknown reasons not related to the use of gentamicin. Nevertheless, since the completion of the present study, the use of gentamicin has been discontinued in our neurosurgical unit and the frequency of isolation of gentamicin-resistant Klebsiella has decreased. Another observation pointing to the possible role of gentamicin in selecting gentamicin-resistant strains in the patients is that these strains were isolated more frequently from patients who had been treated with gentamicin than from those who had received the combination. Although it is desirable to restrict as far as possible the use of prophylactic antibiotics especially in hospitalized patients to prevent the emergence of antibiotic-resistant bacteria, 10 there are circumstances in which such a practice might be beneficial. 1 3 4.6 In these conditions it might seem advisable to use for prophylaxis antibiotics with less unique antimicrobial properties than gentamicin. The endotracheal administration of antibiotics that are less useful as systemic treatments might then be considered. It may be that therapy should be based on longterm plans for rotation of antibiotic treatments over months or years and the withdrawal of certain antibiotics when strains resistant to it begin to appear in large number. ACKNOWLEDGMENTS: The present study was supported in part by a grant from the Fonds de Ia Recherche Scientiflque Medicale, Bruxelles, Belgium ( n 20.368) and a grant from Farmitalia (Milano, Italy) which also provided the aminosidin ( Gabromicina) for the study. The technical assistance of Mrs. D. Weerts, L. Vandenborre and R Menne is fully acknowl- edged as well as the secretarial help of Mrs. R. Andries. The authors also wish to express their thanks to the nursing staff of the neurosurgical intensive care unit at the Institut Jules Bordet for their assistance during this study and to Prof. J. Brihaye for permission to study his patients. REFERENCES 1 Klastersky J, Huysmans E, Weerts D : Endotracheal gentamicin for the prevention of infections of the respiratory tract in tracheotomized patients (a double-blind study). Chest 65:650, 1974 2 Klastersky J, Bogaerts AM, Noterman J, et al : Infections caused by Providence bacilli. Scand J Infect Dis 6 :153, 1974 3 Greenfield S, Teres D, Bushnell LS, et al : Prevention of gram negative bacillary pneumonia using aerosol polymyxin as prophylaxis: I. Effect on the colonization pattern of the upper respiratory tract of seriously ill patients. J Clin Invest 52:2935, 1973 4 Lepper MH, Hofman S, Blatt N et al : Effect of eight antibiotics used singly and in combination on the tracheal flora following tracheotomy in poliomyelitis. Antibiot Chemother 4 :829, 1954 5 Ramirez JR, O'Neill EF: Endobronchial polymyxin B: experimental observations in chronic bronchitis. Chest 58:352, 1970 6 Kass EH, Sossen HS: Prevention of infection of urinary tract in presence of indwelling catheters: description of electromechanical valve to provide intermittent drainage of the bladder. JAMA 9:1181, 1959 7 Klastersky J, Cappel R, Noterman J : Endotracheal gentamicin for the prevention of bronchial infections in patients with tracheostomy. Int J Clin Pharmacol4:279, 1973 8 Steers E, Foltz EL, Graves BS : Inocula-replicating-apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot Otemother (Basel) 9:309, 1959 9 Simmons RL, Martin AM, Heisterkamp CA, et al : Respiratory insufficiency in combat casualties. II. Pulmonary edema following head injury. Ann Surg 170:39, 1969 10 Price DJE, Sleigh JD: Control of infection due to Klebsiella aerogenes in a neurosurgical unit by withdrawal of all antibiotics. Lancet 1: 1213, 1970 306 KLASTERSKY ET Al