Ceftazidime therapy in patients with cystic fibrosis and multiply-drug-resistant pseudomonas

Ceftazidime Therapy in Patients with Cystic Fibrosis and Multiply-Drug-Resistant Pseudomonas

JEFFREY L. BLUMER, Ph.D., M.D. ROBERT C. STERN, M.D. JEFFREY D. KLINGER, Ph.D. TOYOKO S. YAMASHITA, Ph.D. CAROLYN M. MEYERS, Ph.D. ADAM BLUM MICHAEL D. REED, Pharm.D. Cleveland, Ohio

From the Divisions of Pediatric Pharmacology and Critical Care, and Pulmonary Medicine, Rainbow Babies and Children’s Hospital, and the Depart- ments of Pediatrics, Pharmacology, and Biometry, Case Western Reserve University, Cleveland, Ohio. This work was supported in part by Grants MOl-RMOO6O and AM-27651 from the National Institutes of Health, Bethesda, Maryland, and a grant from Glaxo Research, Inc., Research Tti- angle Park, North Carolina. A preliminary report of this work appeared in the Journal of Antimicrobial Chemotherapy [1966; 12 (suppl A): 269-2961. Requests for reprtnts should be addressed to Or. Jeffrey L. Blumer, Department of Pediatrics, Rain- bow Babies and Children’s Hospital, 2101 Adelbert Road, Cleveland, ohi0 44106.

The in vitro activity of ceftaxidime against Pseudomonas aeruginosa and P. cepacia isolates from patients with cystic fibrosis was compared with that of other antipseudomonai drugs. Ceftazidime was as potent as imipsnem against P. aeruginosa and the only drug effective against P. cepacia. An evaluation of the elimination klnet- its of ceftaxidlme in 20 cystic fibrosis patients revealed an elimination half-life of 1.76 hours, an apparent distribution volume of 0.27 liters/kg, and a serum clearance rate of 133.9 ml/minute/l .73m2. Uri- nary recovery of ceftaxidime was 67 percent within the first 24 hours after admlnistration of the drug, wlth 65 percent recovered in the first two-hour fraction. Probenecid administration had no effect on the eliminatlon kinetics of ceftazfdime. Forty-three patients who had either shown no response to conventional therapy or had sputum Pseudomonas isolates that were susceptible only to ceftazidime received 75 courses of therapy. In 67 percent of these patients, the clinical response, when evaluated using an objective clinical efficacy scoring system, was considered favorable. Clinical failures were not associated with the development of drug resistance. Thus, ceftaxidime can be recommended for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

Cystic fibrosis is a heritable disorder that is usually fatal within the first four decades of life [1,2]. The chronic lung disease associated with cystic fibrosis increases in severity as a patient ages. Although the initial bacterial pathogens appear to be Staphylococcus aureus and Hemophilus in- fluenzae, all the patients eventually have a chronic infection with various species of Pseudomonas [3-51. As a result, patients are subjected to repeated courses of high-dose, broad-spectrum antibiotics. This therapy is clearly palliative since it seldom results in total eradication of the bacterial pathogens from the sputum. However, the repeated courses of therapy often lead to the development of antibiotic resistance. Furthermore, since the infection in cystic fibrosis is endobronchial rather than paren- chymal [6], parenterally administered drugs must penetrate through the bronchial wall and into the sputum to be effective.

At our center, the median survival time for patients with cystic fibrosis is approximately 30 years. We attribute this rather long survival to the use of aggressive pulmonary toilet and the liberal use of antipseudomonal and antimicrobial agents. However, our use of high-dose, broad-spectrum antibiotics has several negative consequences. First, a large number of our older patients with cystic fibrosis are colonized with multiply-drug-resistant P. aeruginosa. Moreover, at least in part because of our aggressive treatment of P. aeruginosa, we are swing the emergence of P. cepacia as a major pathogen among our patients.

August 9,1995 The American Journal ot Medlclna Volume 79 (suppl2A) 37

SYMPOSIUM ON ADVANCES IN CEPHALOSPORIN THERAPY-BLUMER ET AL

TABLE I

Age Sex

Patient Characteristics

Mean (*SW

18

ilaw

8-30

Male 11 Female 9

Blood bicarbonate (mM/liter) Total bilirubin (rng/dl) Serum glutamic-oxaloacetic

24 2 4 0.4 * 0.2

(nomlal22-30) (normal 0.1-l .2)

lution method in Mueller-Hinton broth. The inoculum size was standardized to a final density of 105 colony-forming units/ml in microtest plate wells containing serial twofold dilutions of the antibiotic. The minimal inhibitory concentration was defined as the lowest antibiotic concentration that resulted in no visible growth after 24-hour incubation at 37%; the minimal bactericidal concentration was defined as the lowest antibiotic concentration that produced a 99.9 percent kill of the inoculum.

transaminase (units/liter) Serum creatinine (mg/dl) Albumin (g/dl)

30’11 0.8 2 0.2 3.7 rt 0.3

(normal 41) (normal 0.7-l ,4) (normal 3.4-5.0)

P. cepacia is resistant to most penicillin and aminogly- coside antibiotics. Although it has been found in the sputum of a number of our patients with cystic fibrosis during the last 10 or 15 years, it has only recently acquired a high level of virulence. Patients with P. cepacia now manifest protracted fevers, rapid pulmonary deterioration, and often a bacteremic phase in the premorbid state. Upon postmortem examination, the lungs appear to be tilled with microabscesses rather than with the cysts and blebs most often associated with P. aeruginosa infection.

During the last several years, it has become apparent that drugs in general, and beta-lactam antibiotics in particular, are handled differently by patients with cystic fibrosis as compared with age-matched unaffected patients. With the beta-lactam antibiotics methicillin [7] and dicloxacillin [8], the elimination rate is almost twice as fast in patients with cystic fibrosis as in control patients.

Sputum for quantitative cultures was collected in pre- weighed sterile containers. The sample was sonicated to iiq- uify the material; 1 ml was then diluted with 49 ml of phosphate-buffered saline, pH 7.2, and homogenized with a Polytron homogenizer for 15 to 30 seconds at a power setting of 5. Serial 1 :lO dilutions of the 150 sputum mixture were prepared by a pipetting 0.2 ml of the original dilution to 1.8 ml of phosphate-buffered saline and repeating dilutions appro- priately. Then 0.1 ml samples of selected dilutions were plated on duplicate plates of appropriate media [ll]. Patient Population. The single-dose pharmacokinetics of ceftazidime were evaluated in volunteers selected from among those followed at the Cystic Fibrosis Center at Rain- bow Babies and Children’s Hospital. All patients were at least five years of age and in good overall general health. The characteristics of these volunteers are shown in Table I. None of the volunteers showed any clinical or biochemical evidence of hepatic or renal insufficiency, and none was hy- percapnic.

Because of the changes in antimicrobial susceptibility patterns and the emergence of P. cepacia as a primary pathogen, we decided to evaluate the safety and efficacy of various antipseudomonal agents in treating acute pulmonary exacerbations in patients with cystic fibrosis. One of these agents, ceftazidime, is a new third-generation cephalosporin possessing a broad spectrum of antimicrobial activity [9,10]. Its high level of potency against various Pseudomonas species suggests that it may be useful in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. In the current series of studies, both the clinical efficacy and pharmacokinetics of ceftazidime were evaluated in a group of patients with cystic fibrosis who had either failed to respond to therapy with conventional antipseudomonal agents or had sputum Pseudomonas isolates that were susceptible only to ceftazidime.

PATiENTS AND METHODS

Patients receiving ceftazidime therapy were selected because either they had failed to show clinical improvement while receiving conventional antipseudomonal therapy or they had sputum Pseudomonas isolates that were susceptible only to ceftazidime. All of these patients were experiencing acute pulmonary exacerbations of their disease as defined by the presence of four or more of the following signs: increasingly productive cough; change in volume, appearance, or color of sputum; increasing respiratory rate or dysp- nea; progressive physical findings on chest auscultation; chest radiographic appearance of new infiltrates; decreased appetite and weight loss; fever; and/or decreased exercise tolerance. All patients received 2 g of ceftazidime every eight hours for the duration of their therapy. in some patients, tobramycin was added to the regimen after two weeks of monotherapy. Pharmacokinetic Analysis. Patients were admitted to the Clinical Research Center at the University Hospitals of Cleve- land. Prior to drug administration, an intravenous catheter was placed in each patient’s arm. The catheter not used for drug administration was kept patent by continuous infusion of 0.9 percent saline. Each patient received 50 mg/kg of ceftazidime by intravenous injection over a period of 30 to 80 seconds. Blood samples (5 ml) were drawn just prior to drug administration, and at five, 10, 15,30, and 45 minutes and at one, one and a half, two, three, four, six, and eight hours after administration of the drug.

in Vitro Susceptlblllty Testing and Quantitative Sputum Upon arrival at the Clinical Research Center, patients were Cuitunts. Pseudomonas isolates from patients with cystic asked to void. Urine voided during the next 24 hours was fibrosis were tested for in vitro antimicrobial susceptibility to obtained in four aliquots (zero to two hours, two to four hours, ceftizidime, ticarcillin, aziodllin, piperaciiiin, tobramycin, imi- four to eight hours, and eight to 24 hours after drug adminis- penem, aztreonam, and cefsuiodln. Minimal inhibitory and tration). The total volume of each sample was measured, and bactericidal concentrations were determined using a microdi- a small aliquot was retained for determining drug excretion.

38 Auguel 9,1985 The American Journal of Medkh Volume 70 (wp~l2A)


TABLE II Rainbow Babies and Children’s Hospital Clinical Efficacy Scoring System

Msasuros Points Measures PWS

Sputum volume (percent change)

0 +10-50 +51-100 -10-50 -51-100

sbeping resplmtory rate 12-16 17-22 23-26 29-34 X.35

5 4 3 2

Cheat phyalcal examlnatlon Rales

No rates 0 1

Anterior PostWiOr I Maximum of 12 points

No air exch&e 0 Fair air exchange 1 Good air exchange 2

Anterior Posterior )

Maximum of 24 points

Carbon dioxlia tanslon 20-25 5 26-30 4 31-35 3 36-40 2 41-45 1 >45 0

ona-wcond forcad apmoly volume (percent expected)

90-100 10 60-69 6 70-79 6 60-69 4 50-59 2 450 0

Exerclw tolerance (exercycle)

Highest setting tolerated Ages>5years

1 point per minute up to 15 points

*

*

Peak terqwature (days of normal temperature)

6-7 5 5-6 4 4-5 3 3-4 2 <2 0

WIghi gain of loss (kg)

&-2.6 0 &0.5-2.5 1 0 2 f0.5-2.5 3 fB2.6 4

oxygan aalumtlon 90-100 5 60-69 4 70-79 3 60-69 2 50-59 1 GO 0

v@ntll-ry wlty (percent expect@

90-100 10 60-69 6 70-79 6 60-69 4 50-59 2 -40 0

The six patients who received probenecid were admitted to the Clinical Research Center on a second occasion. Ceftazi- dime was administered 30 minutes after a 1 g oral dose of prober&d, and serum and urine samples were obtained as previously described.

In patients receiving ceftazidime therapy, the sputum accumulation of the drug was assessed during the first 10 days of therapy using sputum samples obtained just prior to drug administration. In addition, in 10 patients, all expectorated sputum from zero to two hours, two to four hours, four to eight hours, and 12 to 24 hours after administration of the last dose of ceftazidime was collected in order to estimate sputum dearance parameters. Analytk Technique. All serum, urine, and sputum samples obtained during the study were stored at -70°C until ana-

Augllat 9,1965 The Amwlcan Journal of Medklna Voluma 79 (auppl2A) 39

lyzed. Under these condtions, there is no loss of drug for up to three months [12]. Ceftazidime concentrations were determined using the high-pressure liquid chromatographic technique described by Myers and Blumer [12]. Briefly, serum proteins were precipitated with ice-cold methanol in a 1:l ratio. Urine was diluted with saline 1:6 to 144 after removal of the sediment by centrifugation. A total of 0.02 ml of serum extract or urine was injected onto a MCH-10 reverse-phase column maintained at 60°C with a heater block. The elution solvent consisted of 20 percent methanol in 60 mM ammo- nium dihydrogen phosphate containing 0.117 mM perchloric acid. The solvent flow rate was 1.5 ml per minute, and the eluate was monitored at 257 nm.

For determination of ceftazidime concentrations in sputum, the samples were sonicated and diluted with an equal volume


TABLE III Antimicrobial Susceptibility Patterns of Sputum Cultures

P. aetu~lnosa P. cepacla

MlC## MB&n mo MB& Antibiotic ho/ml) (reW

Ceftazidime 4 8 4 8 Ticarcillin >128 ~128 z-128 >128 Mocillin 64 X4 64 84 Piperacillin 2 18 16 64 Tobramycin 1 z-2 >2 >2 Aztreonam 4 8 32 64 lmipenem 4. 16 X4 M4

MC = minimal inhibitory concentration; MBC = minimal bactericidal concentration.

of acetonitrile to precipitate protein. After centrifugation, the organic phase was extracted into four volumes of methylene chloride, and 50 ~1 of the aqueous phase was injected onto the column. Conditions for chromatography were identical to those used for serum samples. Pharmacokinetic Data Analysis. Serum concentration- time data after administration of an intravenous bolus of ceftazidime were fitted individually to equation 1 using the non- linear least-squares program NONLIN [13]. In each case, a weighting factor of l/(observed concentration)* was applied [14,15]:

c = Ae-a’ + b-fit (1)

A and B are the coefficients of the biexponential equation defined as:

A= Wa - K21)

vc b - B) (2)

B=M a (3)

p and a are the disposition constants during the distribution and elimination phases, respectively, and K2, is the equilibrium rate constant for distribution from the peripheral to central compartment. Vc is the apparent volume of the central compartment, which is defined as:

v+& a

(4)

where D is the dose of drug administered. The area under the ceftazidime concentration versus time curve (AUC) was calculated from the coefficients A and B and disposition constants a and /3 as follows:

A B AUC”=-+- 0 a B (5)

This value was then used to calculate the total body clearance (Cl,) of ceftazidime:

CIB = -j&-r (6) 0

The volume of distribution for ceftazidime was calculated using the apparent volume of the central compartment, Vc, and the intercompartmental equilibrium rate constants as follows:

The elimination half-life for ceftazidime was calculated from the terminal elimination phase according to the equation:

The renal clearance (Cl,) of ceftazidime was calculated as follows:

where A is the cumulative amount of drug excreted [15]. Determination of Cllnical Efficacy and Safety of Ceftazi- dime in Patients with Cystic Fibrosis. To provide an objective basis for the evaluation of the effiicy and safety of ceftazidime, patients were scored before beginning therapy, every seven days during therapy, and at the end of therapy using a clinical efficacy scoring system (Table II). Microbio- logic efficacy was estimated from the change in sputum colony counts. Safety was determined by daily physical exami- nations and interviews, along with the determination of the following laboratory values before therapy, every four days during therapy, and at the conclusion of therapy: complete blood cell count, differential and platelet counts, prothrombin time, partial thromboplastin time, direct Coombs’ reaction, serum electrolytes, serum glutamic-pyruvic transaminase, serum glutamic-oxalacetic transaminase, creatinine, calcium, albumin, bilirubin, uric acid, alkaline phosphates, and urinaly- sis.

RESULTS In Vitro Susceptibility of Multiply-Drug-Resistant Pseudomonas. To determine the potential usefulness of ceftazidime in the treatment of acute pulmonary exacerbations in cystic fibrosis, the in vitro efficacy of ceftazidime

against cystic fibrosis Pseudomonas isolates was compared with that of a number of other antipseudomonal drugs (Table III). All the P. cepacia isolates and 60 percent of the P. aeruginosa isolates were susceptible to ceftazidime. Other than ceftazidime, only piperacillin showed any in vitro activity against P. cepacia.

Single-Dose Serum Pharmacokinetics of Ceftazidime. Figure 1 shows the serum elimination kinetics of cef-

tazidime in 20 patients with cystic fibrosis after administration of a 50 mg/kg bolus dose. Peak serum concentrations ranged from 200 to 300 @ml. Pharmacokinetic data from individual patients are shown in Table IV. Fol- lowing a distribution phase of 0.45 f 0.20 hour (mean +

SD), the drug displayed a terminal elimination half-life of 1.76 + 0.61 hours. The apparent volume of distribution of the central compartment was 200 + 50 ml/kg, and the total apparent volume of distribution was 270 -t 50 ml/kg. Total body ceftazidime clearance was 133.9 f 23.3 ml/minute/l .73m*, ‘which approximated the creatinine clearance rate obsenred in this patient population.

Fractional urine samples were collected for 24 hours after drug administr&ion. Over the entire collection period, 67 f 6 percent of the administered dose was recovered

40 August 9,1995 The Am&can Journal of Medklne Volume 79 (ruppl2A)


unchanged in the urine (Figure 2). More than 65 percent was eliminated during the first two hours after drug administration. The remainder was eliminated in an exponential fashion, with less than 5 percent being recovered in the sample obtained at eight to 24 hours. The renal clearance of ceftazidime averaged 110.0 2 22.2 ml/minute/l .732, correlating strongly with plasma clearance (r = 0.62). Effect of Probenecid on Ceftazldime Elimination Ki- netics. Six patients were studied before and after receiving a 1 g oral dose of probenecid. Figure 3 depicts the overall elimination of ceftazidime in those patients before and after probenecid administration. No effect was observed on the distribution or elimination half-lives, the apparent volume of distribution of the peripheral or central compartments, or the total body clearance of ceftazidime (Table V). Urinary recovery of ceftazidime was unaffected by pretreatment with probenecid. Sputum Penetration of Ceftazidime during Therapy. Figure 4 depicts ceftazidime concentrations in sputum determined just prior to dosing during the first 10 days of therapy. Overall, no drug accumulation was noted. When the sputum elimination of the last dose was monitored over 24 hours, the drug concentration was found to increase in the sputum for two to four hours and then decrease over the next 20 hours with an apparent half-life of four to six hours (Figure 5). The ratio of sputum to serum area under the concentration curves was equal to 0.6, suggesting excellent overall penetration. Clinical and Bacteriologic Efficacy of Ceftazidlme. A total of 43 patients received 75 courses of ceftazidime

0 60 120 100 240 300 360 420 400 TIME (mid

F/gun, 1. Overall ceftazidime serum concentration versus time curve. Each point represents the mean (SE) of duplicate determinations performed in 20 patients.

TABLE IV Pharmacokhwtic Evaluation of Ceftazidims In Patients with Cystic Fibrosis

Patlet

DlSMltfOll Ellmlnatlon Velume ol Volume el Ama under Concentmtlonl Half-Llfa HWfe Ceniral Compartment Dlstrtbutlon Time Curia muw lhoun) mml) lI~en/lro) (pg - hour-‘/ml-‘)

Clearance (ml/mlnutekT3m*)

Total Body Renal

1 2 3 4 5 6 7 6 9

10 11 12 13 14 15 16 17 16 19 20

0.76 1.16 0.24 0.25 254.75 148.44 0.71 1.74 0.21 0.25 381.31 127.45 0.36 1.43 0.15 0.23 311.64 122.82 0.31 0.96 0.24 0.30 191.54 173.39 0.41 1.90 0.16 0.28 382.83 107.28 0.52 1.67 0.21 0.31 262.54 131.23 0.63 2.38 0.29 0.37 409.63 92.88 0.17 1.16 0.11 0.18 395.56 132.03 0.33 1.21 0.20 0.28 247.26 154.83 0.67 2.13 0.16 0.24 487.43 113.05 0.53 2.21 0.19 0.30 286.75 137.64 0.27 1.61 0.15 0.26 361.81 119.36 0.45 1.84 0.18 0.28 358.47 149.25 0.42 2.13 0.20 0.33 392.15 109.34 0.76 3.75 0.13 0.18 235.92 133.05 0.42 1.50 0.26 0.34 274.41 188.01 0.65 1.66 0.22 0.27 339.03 132.71 0.48 1.56 0.19 0.27 271.91 128.41 0.13 1.22 0.33 0.33 252.33 148.22 0.04 1.64 0.15 0.23 374.91 128.62

0.45 1.76 0.20 0.27 323.61 133.90 0.21 0.61 0.05 0.05 75.25 23.32

124.1 -

77.3 181.2

96.8 83.8 92.9

124.3 -

99.3 130.0 100.5

-

102.1 113.3 164.0 126.9 127.2 124.8 101.9

110.0 22.2

August 9,1S85 The Anwlcan Journal of Medlchte Volume 79 (suppl2A) 41

SYMPOSIUM ON ADVANCES IN CEPHALOSPCRIN THERAPY-BLUMER ET AL

G 100 T I 0 00

E t 60

5 5 40

5 w 20 E L

o-2 2-4 4-8 8-24 O-24

TIME (hours) d Figure 2. Urinary recovery of cetiazidime. The percent recovery was defined as: Percent recovery = ceftazidime concentration (mglliter) x urine volume (liter) x 1OOldose ceftazidime administered (mg).

TABLE V Effect of Probenecid on Ceftazidlme Ellminatlon Kinetics’

wllboul Wllb Prebenscld Pmbenscid

Distribution half-lie (hw=) 0.49 rt 38 0.47 2 .21

Elimination half-life (hours) 1.94+.36 2.15 + .65

Volume of central compartment (IiteMs) 0.22 t .05 0.21 2 .05

Total body dearanoe (ml/minute/l .73m*) 134.28 + 33.14 128.33 2 24.02

‘Each value represents the mean &SD for the six patients studied.

2.8

2.8 I I

.f. 1 2 3 4 6 8 7 8 9 10 DAY OF THERAPY

I-

F/gum 4. Trough sputum ceftazidime concentrations. Each point represents the mean (&SE) for the sputum ceftazidime concentration obtained just prior to dosing in 15 patients during the first 10 days of therapy.

0.6 - PROSENECID

0 .

0 60 120 180 240 300 360 420 480

TIME (mitt)

F/gum 3. Effect of probenecid on ceftazidime elimination. Serum samples wem obtained at the times indicated and serum ceftazidime concentrations were determined as described under the Patients and Methods Section.

3.4

3.3 I 3.0-

WE I\ 28- . = 3 -- 2.6-

r;jz t 0 2.4- Lup 0 $ 2.2-

E+ > 2 2.0-

‘;s zg ‘a- 0 1.6-

3 6 1 .o f

f

f

5 Ol

1 I I ,. o-2 2-4 4-8 ’ 12-24

HOURS AFTER BOLUS DOSE

F/guru 5. Sputum elimination of ceftazidime. Each point represents the mean (&SE) of the ceftazidime concentrations in the total expectorated sputum during the time inter- vals shown for 10 patients receiving their last dose of drug.

42 Auguot a,1999 lha Am&cm Journal of Madklna Volume 79 (suppl2A)

SYMPOSIUM ON ADVANCES IN CEPHALOSPORIN THERAPY-SLUMER ET AL

TABLE VI Characteristics and Outcome in Patients with Cystic Fibrosis Receiving Ceftazidime Therapy

Total patients 43 Malezfemale 20:23 Age (yeam) 9-35

Duration of therapy (days) 5-55 Treatment courses 75

Outcome

improved Not improved Worsened Died

Overall First Course

51 29 11 5

2 0 11 9

TABLE VIII Sputum Pathogens and Ceftazidime Susceptibilities in Patients Whose Condition Dld Not Improve or Worsened

Number Minimal lnhibltory

Concentmtlon (&ml)

Total courses P. aetuginosa

Pre-therapy isolates Postmortem isolates Increased minimal

inhibitory concentration P. cepacia

Pre-therapy isolates Postmortem isolates Increased minimal

inhibitory concentration

12

8 8-X4 5 18->84

1

10 l-8 11 l-x4

2

(Table VI). There were 20 males and 23 females, with an age range of nine to 35 years. Of the 43 patients treated, 20 had participated in the pharmacokinetic arm of the study. Overall, 51 of the treatment courses were considered to result in clinical improvement; in 11 courses, the patient’s condition did not improve; in two courses, the patient’s condition worsened; and in 11 courses, the patient died during therapy. Nine of the 11 deaths occurred during the first course of treatment.

Of the 75 pairs of pre- and post-therapy sputum isolates, P. aeruginosa was isolated from 75 percent of pre- therapy and 45 percent of post-therapy samples; P. cepacia was isolated from 82 percent of pre-therapy and 88 percent of post-therapy samples (Table VII). Twenty- one percent of the pre-therapy samples and 45 percent of the post-therapy samples contained P. cepacia alone. After therapy, 11 percent of the P. aeruginosa isolates and 14 percent of the P. cepacia isolates showed a decreased susceptibility to ceftazidime. None of the patients with persistent P. cepacia or P. aeruginosa remaining at the end of therapy showed a decrease in sputum colony count.

August 9,1985

TABLE VII Effect of Ceftazidime Therapy on Sputum Colonization with Pseudomonas

Before Therapy After Therapy

Number Percent Number Percent

Total samples 75 100 75 100 P. aeruginosa 58 75 34 45 P. cepacia 82 82 88 88 P. cepacia alone 18 21 34 45 P. cepacia post-

treatment only - - 7 9 Significant increase

in minimal inhibitory concentration’

P. aeruginosa - - 8 11 P. cepacia - - 9 14

*An increase of two or more tubes in the agar dilution procedure.

TABLE IX Sputum Pathogens and Ceftazidime Susceptibilities in Patients Who Dled

Mlnlmrl lnhlbltoly Number Concentmtlon (&ml)

Total patients 11 P. aeruginosa

Pre-therapy isolates 8 2->84 Post-therapy isolates 5 l-x4 Increased minimal

inhibitory concentration 0 P. cepacia

Antemottem isolates 9 0.5-4 Postmortem isolates 11 1-18 Increased minimal

inhibitory concentration 1

The patients whose conditions failed to improve or worsened during therapy were evaluated in greater detail. A total of 12 treatment courses were associated with no improvement. In 10 of the 12 patients, P. cepacia was isolated from the sputum before therapy (Table VIII). This pathogen persisted in all 10 patients and was isolated as the sole pathogen following treatment in one additional patient. One P. aeruginosa isolate and two P. cepacia isolates showed a significant increase in ceftazidime minimal inhibitory concentration following therapy. A similar evaluation performed for the patients who died revealed only one patient with a significant increase in ceftazidime minimal inhibitory concentration for P. cepacia (Table IX).

When patients were evaluated using the antibiotic clinical efficacy score, a significant improvement (p < 0.001) was observed between the score before therapy and the score at the end of ceftazidime monotherapy (Table X). Most of this improvement was noted during the first week of treatment. When the changes in scores for patients with improvement were compared with those for patients with- out improvement, it was noted that the pre-therapy scores

lM American Journal of Medlclne Volume 79 (sup@ 2A) 43


TABLE X Rate of lmprovsment in Antlbiotlc Clinical Efficacy Bcom

mofThswY

0 1 14 21

score 37.2 46.6 53.9 50.1 *SD

p value

11.5, p.4, j5.4, ,ll.l

<O.DDl \

co.05 /NS

‘<O.Wl

NS = not significant.

TABLE Xi Comparatlvs Ratw of improvement in Antlblbtic Cilnkai Efficacy Bcorss

DqdlBampy(scontSD)

Cllnlul Status 0 7 14

Improved 392 13 5ok 14 572 13 Not Improved 37 + 4 4621 46.2 14

TABLE Xii Safety and Tolerability of Ceftazidims In Patlents wlth Cystic Fibrosis

Side E&cl Psfunl sl Tmbnrnl cwrsss

Nausea Diarrhea Rash Fever Elevated serum glutamicpyruvic

transaminase Elevated serum creatinine Neutmpsnia (cl ,OOD/mms) Eosinophilia (%5D/mm3)

10.6 1.3 2.6 0

0 0 4.0 0

were identical in the two groups (Table Xl). After two weeks of therapy, patients judged to have clinical improvement showed a .mean increase in their clinical efficacy score of 18; patients judged not to have clinical improvement or to have a worsened condition showed a mean increase of only 8. Repeated courses of ceftazldime separated by one to eight months resulted in a favorable clinical response in 79 percent of the cases. Safety and Tobrability of Cettazidi.ms Therapy. Cef- tazidime therapy was well tolerated in virtually all of the patients treated. In no case was drug therapy discontin- ued because of drug-associated side effects. Tabls XII shows the frequency of clinical and laboratory adverse events that were observed.

COMMENTS

Ceftazidime is a new aminoihiazolyl cephalosporin with remarkable potency against Pseudomonas [18]. in most cases, the in vitro minimal inhibitory concentrations are

twofold to lo-fold lower than those of currently available third-generation cephalosporins. Additionally, ceftazidime is highly stable to bacterial beta-lactamases, binds mini- matly to plasma proteins, produces high, persistent serum and tissue concentrations, and is metabolically stable [9]. In Vitro Efficacy. In this study, the in vitro antimicrobial efficacy of ceftazidime suggests that ft may be a suitable alternative to ticarcillin and/or tobramycin for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. A retrospective review of more than 500 Pseudo- monas isolates from patients with cystic fibrosis has revealed that ail isolates susceptible to ticarcillin (the beta- lactam antibiotic routinely used in our institution) were also susceptible to ceftazidime (unpublished observation). Among the newer antipseudomonai agents, ceftazidime showed the most consistent in vitro efficacy with both P. aeruginosa and P. cepacia isolates. Its potency against the former rivaled that of imipenem; against the latter, it proved uniquely effective. Single-Doss Pharmacokinetlcs. Our data on the single-dose pharmacokinetics of ceftazidime in cystic fibrosis show that the half-life of distribution is relatively long, av- eraging 27 minutes after a one-minute bolus injection. Such a prolonged distribution phase is unexpected, but a similar value has been reported in normal adults for cefoperazone as well [17j. The fact that drugs that are so chemically different show similar distribution half-lives and apparent distribution volumes (Table IV and [2]) suggests that these characteristics are unrelated to factors such as protein binding (90 percent for cefoperazone; 20 percent for ceftazidime) and route of elimination (primarily biiary for cefoperazone; almost exclusively renal for ceftazidime). It is possible that the prolonged distribution phase is characteristic of this particular disease entity. It is more likely, however, that this value reflects the large number of sample points obtained during the distribution phase in both the current study and the study of Bolten et al [17j. In this way, more certainty may be ascribed to the distribution-phase data than is possible with the one or two points customarily included to justify analysis by a two-compartment pharmacokinetic model.

The elimination half-life in our patients with cystic fibrosis (Table IV) appears similar to that reported for normal adult volunteers [18-20). Although this suggests that similar elimination mechanisms may operate in both popula- tions, it also reflects the insensitivity of equating elimination half-life to overall clearance mechanisms. As with several other new beta-lactam agents, including moxaiactam [21], cefoperazone [22], and ceftriaxone [23], the renal elimination of ceftazidime appears to involve only giomeruiar filtration. Thus, probenecid administered 30 minutes prior to administration of an intravenous bolus of ceftazidime did not affect its elimination kinetics (Table V, Figure 3).

The apparent volume of distribution for ceftazidime in

44 August 9,1965 The Amorkm downd of Madkiln@ Volunw 79 (suppl2A)


patients with cystic fibrosis, 0.27 liters/kg, is greater than that reported for normal adult volunteers [18-201. This, however, appears to be typical for patients with cystic fibrosis. As reported in liters/kg, the apparent distribution volumes for methicillin [A, gentamicin [24], tobramycin [25], piperacillin [28], and theophylline [27,28] were all greater in patients with cystic fibrosis than in normal subjects. It is likely that these data reflect the smaller than normal proportion of body weight comprised of adipose tissue in patients with cystic fibrosis.

As suggested by our data and as shown by others, the total body clearance of ceftazidime in patients with cystic fibrosis is greater than that in age-matched patients [20]. Additionally, patients with cystic fibrosis exhibit an increased ceftazidime renal clearance, which partially ex- plains the overall increase observed in total body clearance [19,20]. However, the exact mechanism(s) for these observed differences in total body clearance and renal clearance remains unknown. Clinical Efficacy of Cbftazidime. In the present study, ceftazidime was employed to treat critically ill patients with cystic fibrosis, which constitutes a rigorous evaluation of the drug’s efficacy. In general, the efficacy of antimicrobial therapy in these patients is difficult to assess because of the following: (1) multiple therapeutic modalities are fre-

quently employed; (2) hospitalization tends to improve compliance with treatment regimens; (3) the bacteria are never eradicated; (4) chest radiographic findings seldom change; and (5) the basic defect remains unknown. Nev- ertheless, the use of an objective clinical efficacy scoring system (Table II) permitted certain conclusions to be drawn.

Patients with cystic fibrosis who did not show clinical improvement in response to conventional therapy or who were colonized with Pseudomonas species susceptible only to ceftazidime showed clinical improvement, as defined by an increase in score equal to or greater than 10 percent, in 67 percent of treatment courses. The improvement seen during the first week of therapy was signifi- cantly better than the improvement during subsequent therapy, and the addition of a second antibiotic after two weeks of monotherapy resulted in no additional improvement (Tables X and Xl). Repeated courses of therapy resulted in a favorable clinical response in 79 percent of the courses, whereas clinical failures seemed unrelated to the development of resistance to ceftazidime during therapy (Tables VIII and IX).

Ceftazidime monotherapy can, therefore, be recommended for patients with cystic fibrosis experiencing acute pulmonary exacerbations.

1. Danks DM, Allan J, Anderson CM: A genetic study of fi- brocystic disease of the pancreas. Ann Hum Genet 1985; 28: 353-388.

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Goldmann DA: Imipenem/cilastatin in acute pulmonary exacerbations of cystic fibrosis. Rev Infect Dis (in press).

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17. Bolton WK, Schekl WM, Spyker DA, Sande MA: Pharmacoki- netics of cefoperazone in normal volunteers and subjects with renal insufficiency. Antimicrob Agents Chemother 1981; 19: 821-825.

18. Harding SM, Monro AJ, Thornton JE, Ayrton J, Hogg MIJ: The comparative pharmacokinetics of ceftazidime and cefotaxime in healthy volunteers. J Antimicrob Chemother 1981: 8 (suppl): 283-272.

19. Sommers DK, Walters L, Van Wyk M, Harding SM, Paton AM, Ayrton J: Pharmacokinetics of ceftazidime in male and female volunteers. Antimicrob Agents Chemother 1983; 23: 892- 896.

20. Leeder JS, Spino M, Isles AF, Tesoro AM, Gold R, MacLeod SM: Ceftazidime disposition in acute and stable cystic ftbro- sis. Clin Pharmacol Ther 1984; 38: 355-382.

21. Reed MD, Bertino JS Jr, Aronoff SC, Speck WT, Blumer JL:

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Documents

Ceftazidime therapy in patients with cystic fibrosis and multiply-drug-resistant pseudomonas