AMERICAN ACADEMY OF PEDIATRICS
`
`Technical Report: Precautions Regarding the Use of
`Aerosolized Antibiotics
`
`Charles G. Prober, MD; Philip D. Walson, MD; Jim Jones, PharmD; and
`the Committee on Infectious Diseases and Committee on Drugs
`
`In 1998, the Food and Drug Administra-
`ABSTRACT.
`tion (FDA) approved the licensure of tobramycin solu-
`tion for inhalation (TOBI). Although a number of addi-
`tional antibiotics,
`including other aminoglycosides,
`␤-lactams, antibiotics in the polymyxin class, and vanco-
`mycin, have been administered as aerosols for many
`years, none are approved by the FDA for administration
`by inhalation.
`TOBI was approved by the FDA for the maintenance
`therapy of patients 6 years or older with cystic fibrosis
`(CF) who have between 25% and 75% of predicted forced
`expiratory volume in 1 second (FEV1), are colonized with
`Pseudomonas aeruginosa, and are able to comply with the
`prescribed medical regimen. TOBI was not approved for
`the therapy of acute pulmonary exacerbations in patients
`with CF nor was it approved for use in patients without
`CF. Currently, no other antibiotics are approved for ad-
`ministration by inhalation to patients with or without
`CF.
`The purpose of this statement is to briefly summarize
`the data that supported approval for licensure of TOBI
`and to provide recommendations for its safe use. The
`pharmacokinetics of inhaled aminoglycosides and prob-
`lems associated with aerosolized antibiotic treatment,
`including environmental contamination, selection of re-
`sistant microbes, and airway exposure to excipients in
`intravenous formulations, will be discussed. Pediatrics
`2000;106(6). URL: http://www.pediatrics.org/cgi/content/
`full/106/6/e89; aerosolized antibiotics, tobramycin solu-
`tion for inhalation; cystic fibrosis; Pseudomonas aerugi-
`nosa.
`
`ABBREVIATIONS. TOBI, tobramycin solution for inhalation; CF,
`cystic fibrosis; FEV1, forced expiratory volume in 1 second; FDA,
`Food and Drug Administration; MIC, minimal inhibitory concen-
`tration.
`
`APPROVED INDICATION FOR TOBRAMYCIN
`SOLUTION FOR INHALATION (TOBI)
`TOBI is approved for maintenance therapy of patients
`with cystic fibrosis (CF) who are known to be colo-
`nized with Pseudomonas aeruginosa. The results of 2
`randomized, double-blind, placebo-controlled, multi-
`centered, 24-week clinical studies demonstrated the
`favorable effects of this therapy.1,2 Each study en-
`rolled subjects 6 years or older who had ⱖ25% and
`ⱕ75% of predicted forced expiratory volume in 1
`
`The recommendations in this statement do not indicate an exclusive course
`of treatment or serve as a standard of medical care. Variations, taking into
`account individual circumstances, may be appropriate.
`PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad-
`emy of Pediatrics.
`
`second (FEV1). Subjects with serum creatinine con-
`centrations above 2 mg/dL and those colonized with
`Burkholderia cepacia were excluded. Study partici-
`pants received alternating 28-day cycles of drug ther-
`apy. Two hundred fifty-eight patients received 300
`mg of TOBI twice daily and 262 received inhaled
`saline placebo. Both drug and placebo were deliv-
`ered by a PARI LC Plus nebulizer (PARI Respiratory
`Equipment Inc, Monterey, CA) with a Pulmo-Aide
`compressor (DeVilbiss Air Power Co, Jackson, TN).
`The drug recipients experienced significant improve-
`ment in pulmonary function compared with the pla-
`cebo recipients; the average improvement in FEV1 at
`the end of the study (week 24) relative to baseline
`(week 0) was 7% to 11% in the treatment group
`versus 0% to 1% in the placebo group (P ⬍ .001).
`Furthermore, TOBI resulted in a significant reduc-
`tion in the number of P aeruginosa colony-forming
`units in sputum during the monthly periods of drug
`administration. Other evidence from these 2 studies
`that supported the possible benefit of chronic inter-
`mittent administration of TOBI included a reduction
`in the average number of hospitalization days during
`the 24-week study, from 8.1 days among the placebo
`recipients to 5.1 days among TOBI recipients (P ⫽
`.001). The average number of days of parenteral an-
`tipseudomonal antibiotic treatment
`in the TOBI
`group also was reduced (9.6 vs 14.1 days; P ⫽ .003)
`during the 24-week study.
`No data support the benefit of TOBI in the man-
`agement of acute exacerbations of pulmonary dis-
`ease in patients with CF; thus, the drug is not rec-
`ommended for hospitalized patients with CF.
`Nonetheless, some centers are prescribing TOBI for
`patients with CF if they are hospitalized during
`months when they already have been scheduled to
`receive their maintenance therapy. Even in the ab-
`sence of supportive data, some centers also are pre-
`scribing TOBI for patients who are hospitalized be-
`cause they are critically ill and/or are awaiting lung
`transplantation. In addition to the lack of clinical
`research studies supporting these practices, the ad-
`ministration of TOBI in hospital environments raises
`concerns regarding development and spread of an-
`tibiotic-resistant bacteria among hospitalized pa-
`tients with CF and other fragile, immunocompro-
`mised hosts.
`A number of antibiotic agents, including other
`aminoglycosides, ␤-lactams, vancomycin, and antibi-
`
`PEDIATRICS Vol. 106 No. 6 December 2000
`http://www.pediatrics.org/cgi/content/full/106/6/e89
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`Once an aerosol is produced, the particle size cre-
`ated has a large impact on delivery. Particles in the
`range of 1 to 5 ␮m in diameter are most desirable for
`pulmonary delivery.26 Within this range, the distri-
`bution of particles is regional. Smaller particles are
`deposited in alveoli and larger particles are depos-
`ited more proximally. Particles ⬎5 ␮m generally are
`delivered to the oropharynx and swallowed. Parti-
`cles ⬍1 ␮m have too small a mass to adhere to the
`respiratory epithelium and thus deliver an insuffi-
`cient quantity of drug.27 The variation between the
`available nebulizers in mean size and range of par-
`ticle sizes generated is wide.27 Volume of fill, surface
`tension of the nebulizer solution, and nebulizing
`flow rate also have been shown to affect drug deliv-
`ery.28 Physiologic factors, including minute ventila-
`tion, pattern of breathing, age, and disease (obstruc-
`tion or inflammation), also have some effect on
`efficiency of aerosol drug delivery.28
`
`Pharmacokinetics
`Even with use of an optimal nebulizer, only ap-
`proximately 10% of the total dose is delivered to the
`lung.29 The rest of the dose is either delivered to the
`oropharynx and swallowed, is left in the dead space
`of the nebulizer or tubing, or is released into the
`environment.30 Potentially, the portions of the drug
`swallowed and delivered to the lung are available for
`systemic absorption. Antibiotics are cleared from the
`lung by mucociliary action, coughing, and absorp-
`tion into the blood with subsequent elimination.31 A
`number of chemical properties of the drug will in-
`fluence drug absorption,
`including molecular
`weight, lipophilicity, and protein binding.32 Absorp-
`tion appears to be highly variable between individ-
`uals.33,34 No clearly defined variables have been
`identified to increase absorption.
`Data regarding serum concentrations of aminogly-
`cosides attained following aerosolization are sum-
`marized in Table 1.2,33–35 These studies demonstrate
`that patients with normal renal function, given the
`
`Disease
`
`Levels† (␮g/mL)
`Mean
`High
`
`Reference
`
`otics in the polymyxin class, have been administered
`as aerosols for many years to patients with CF.3–17
`However, none of these agents have been approved
`for inhalation and studies evaluating their efficacy
`have substantial problems in study design, includ-
`ing: small sample size, inadequate blinding of par-
`ticipants, lack of appropriate controls, and failure to
`consider potential carryover effects in crossover de-
`signs. Other aminoglycosides,18 –20 vancomycin,21,22
`and polymyxin23 also have been administered by
`inhalation in different circumstances to patients
`without CF. However, their efficacy has not been
`evaluated in any randomized, controlled trials and
`their use in aerosolized form has not been approved
`by the Food and Drug Administration (FDA).
`
`DELIVERY AND PHARMACOKINETICS
`Aerosolized antibiotics have been used since the
`1950s. Although understanding of the science of this
`form of medication delivery has increased, much still
`remains to be studied. Understanding how to admin-
`ister aerosolized medications to patients requires an
`appreciation of the physiologic, physical, chemical,
`and mechanical limitations of this form of delivery.
`
`Delivery Considerations
`Two devices are most commonly used to aerosol-
`ize antibiotics—ultrasonic and jet nebulizers. Ultra-
`sonic nebulizers produce an aerosol from the shear
`force created by a vibrating piezoelectric crystal. This
`class of nebulizer produces the most consistent and
`efficient aerosol,24 but has a number of limitations,
`such as: cost of the device, high maintenance needs,
`and the need to heat the aerosol solution, which may
`cause degradation of some drugs. Jet nebulizers pro-
`duce an aerosol by forcing a compressed jet of gas
`over the medication solution. The source of com-
`pressed gas (eg, wall gas in institutions or a compres-
`sor), use of a T-tube, breath-enhanced design, and
`recirculating bag or face mask all affect delivery and,
`hence, dose of the medication delivered.25
`
`TABLE 1.
`
`Drug
`
`Pharmacokinetics of Aerosolized Aminoglycosides*
`Number
`Dose
`Nebulizer
`Subjects
`
`Tobramycin
`Tobramycin
`TOBI
`Tobramycin㛳
`
`Tobramycin
`Tobramycin
`
`61
`61
`520
`5
`5
`6
`5
`5
`
`300 mg BID
`300 mg BID
`300 mg BID
`400 mg
`600 mg
`600 mg ⫻ 1
`300 mg ⫻ 1
`
`Pari LC‡
`Sidestream§
`Pari LC Plus‡
`Ultra Neb 99¶
`Ultra Neb 99¶
`Ultrasonic‡
`Not listed
`
`Tobramycin
`
`5
`14
`
`80 mg BID
`
`CF
`CF
`CF
`CF
`CF
`CF
`Healthy
`Mechanical ventilation;
`no lung disease
`Lung cancer
`CF
`
`0.57
`0.74
`0.98
`0.44
`0.58
`1.27
`.27
`1.07
`
`0.95
`1.17
`3.41
`⬎20㛳
`0.7
`2.57
`NL
`1.6
`
`42
`
`40
`41
`
`38
`37
`
`0.55
`NL
`
`0.55
`0.4
`
`43
`
`39
`
`Pariboy or Pari-
`Privat jet‡
`4.2
`2.48
`CF
`Jet type
`600 mg
`8
`Gentamicin
`* Does not include aminoglycosides given endotracheally. BID indicates twice daily; CF, cystic fibrosis; NL, not listed.
`† Obtained at approximately 1 hour “peak” values.
`‡ PARI Respiratory Equipment Inc, Monterey, CA.
`§ Invacare, Elyria, OH.
`¶ DeVilbiss Air Power Co, Jackson, TN.
`㛳 Not clear if this value represents absorption or spurious contamination. Mean value does not include high value since not quantitated
`(⬎20 ␮g/mL).
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`currently recommended doses, rarely have signifi-
`cant drug accumulation. As this therapy is used in a
`greater number of patients with a variety of disease
`states, range of physiologic function, ages, nebuliz-
`ers, concomitant medications (Pulmozyme [Genen-
`tech, San Francisco, CA], ␤-agonists), and dosing
`strategies, some individuals may achieve levels in
`the toxic range. Absorption appears to occur in a
`dose-dependent fashion as demonstrated in a study
`of 8 patients 6 to 20 years of age with CF who were
`given single doses (120, 360, and 600 mg) of genta-
`micin using an unspecified jet-type nebulizer. Sys-
`temic absorption increased as the dose was in-
`creased. At the highest dose (600 mg), the highest
`peak plasma concentration was 4.2 ␮g/mL (mean,
`2.48 ␮g/mL). At all doses, drug was undetectable
`after 8 hours. This was a single-dose study and
`steady state values may be higher. In the TOBI trial,
`serum concentrations were measured 1 hour after
`administration to approximate a “peak.”2 On day 1,
`the mean peak concentration was 0.94 ␮g/mL
`(range: 0.18–3.62) and during week 20 of therapy, the
`mean peak concentration was 0.98 ␮g/mL (range:
`0.18–3.41). Because absorption of drug from this lung
`depot is variable, the actual peak may occur earlier
`or later.
`Sputum concentrations attained after inhalation of
`antibiotics were highly variable. In addition to drug
`delivery variability, some of this variability may re-
`flect differences in sampling technique and some
`may reflect the lack of standardization of bioassays
`for sputum specimens. Mean sputum concentrations
`of tobramycin in subjects participating in the phase
`III TOBI trials were approximately 1200 ␮g/mL 10
`minutes after dosing. Concentrations were more
`than 10 times the minimal inhibitory concentration
`(MIC) of the most resistant isolate in 98% of patients
`and more than 25 times the MIC of the most resistant
`isolate in 95% of patients.1,2
`
`ADVERSE EVENTS
`The prolonged use and/or repetitive cycles of use
`of aerosolized antibiotics in patients with and with-
`out CF raise safety concerns with regard to possible
`toxicities of the antibiotic or other component(s) in
`the aerosol for the patient and the potential for se-
`lection of antibiotic-resistant organisms in the patient
`and the home or hospital environment.
`
`Potential Toxicity for Patients
`The occurrence of ototoxicity and nephrotoxicity
`have been carefully assessed in a number of prospec-
`tive, randomized controlled studies of both pro-
`longed use and repetitive cycles of use of aerosolized
`tobramycin. No toxicity has been detected.1,6,8,9,36 –38
`Even aerosolized doses of 600 mg of tobramycin
`administered 3 times per day for 12 weeks in a small
`study of 22 patients were not associated with demon-
`strable ototoxicity or nephrotoxicity.37 This lack of
`toxicity probably is related to the low and unsus-
`tained (⬍8 hours) serum concentrations achieved.
`Both aerosolized tobramycin and gentamicin have
`been associated with acute bronchial constriction39,40
`when the intravenous preparation of aminoglycoside
`
`has been used for aerosol administration. These
`preparations contain antioxidants and preservatives
`that may contribute to bronchospasm. The aerosol
`preparation of tobramycin licensed by the FDA is
`preservative free, and in clinical studies has been
`found to be less irritating than the parenteral formu-
`lation administered by aerosol, although broncho-
`spasms were observed occasionally.2,9
`In order to ensure correct delivery and evaluate
`drug tolerance, the first dose of TOBI should be
`given in the presence of a trained health professional.
`During this administration, patients or their caregiv-
`ers should be trained to monitor for bronchospasm,
`urticaria, and/or perioral and periorbital edema. Pa-
`tients or their caregivers should be advised to stop
`the medication and contact their physician if any of
`these adverse reactions occur.
`
`Potential for Selection of Antibiotic-Resistant
`Organisms: Patient Risk; Environmental Risk
`The most serious concern about prolonged use of
`aerosolized antibiotics is selection of resistant organ-
`isms from the primary microbial population or over-
`growth of genera intrinsically resistant to the admin-
`istered antibiotic. For patients with CF in whom
`eradication of P aeruginosa from the respiratory tract
`usually is not possible, even with aggressive therapy,
`emergence of multiply resistant organisms is a well-
`recognized problem associated with multiple courses
`of parenteral antibiotics administered for pulmonary
`exacerbations.41– 43
`Development of tobramycin-resistant P aeruginosa
`during prolonged use or with repetitive cycles of
`aerosolized tobramycin has been reported. For exam-
`ple, after 3 months of continuous use of 600 mg of
`tobramycin 3 times daily by aerosolized administra-
`tion, the percentage of patients having P aeruginosa
`with a tobramycin MIC ⱖ8 ␮g/mL increased from
`29% to 73%.37 Furthermore, among patients with CF
`in the phase III TOBI trials, who received 300 mg of
`tobramycin by aerosol twice daily in 4-week cycles
`on drug, followed by 4 weeks off drug, the propor-
`tion of patients with P aeruginosa having a tobramy-
`cin MIC ⱖ16 ␮g/mL was significantly higher in the
`TOBI group than the placebo group at week 20 (26%
`vs 17%; P ⫽ .03) and week 24 (23% vs 8%; P ⬍ .001).44
`The tobramycin MIC90 for P aeruginosa isolates in-
`creased from 8 to 16 ␮g/mL in the TOBI group
`whereas it decreased from 8 to 4 ␮g/mL in the
`placebo group. Although the effects of more pro-
`longed therapy are not known, preliminary analysis
`of 145 patients who have received inhaled tobramy-
`cin for 9 cycles demonstrates continued efficacy de-
`spite an increase in MIC90 to 32 ␮g/mL.37
`In addition to a transient increase in the MIC of P
`aeruginosa isolates, treatment with inhaled tobramy-
`cin was associated with an increased isolation rate of
`Candida albicans and Aspergillus species from spu-
`tum.37 Treatment-emergent C albicans was isolated in
`22% of patients in the tobramycin group, compared
`with 16% in the placebo group (P ⫽ .06). Treatment-
`emergent Aspergillus species was isolated in 18% and
`8%, respectively (P ⫽ .001). Fortunately, the in-
`creased rate of isolation of fungal species was not
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`associated with any recognized, clinically relevant
`adverse effects (eg, allergic bronchopulmonary as-
`pergillosis or fungal pneumonia). Inhalation of to-
`bramycin did not increase the isolation of multiply
`resistant P aeruginosa, B cepacia, Stenotrophomonas mal-
`tophilia, orAlcaligenes xylosoxidans.
`An even greater concern than the potential for
`emergence of resistant organisms in the patient is the
`potential for antibiotic contamination of the local
`environment resulting in selection of multiply resis-
`tant organisms both in hospitals and in communities.
`A recent study by Jones et al45 demonstrated that
`antibiotic contamination of the environment occurs
`easily and often. Although delivery to the lungs is
`enhanced by aerosolization, so is delivery to the local
`environment, an effect that does not occur with in-
`travenous or oral delivery. Furthermore, the antibi-
`otic accumulates in the local environment as more
`doses are given. Presence of tobramycin on patients’
`skin also was observed, resulting in spuriously high
`serum concentrations attributable to needle contam-
`ination at the time of skin puncture.45
`Environmental contamination with aminoglyco-
`sides is potentially problematic in hospitals where
`multiply resistant gram-negative organisms already
`represent a serious problem. The potential for a sub-
`stantial increase in tobramycin resistance is large and
`measures to minimize environmental contamination,
`such as the use of nebulizer exhaust circuit filters and
`vent-free nebulizers, should be identified and used if
`this problem is to be prevented. Although data are
`not available concerning environmental contamina-
`tion through use of other aerosolized antibiotics, lo-
`cal environmental contamination is inherent in the
`usual aerosol technique and is not a function of the
`specific antimicrobial agent.
`A further area of concern for patients receiving
`aerosolized antibiotics is the potential for microbial
`contamination of the nebulizer equipment. Inade-
`quate cleansing, improper drying, and reuse of dis-
`posable equipment can lead to nebulization of mi-
`crobes as well as the aerosol antibiotic.46,47 Although
`nebulizers are recognized as potential sources for
`nosocomial infection in hospitals,48 home use with
`less experienced caregivers operating the equipment
`can further aggravate the risk.
`
`SUMMARY
`1. TOBI has been approved and may be considered
`for maintenance therapy of patients with CF who
`are 6 years or older.
`2. TOBI is the only antibiotic that has been ap-
`proved by the FDA for administration by inha-
`lation to patients with or without CF. The safety
`and effectiveness of antibiotics other than TOBI,
`when delivered by this route, have not been
`proven and many of these formulations may con-
`tain ingredients that can cause adverse effects
`when administered by inhalation.
`3. Because only small amounts of aerosolized to-
`bramycin reach the systemic circulation and
`drug accumulation has not been demonstrated,
`routine monitoring of serum tobramycin concen-
`trations is unnecessary if the patient is receiving
`
`the recommended dose of TOBI and has normal
`renal function.
`4. Patients with CF who are receiving TOBI should
`be monitored for renal tubular toxicity (urinaly-
`sis, blood urea nitrogen, and creatinine) and
`eighth nerve toxicity (audiogram at 500-8000 Hz
`range) if they are receiving concomitant therapy
`with other nephrotoxic or ototoxic agents or have
`preexisting renal or auditory dysfunction, or rec-
`ognized predisposition to toxicity (eg, family his-
`tory of aminoglycoside intolerance). In addition,
`any patient receiving TOBI who develops signs
`or symptoms of auditory toxicity, such as tinni-
`tus, should have an audiogram performed.
`5. The initial dose of TOBI should be given in the
`presence of a trained health care professional
`who will monitor the patient for wheezing and
`respiratory distress, and instruct the patient in
`the proper technique of delivery.
`6. Patients or their caregivers should be trained to
`monitor for bronchospasm, urticaria, and peri-
`oral or periorbital edema, and be advised to stop
`the medication and consult their physician if any
`of these or other adverse reactions to therapy
`occur.
`7. When aerosolized TOBI administration is main-
`tained, evaluation of long-term efficacy is recom-
`mended within 6 to 12 months of initiating ther-
`apy. Monitoring factors such as reduction in the
`frequency of hospitalization and intravenous an-
`tibiotic administration, sense of well-being, work
`or school performance and absenteeism, and
`cough frequency is recommended.
`8. To minimize microbial contamination of nebu-
`lizer equipment, centers should develop policies
`for aerosolized antibiotic use in the home, clinic,
`and inpatient facility. Such a policy should ad-
`dress barrier techniques, filters, exhaust, envi-
`ronmental contamination, disposal of unused
`product, and cleaning of nebulizers.
`9. Monitoring of antibiotic resistance patterns for
`specific pathogens and specific patient popula-
`tions is recommended for institutions caring for
`patients who receive aerosolized tobramycin.
`10. Strict adherence to infection control policies to
`minimize transmission of resistant organisms
`within the hospital environment
`is
`recom-
`mended for institutions caring for patients who
`receive aerosolized tobramycin.
`
`Committee on Infectious Diseases, 2000 –2001
`Jon S. Abramson, MD, Chairperson
`Carol J. Baker, MD
`Margaret C. Fisher, MD
`Michael A. Gerber, MD
`H. Cody Meissner, MD
`Dennis L. Murray, MD
`Gary D. Overturf, MD
`Charles G. Prober, MD
`Margaret B. Rennels, MD
`Thomas N. Saari, MD
`Leonard B. Weiner, MD
`Richard J. Whitley, MD
`Ex Officio
`Larry K. Pickering, MD
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`Liaisons
`Lance Chilton, MD
`AAP Pediatric Practice Action Group
`Scott F. Dowell, MD, MPH
`Centers for Disease Control and Prevention
`Joanne Embree, MD
`Canadian Paediatric Society
`Martin G. Myers, MD
`National Vaccine Program Office
`Walter A. Orenstein, MD
`Centers for Disease Control and Prevention
`Peter A. Patriarca, MD
`Food and Drug Administration
`Jeffrey R. Starke, MD
`American Thoracic Society
`Consultant
`Edgar O. Ledbetter, MD
`Staff
`Joann Kim, MD
`Committee on Drugs, 2000 –2001
`Robert M. Ward, MD, Chairperson
`Brian A. Bates, MD
`William E. Benitz, MD
`David J. Burchfield, MD
`John C. Ring, MD
`Richard P. Walls, MD, PhD
`Philip D. Walson, MD
`Liaisons
`Donald R. Bennett, MD, PhD
`American Medical Association/United States
`Pharmacopeia
`Therese Cvetkovich, MD
`Food and Drug Administration
`Owen R. Hagino, MD
`American Academy of Child and Adolescent
`Psychiatry
`Stuart M. MacLeod, MD, PhD
`Canadian Paediatric Society
`Siddika Mithani, MD
`Bureau of Pharmaceutical Assessment Health
`Protection Branch, Canada
`Joseph Mulinare, MD, MSPH
`Centers for Disease Control and Prevention
`Laura E. Riley, MD
`American College of Obstetricians and
`Gynecologists
`Sumner J. Yaffe, MD
`National Institutes of Health
`Section Liaisons
`Charles J. Cote´, MD
`Section on Anesthesiology
`Eli O. Meltzer, MD
`Section on Allergy and Immunology
`Consultants
`Preston Campbell, MD
`Jim Jones, PharmD
`Staff
`Raymond J. Koteras, MHA
`
`REFERENCES
`1. Ramsey B, Burns J, Smith AL. Safety and efficacy of tobramycin solution
`for inhalation in patients with cystic fibrosis. The results of two phase III
`placebo controlled clinical trials. Pediatr Pulmonol. 1997;24(suppl 14):
`137–138
`2. Ramsey B, Pepe MS, Quan JM, et al. Intermittent administration of
`inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis In-
`haled Tobramycin Study Group. N Engl J Med. 1999;340:23–30
`
`3. Hodson ME, Penketh AR, Batten JC. Aerosol carbenicillin and genta-
`micin treatment of Pseudomonas aeruginosa infection in patients with
`cystic fibrosis. Lancet. 1981;2(8256):1137–1139
`4. Carswell F, Ward C, Cook DA, Speller DC. A controlled trial of nebu-
`lized aminoglycoside and oral flucloxacillin versus placebo in the out-
`patient management of children with cystic fibrosis. Br J Dis Chest.
`1987;81:356–360
`5. Stead RJ, Hodson ME, Batten JC. Inhaled ceftazidime compared with
`gentamicin and carbenicillin in older patients with cystic fibrosis in-
`fected with Pseudomonas aeruginosa. Br J Dis Chest. 1987;81:272–279
`6. Steinkamp G, Trummler B, Gappa M, et al. Long-term tobramycin
`aerosol therapy in cystic fibrosis. Pediatr Pulmonol. 1989;6:91–98
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