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We investigated the effects of aerosolized pentamidine isethionate on airway constriction and microvascular leakage in the guinea pig, and the role of tachykinins in these abnormalities. The bronchoconstrictor response to pentamidine was determined in anesthetized, tracheotomized and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized pentamidine (5 to 30 mg/ml; 60 breaths). Respiratory system resistance was measured by the occlusion method. Airway microvascular permeability was evaluated by measuring the Evans blue dye concentration in the trachea and main bronchi. Aerosolized pentamidine caused a concentration-related increase in respiratory system resistance that was prevented by pretreatment with 50 mg/kg capsaicin given subcutaneously 2 wk before pentamidine and was significantly reduced by pretreatment with 1 mg/kg morphine given intravenously. Pretreatment with 10(-4) M aerosolized phosphoramidon (90 breaths) significantly enhanced the bronchoconstrictor response to pentamidine. Aerosolized pentamidine (50 mg/ml; 90 breaths) increased airway microvascular permeability, as the Evans blue dye concentration was 72.6 +/- 3.7 ng/mg tissue in guinea pigs aerosolized with pentamidine versus 34.2 +/- 3.5 ng/mg tissue in the controls. Capsaicin pretreatment inhibited the increase in microvascular leakage induced by pentamidine. Pretreatment with 5 mg/ml aerosolized albuterol (90 breaths) prevented the bronchoconstrictor response to pentamidine but failed to prevent the pentamidine-induced increase in microvascular permeability. Atropine did not modify the bronchoconstrictor response to pentamidine. These results indicate that in the guinea pig, pentamidine isethionate induces bronchoconstriction and airway microvascular leakage, which are mediated by tachykinins released from sensory nerves. Albuterol, which is used in humans to prevent bronchoconstriction, does not seem able to prevent airway edema.

The yields of both induced sputum examination and bronchoalveolar lavage (BAL) have been reported to be decreased for breakthrough episodes of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis. This study assessed whether the yield of a single middle or lower lobe BAL could be increased by the utilization of two techniques: (1) indirect immunofluorescent staining with a combination of two murine monoclonal anti-Pneumocystis antibodies in addition to routine toluidine blue O and cytopathologic staining, and (2) the performance of multiple lobe, site-directed BAL (i.e., both upper lobe and middle or lower lobe lavage, including the lobe with the greatest radiographic abnormality). Results of 252 fiberoptic bronchoscopies performed at the National Institutes of Health and the Los Angeles County-University of Southern California Medical Center were analyzed. P. carinii pneumonia was documented in 21 episodes in patients who did not receive prior anti-Pneumocystis chemoprophylaxis and in 41 episodes in patients who received aerosolized pentamidine. Monoclonal antibody staining and multiple lobe, site-directed BAL resulted in similar diagnostic yields for P. carinii in the nonprophylaxis (100%) and aerosolized pentamidine (98%) groups. If BAL had been performed without monoclonal antibody staining and multiple lobe, site-directed lavage, then the yield would have decreased to 95% in the nonprophylaxis group and to 80% in the aerosolized pentamidine group.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine if the use of aerosolized pentamidine prophylaxis decreases the clinical severity or the sensitivity of diagnostic tests for Pneumocystis carinii pneumonia (PCP), we conducted a retrospective matched cohort comparison study of patients admitted to San Francisco General Hospital with PCP from August 1, 1989, to June 30, 1990. Patients who had received pentamidine prophylaxis during at least the 2 months prior to the diagnosis of PCP were matched with patients who had not received the drug. Matching was based on the number of prior episodes of PCP, sex, age, and risk factors for human immunodeficiency virus infection. As markers of clinical severity, we chose alveolar-arterial oxygen difference, serum lactate dehydrogenase levels, outpatient versus inpatient treatment, length of hospitalization, length of intravenous anti-pneumocystis treatment, development of respiratory failure, in-hospital mortality, and chest radiographic appearance. Although, of the 27 matched pairs identified, significantly fewer of the pentamidine cohort were treated as inpatients, and significantly more of this cohort had upper lobe dominant disease on chest radiograph, we found no other significant differences between markers of clinical severity for the two cohorts. In addition, we found no significant differences in the rate of sputum or bronchoalveolar lavage positivity for P. carinii between the two cohorts. We conclude that, although hospitalization is less common in patients with a history of prophylactic pentamidine use, aerosolized pentamidine prophylaxis does not decrease the clinical severity or the sensitivities of sputum induction or bronchoalveolar lavage as diagnostic tests for PCP.

Trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine are both licensed for the treatment of Pneumocystis carinii pneumonia (PCP). However, their use is associated with various adverse side effects. In this prospective study, 26 AIDS patients with 32 episodes of PCP were treated with pentamidine (4 mg/kg/d). Each patient was treated for 12 to 21 days, depending on the rapidity of onset of the clinical response. During the 32 PCP episodes, hypoglycemia occurred in 16 instances, azotemia in 12, liver toxicity in 10, and leukopenia in 8. The occurrence of thrombopenia, leukopenia, and liver toxicity was not related to age, pentamidine levels, or other complications. However, patients who had hypoglycemia during pentamidine treatment had higher serum pentamidine levels than patients who did not have hypoglycemia (107 +/- 40 versus 70 +/- 26 ng/ml, p less than 0.004). In addition, we observed that patients with azotemia showed higher pentamidine levels during treatment (120 +/- 35 versus 64 +/- 22 ng/ml, p less than 0.001). In fact, 100% (11/11) of patients with serum pentamidine concentration greater than 100 ng/ml had fasting hypoglycemia and/or azotemia, while 33% (7/21) of those with pentamidine levels less than 100 ng/ml had these side effects (p less than 0.001). The relative risk of these complications with pentamidine levels greater than 100 ng/ml was 3 (95% confidence interval, 1.6 to 5.5). Fine-tuning the dose of pentamidine may eventually prove useful to avoid toxicity and optimize therapy.

Pentamidine isethionate was administered by the tracheal route to control rats and immunodepressed rats with Pneumocystis carinii pneumonia (PCP). The serum concentration of pentamidine base 20 min after the administration was higher in the PCP rats (309 +/- 165 ng/ml) than in the control animals (71 +/- 36 mg/ml; p less than 0.001); 90 min after the injection the proportion of the pentamidine administered was lower in the right lung of the PCP rats (29 +/- 15%) than in the control rats (57 +/- 23%; p = 0.038); the proportion of pentamidine in the left kidney was higher in the PCP rats (14 +/- 4%) than in the control animals (4 +/- 2%; p less than 0.001). Respiratory clearance of 99mTc-DTPA, an index of the permeability of the respiratory epithelium, was higher in the PCP rats (1.84 +/- 0.42 %/min) than in the controls (0.44 +/- 0.11 %/min; p less than 0.001). We conclude that the more rapid diffusion of pentamidine from the alveolar lumen to the pulmonary circulation is explained by the increased alveolocapillary permeability as a result of pneumocystosis.

In the setting of mechanical ventilation, recent studies have cast doubt on the ability of nebulizer systems to deliver adequate amounts of medication. We therefore studied ventilator-related and nebulizer-related factors that could potentially affect the amount of aerosol inhaled by an intubated subject. Utilizing two separate protocols, we used a bench model of a ventilator circuit, radiolabeled (technetium pertechnetate, 99mTc) saline droplets and a filter technique to measure the percentage of radioaerosol delivered. First, we compared four commercially available jet nebulizers and found that there were significant differences in rate of aerosol production between systems, ranging from 3 to 37%. Delivered aerosol was measured at different ventilator settings, and it was found that the duty cycle can potentially influence output by sevenfold. Some nebulizers were also sensitive to changes in the initial volume of solution placed in the nebulizer. The inclusion of a humidification device significantly reduced output by a mean of 41 +/- 3.5%, but it did not affect particle distribution. Endotracheal tube diameter was not an important variable. Then, with the effects of the above variables established, a separate series of experiments was performed to test whether the use of different radiolabeling compounds can confound the measurement of inhaled drugs. Two nebulizers (AeroTech II and Twin Jet) and pentamidine as the test drug were studied with fixed ventilator settings, treatment time, endotracheal tube size, and volume fill. No humidification was used. The nebulizer solution was labeled with 99mTc, which was bound to either human serum albumin (HSA) or sulfur colloid (SC).(ABSTRACT TRUNCATED AT 250 WORDS)

Tracheal instillation of pentamidine in a surfactant vehicle may be an effective direct method of antibiotic delivery to the lungs. In 10 healthy hamsters, we compared the pulmonary distribution of 99mTc sulfur colloid (TcSC) mixed with pentamidine, using as a vehicle either surfactant (n = 5) or saline (n = 5). Each animal was instilled with 0.25 ml/kg of suspension containing 0.0018 mCi TcSC and pentamidine mixed with either surfactant or saline. After 4 h of spontaneous respiration, the lungs were excised, inflated to TLC, dried, and sliced into 3-mm cross sections from apex to base. Autoradiographs were examined to evaluate 99mTc distribution. The surfactant group had detectable radioactivity in 93% of all slices compared with 72% in the saline group (p = 0.02). Six slices per animal (43% of total) and their corresponding autoradiographs were analyzed for distribution of radioactivity. Lung slice area was determined by planimetry, and autoradiograph area was determined by video densitometry. We calculated the fraction of each lung slice with detectable radioactivity. The surfactant group had 41% of the lung slice areas exposed compared with 21% in the saline group (p = 0.02). The coefficient of variation of radioactive intensities within each slice was used as an index of spatial uniformity. There was a trend towards more uniform distribution in the surfactant group, with a narrower range of variation of intensities (1.51 to 2.56) than the saline group (1.95 to 6.47). We conclude that a surfactant vehicle significantly increases airspace deposition of TcSC and pentamidine instilled intratracheally in normal hamster lungs, and may improve uniformity of spread.

This study assessed the effect of aerosolized pentamidine prophylaxis on the clinical presentation and diagnostic sensitivity of induced sputum examination for Pneumocystis carinii pneumonia. Between January 1, 1988 and October 27, 1990, 348 induced sputum examinations were performed as the initial diagnostic procedure for P. carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). Medical records were reviewed for all induced sputum examinations, and the study group consisted of patients who either had not received prophylactic therapy (n = 193) or had received aerosolized pentamidine prophylaxis (n = 126). A total of 29 induced sputum examinations in patients receiving either other prophylactic regimens or ongoing therapy for previously documented P. carinii pneumonia were excluded from the study group. A total of 72 consecutive episodes of P. carinii pneumonia were subsequently documented by induced sputum examination (n = 54), bronchoalveolar lavage (n = 16), thoracocentesis (n = 1), or autopsy (n = 1). A total of 44 episodes occurred in patients who had not received antipneumocystis prophylaxis, and 28 episodes occurred in patients who had received aerosolized pentamidine. Of patients capable of producing a sputum specimen for analysis, induced sputum examination had a significantly lower diagnostic yield of 64.3% in patients who had received aerosolized pentamidine prophylaxis compared with 92.3% in patients who did not receive prophylaxis (p less than 0.02, Fisher's exact test). When the data were analyzed on an intention to treat basis, although there was a trend suggesting a lower overall yield in the aerosolized pentamidine patients, the difference was not statistically significant (64.3 versus 81.8%, p = 0.17, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS)

Although aerosolized pentamidine (AP) has recently been approved for prophylaxis and is undergoing clinical trials for treatment of pneumocystis, pneumonia (PCP), factors important in the deposition of AP have not been described. Using radioaerosol techniques, deposition was measured in 22 patients receiving AP for prophylaxis or treatment of PCP. In all patients total and regional deposition of pentamidine, breathing pattern, pulmonary function (PFT), regional ventilation, and type of nebulizer were analyzed. Bronchoalveolar lavage (BAL) was performed 24 h after inhalation to assess the relationship between pentamidine levels in BAL fluid and measured aerosol deposition. The nebulizers tested were the Marquest Respirgard II and the Cadema AeroTech II, both previously characterized in our laboratory. The aerosol particles consist of water droplets containing dissolved pentamidine and technetium 99m bound to albumin. Analysis of particles sampled during inhalation via cascade impaction confirmed a close relationship between radioactivity in the droplets and the concentration of pentamidine as measured by HPLC (r = 0.971, p less than 0.0001; n = 18). Deposition was measured by capturing inhaled and exhaled particles on absolute filters and measuring radioactivity. This technique allows the determination of the deposition fraction (DF, the fraction of the amount inhaled that is deposited), which provides information on factors strictly related to the patient. To confirm the filter measurements, pentamidine deposition was also measured by gamma camera. The camera measurement was possible because each patient's thoracic attenuation of radioactivity was determined by a quantitative perfusion scan (mg pentamidine deposited via both techniques, r = 0.949, p less than 0.0001; n = 26). Regional lung volume and ventilation were determined by xenon 133 equilibrium scan and washout. Pentamidine deposition varied markedly between patients, but BAL levels of pentamidine significantly correlated with measured deposition (r = 0.819, p less than 0.01; n = 9). DF averaged 0.621 +/- 0.027 (SEM) and did not correlate with any measured lung parameter, including breathing pattern and PFT. Regional deposition did not correlate with regional ventilation. The major factor influencing pentamidine deposition was aerosol delivery (mg deposited versus mg inhaled; r = 0.963, p less than 0.0001; n = 26). The nebulizer was an important determinant of aerosol delivery, with the AeroTech delivering between 2.5 and 5 times more drug than the Respirgard. These observations are important in assessing treatment failure and cost of therapy.

Aerosolized pentamidine isoethionate is retained in the lung and appears to prevent Pneumocystis carinii pneumonia (PCP) in many AIDS patients. We evaluated alternative formulations of pentamidine that might reduce the airway irritation associated with aerosolized pentamidine isoethionate. Specifically, we assessed the biodistribution, histologic response, and lung retention of the isoethionate, gluconate, and lactate salts of pentamidine after aerosol administration to mice. For each of the three aerosolized salts tested, greater than 50% of the pentamidine initially recovered from the lungs after one dose was still retained there 14 days later. Thus, significant levels of pentamidine, aerosolized as three different salts, are retained in the lung for at least 2 wk after a single dose. The three salts of pentamidine each produced high lung to extrapulmonary drug ratios, the converse of that produced by intravenous injection of pentamidine isoethionate. At very high aerosol doses, the ability of the lung to retain pentamidine appeared saturable. Even aerosolized daily for 2 wk at very high doses, none of the three pentamidine salts produced histologic evidence of organ toxicity. A Phase 1 trial of aerosolized pentamidine gluconate in AIDS-PCP patients is now in progress to determine if this approach can reduce airway irritation.

Nebulizer systems that deposit a high proportion of aerosolized pentamidine on large airways are likely to be associated with marked adverse side effects, which may lead to premature cessation of treatment. We have measured alveolar deposition and large airway-related side effects (e.g., cough, breathlessness, and effect on pulmonary function) after aerosolization of 150 mg pentamidine isethionate labeled with 99mTc-Sn-colloid. Nine patients with AIDS were studied using three nebulizer systems producing different droplet size profiles: the Acorn System 22, Respirgard II, and Respirgard II with the inspiratory baffle removed. Alveolar deposition was greatest and side effects least with the nebulizer producing the smallest droplet size profile (Respirgard II), whereas large airway-related side effects were prominent and alveolar deposition lowest with the nebulizer producing the largest droplet size (Acorn System 22). Values for alveolar deposition and adverse airway effects were intermediate using the Respirgard with inspiratory baffle removed, thus indicating the importance of the baffle valve in determining droplet size. Addition of a similar baffle valve to the Acorn System 22 produced a marked improvement in droplet size profile. Selection of a nebulizer that produces an optimal droplet size range offers the advantage of enhancing alveolar targeting of aerosolized pentamidine while reducing large airway-related side effects.

We examined the tissue distribution of pentamidine, both as free drug and encapsulated in liposomes, after intravenous (iv) and aerosol administration in healthy rodents. After iv injection, drug levels in the lung were increased as much as 34-fold by administration in liposomes. Concurrently, peak liver uptake was increased 4-fold and renal deposition reduced 3-fold. Liposome-mediated lung delivery was highly dependent on liposome size. Decreasing liposome mean diameter from 2.5 to 0.4 micron reduced lung uptake of pentamidine 90-fold while affecting extrapulmonary organ deposition to a much lesser degree. Aerosol delivery of pentamidine produced high, sustained lung levels, with no evidence of drug clearance from the lung between 1 and 48 h after administration. Extrapulmonary drug levels produced by aerosol delivery were negligible throughout this period. There were no significant differences in the organ distribution of aerosolized free versus liposome-encapsulated drug, apparently because of sequestration of pentamidine within the lung. Comparison of drug levels in material recovered by bronchoalveolar lavage suggests that aerosol delivery of pentamidine produces substantially higher deposition in the alveolar space than does iv drug injection. Light and electron microscopic (EM) examination of lung, kidney, and liver after iv or aerosol administration of liposomes revealed no tissue abnormalities, although isolated platelet clumps were noted in pulmonary capillaries by EM examination.

Pentamidine concentrations were determined in plasma after a single aerosolization of 4 mg/kg pentamidine base on 18 patients breathing spontaneously (Group I) and in eight patients receiving mechanical ventilation (Group II). All the patients had documented pneumocystosis. Large interindividual variations in concentrations appeared, especially in Group I. Low concentrations were observed in Group I: Cmax = 65.6 +/- 9.4 micrograms/L (mean +/- SEM), contrasting with high levels in Group II: Cmax = 215.8 +/- 49.8 micrograms/L (mean +/- SEM). Consequently, the mean area under the curve from zero to 4 h was 2.6-fold higher in Group II than in Group I. These findings underline the risk of dose-related pentamidine toxicity in ventilated patients treated with aerosolized pentamidine and the interest of plasma pentamidine monitoring.

In 8 patients with diffuse infiltrates on chest radiograph undergoing fiberoptic bronchoscopy for suspected Pneumocystis carinii pneumonia, bronchoalveolar lavage sediment and supernatant concentrations of pentamidine were compared 18 to 24 h after administration of 4 mg/kg intravenous (n = 3) and aerosolized (n = 5) pentamidine isethionate. Aerosol was inhaled for 35 to 40 min with 300 mg of pentamidine isethionate in a jet nebulizer, baffled to decrease the particle size to 1.42 micron +/- 1.88 (mass median aerodynamic diameter +/- geometric standard deviation). Bronchoalveolar pentamidine concentrations were: In sediment, 9.34 +/- 1.74 postintravenous versus 705 +/- 242 ng/ml postaerosol (mean +/- SEM, p less than 0.05); supernatant, 2.64 +/- 0.73 postintravenous versus 23.2 +/- 7.75 ng/ml postaerosol (mean +/- SEM, p less than 0.05). Serum pentamidine levels were low or undetectable after aerosolization. Aerosol administration delivers significantly higher concentrations of pentamidine to the air spaces than does intravenous delivery in patients with diffuse alveolar infiltrates.