Pharmacologic Therapy

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Pulmonary System

Treating Obstruction and Inflammation (Table 16-1)

Airway clearance therapy is usually accompanied by bronchodilator treatment (alb-uterol [also known as salbut-amol outside the United States] by nebulizer or metered-dose inhaler) to stimulate mucociliary clearance and prevent bronchospasm associated with other inhaled agents.

A mucolytic agent may be administered subsequently to reduce sputum viscosity and enhance clearance. Dornase alfa (Pulmozyme) is a recombinant human (rh) DNase that selectively cleaves extracellular DNA. This DNA is released during neutrophil degradation and contributes to the high viscosity of CF sputum. Nebulization of dornase alfa 2.5 mg once or twice daily improves daily pulmonary symptoms and function, reduces pulmonary exacerbations, and improves quality of life.16

Table 16-1 Common Pulmonary Medications in CF

MrdltAllAn

Adult Don

Albulerol {salbutainotl

Dornte alfa l-typei ionic ialine 7%, IWtOf At Ini i jn JIVJI tui liCOSWi wh' Beclomethasons ButKSurikti FlynUoWe FKilKjiont1 MonmasiXie Triamcinolone

Amihätamlnef A/cbsliw OMMltm DtsloriUdhil Fexofenadine tfMtv'HiliriJifnf Uy-JtJdifVJ

llHJpoAw l.i mg nebulised wllb che&1 ptnyiiothei.dpy (imi> tijily: ¿lldi'UlivKty. two ijuffo mMe^-dc**1 inhaler may In? '^itjiiiRirifd 2.5 mg nebtj:.sed orKeor twee daily Jim nehuli/ed limev/tlay

1-7 sprays pach noitnil twice daiy 1-J Suidyi uäth iiOiHil ifJilv i-7 ififi/i each ncMni twice iiAiy 1-J sprays eacli nosM'i daily 1 SiXiiyfrKh noiliil daily I spay wch fwtinl (till/

1 tjch nusnil tvrfec djily J.h-^rTkjdailyOftlivided tlwiif1 iiilly mg daily 15 30 mr| nvke daily IS nvj daily 5-10 mg diily

Body weight kg: HO ring on Monday:,

WwJnuidayi, ind Fridays J0-S0 nifl/logAioj-(jivfii iwjh* dally

3.i mg nebulired with ch«( phywiltieiapy 3 to 4 Sm« tl&f. JlteorutrviHy, Two |i/fs vu rneifiiid-dosi1 iniwifv may be tttoWufed 25 mg nebulised once a twice daily 4 ml nehulimi 1-4 tinned/may

1-} spaiys «ach nculril 1wice daily

2-4-Küiyi weh <V>ilril daily ivonril iw*:e daily 2 sprays each noSK il daily 2 Sl>Jyi »(h nostril tLjily Of |mice<iaily J sprays each nostril daily or iwrtnc dally

2 sprays racti nosd il twite tViily S-10 mg dstyer dwdid iwsce daily S mg daily

M mg Idaily m 160 niy d jily

Body weight 40 kg o< moief MOmgon Mand^i,

Wednesdays, and Fridays J0-3O mgrtgWose grv?n iiw<i daily

:( cmymjIe .3 fytiul ik cicmrH | irfcrm r .Irn.I iriMMl jnr rntHi' ^ mv ¡Ik .Kpr irl.iti'il ni irririH'iyJ.ritK^ 1 .11 h ¡ikxIih i h.r, [IiHititiI .Kjr rang« and dosing teoomirendai pons.

' Inn ,irkd'.,il ciriinciieioldt may hi»1 mated tvivtl on response -ji■: I prc.v.lun.J y l^n-Vil dwgH fir age.

Adju^tfd to ichiiv:* peakplasim corv.emiarKins<if 5Dio 100 mcg/ml (jmOVIl-Mainrain chmmc deslncfwirh ume do^agfrform arrf manufacture. Note that ttierapy e nol always oonhnued into adulthocd.

Hypertonie saline for inhalation (Hyper-Sal) 7% or 3.5% is sometimes used as an add-on mucolytic agent or for sputum induction. It must be preceded by a bron-chodilator due to a greater incidence of bronchospasm and may not be tolerated by

some patients. N-acetylcysteine is another mucolytic agent, but its unpleasant odor and taste limit patient acceptance.5

Many patients with CF also have reactive airways or concurrent asthma and benefit from long-acting P2-agonists.5 Patients with recurrent wheezing or dyspnea who have demonstrated improvement with albuterol (known as salbutamol outside the Un ited States) should be considered for maintenance therapy, as should patients with bronchodilator-responsive pulmonary function tests (PFTs). Inhaled corticosteroids may also attenuate reactive airways and reduce airway inflammation in some patients; however, clear benefit in CF has not been established.1,18 Drug delivery to the site of inflammation is limited by the severity of lung disease, which may limit efficacy. Patients on inhaled corticosteroids and/or long-acting P2-agonists should administer these medications after airway clearance therapies to optimize drug delivery. Mon-telukast, antihistamines, and/or intranasal steroids are sometimes used for CF patients with reactive airways or allergic rhinitis symptoms.

Long-term systemic corticosteroids have been shown to reduce airway inflammation and improve lung function. However, beneficial effects diminish upon discontinuation, and concern for long-term adverse effects limits their use as mainten-18

ance therapy. In clinical practice, systemic corticosteroids may be added for short courses in acute exacerbations or for treatment of allergic response to Aspergillus colonization (allergic bronchopulmonary a1pergillosis or ABPA); however, dose and duration of therapy should be minimized.1,1

High-dose ibuprofen to achieve peak concentrations of 50 to 100 mcg/mL (243-485 ^mol/L) has been shown to slow progression of disease, particularly in children 5 to 13 years of age with mild lung disease (FEV1 greater than 60%). At high doses, ibuprofen inhibits the lipoxygenase pathway, reducing neutrophil migration and function as well as release of lysosomal enzymes. At the lower concentrations achieved with analgesic dosing, neutrophil migration increases, potentially increasing 20 21

inflammation. ' A dose of 20 to 30 mg/kg given twice daily is usually needed to attain target levels, but interpatient variability necessitates serum concentration monitoring.2 Due to the need for pharmacokinetic monitoring and concerns regarding long-term safety and tolerability, only a few CF centers currently prescribe high-dose ibuprofen.1,18

Azithromycin is a macrolide antibiotic commonly used in CF as an anti-inflammatory agent. The exact mechanism for this activity is unclear, but azithromycin has been shown to improve overall lung function. Proposed mechanisms include interference with Pseudomonas alginate biofilm production, bactericidal activity during stationary

Pseudomonas growth, neutrophil inhibition, interleukin-8 reduction, and reduction in

22,23

sputum viscosity. Due to its long tissue half-life, azithromycin is typically dosed 3 days per week (Monday, Wednesday, and Friday), with a dose of 500 mg for patients weighing at least 40 kg and 250 mg for patients weighing 25 to 39 kg. Alternat ively, patients may take 500 mg or 250 mg either every day or only Monday through Friday, based on the same weight parameters. To minimize the risk of selecting for macrolide-resistant nontuberculous mycobacteria (a contraindication to chronic azithromycin therapy), patients should have a screening acid-fast bacillus sputum culture obtained prior to initiation and then every 6 months.18

Antibiotic Therapy

® Antibiotic therapy is used in three distinct clinical settings within the course ofCF: (a) eradication and delay of colonization in early lung disease; (b) suppression of bacterial growth once colonization is present; and (c) reduction of bacterial load in acute exacerbations in an attempt to return lung function to pre-exacerbation levels or greater. Antibiotic selection is based on periodic culture and sensitivity data, typically covering all organisms identified during the preceding year. If no culture data are available, empiric antibiotics should cover the most likely organisms for the patient's age group. Due to altered pharmacokinetics and microorganism resistance, care must be taken to ensure that optimal doses are prescribed (Table 16-2).

Severity of pulmonary symptoms also guides selection of antibiotic regimens for treatment of acute exacerbations. For recent-onset or mild symptoms, patients may be treated with outpatient oral and inhaled antibiotics for 14 to 21 days. Oral fluoroquinolones are a mainstay among CF patients infected with P. aeruginosa, even in children. Despite concerns regarding cartilage and tendon toxicity in young animals, clinical practice has not shown an increased risk in human children. To prevent development of resistance and promote synergy, inhaled tobramycin or colistin

is usually added for double coverage. ' Methicillin-sensitive S. aureus (MSSA) may be treated with oral amoxicillin-clavulanic acid, dicloxacillin, first-or second-generation cephalosporins, trimethoprim-sulfamethoxazole, or clindamycin, depending on sensitivity. Likewise, methicillin-resistant S. aureus (MRSA) may be treated with oral trimethoprim-sulfamethoxazole, clindamycin, minocycline, or linezolid. H. influenzae often produces P-lactamases but can usually be treated with amoxicillin-clavu-lanic acid, a cephalosporin, or trimethoprim-sulfamethoxazole. Oral trimethoprim-sulfamethoxazole or minocycline may be used to treat S. maltophilia.

Table 16-2 Antibiotic Dosing in CFa

Antibiotic

Pediatric Adult Dose(mg/kg/ Maximum Interval day)_Daily Dose (hours)

Intravenous

Tobramycin,

10

None

8-24

gentamicin*

Amikacin*

30

None

8-24

Ceftazidime

150

6g

8

Cefepime

150

6g

8

Piperacillin-

400

16 g

6

tazobactam

Ticarcillin-

400-600

12-18g

4-6

davulanate

Meropenem

120

6g

8

Imipenem-cilastatin

100

2g

6

Aztreonam

200

8g

6

Ciprofloxacin

30

1.2 g

8-12

Levofloxacin

10-20

750 mg

12-24

Nafcillin

200

12 g

4-6

Vancomycin0

40-60

None

6-1?

Linezolid

20-30

1.2 g

8-12

Colistin

5-8

480 mg

8

Chloramphenicol

60-80

4g

Amoxicillin ± 45-90 4g 12

davulanic acid

Dlcloxatillin 100 2g 6

Cephalexin 5o-ioQ 4 g 6-8

CefLrroxirrie 30 I g 12

Iri met ha prim- 10-20 lr230 mg 6-12 sulfamethoxazole*

Clindamycin 30 1.8 g 6-8

Ciprofloxacin 40 2g 12

Levofloxacin 10-20 750 mg 12-24

Minocycline^ 4 200 mg 12

Linerclid 20-30 1.2 g 8-12

Inhaled

Tobramycin 160-600 mg/day 600 mg 12

Co I is Lin 75 150 rug/day 300 mg 12

JAII doses assume normal renal and hepatic function. Consult a specialized drug reference for dosage adjustment if function is impaired. Dose and/or interval may require adjustment.

'■Empiric starting doses only. Adjust dose per therapeutic drug monitoring.

Dose based on Trimethoprim component. ■'"Children older than S years of ayc\

For more severe infections or patients failing outpatient therapy, IV antibiotic therapy is prescribed for 2 to 3 weeks as inpatient therapy. However, depending on the availability of home health services, some patients may be discharged to finish their course or even receive their entire course at home. Typical regimens for severe infections include an antipseudomonal ft-lactam plus an aminoglycoside for added synergy and delay of resistance development.1,1 Cephalosporins tend to be better tol erated and offer the benefit of administration every 8 hours. Extended-spectrum penicillins have been associated with a higher incidence of allergy. Aztreonam offers the added benefit of little cross-reactivity in penicillin-or cephalosporin-allergic patients; however, it has no gram-positive coverage. Meropenem should be reserved for organisms resistant to all other antibiotics to minimize development of resistance in the carbapenem drug class, as it is the last line of defense against extended-spectrum P-lactamase (ESBL)-producing organisms.

Tobramycin IV is generally the first-line aminoglycoside. Isolates are usually resistant to gentamicin, and amikacin is reserved for tobramycin-resistant strains. Pharmacokinetic goals are listed in Table 16-3. In general, higher peak serum concentrations are targeted to maximize efficacy, whereas lower serum trough levels are targeted to reduce the risk of toxicity. Some centers use once-daily aminoglycoside dosing (tobramycin 10-15 mg/kg/day or amikacin 35 mg/kg/day) to achieve higher peaks and lower troughs. Because aminoglycosides exhibit concentration-dependent killing, once-daily dosing may optimize this effect. However, time below the minimum inhibitory concentration (MIC) is prolonged with once-daily administration in children, possibly leading to loss of synergy for a substantial portion of the dosing interval. Due to a shorter half-life, once-daily aminoglycoside dosing is not optimal for younger children. However, it may be a reasonable option in adults and older teens, in whom the time below the MIC can be minimized. Long-term studies are needed to examine the efficacy and resistance patterns associated with once-daily aminoglycosides in the CF population.1,3

Most other serious gram-negative infections are also treated with combination therapy. S. maltophilia is highly resistant and is most often treated with trimethoprim-sulfamethoxazole or ticarcillin-clavulanate. A. xylosoxidans and B. cepacia are also highly resistant and may have minimal therapeutic options. In some cases, fluoroquinolones maybe substituted for aminoglycosides based on sensitivity data or if renal dysfunction and/or ototoxicity are present. Due to excellent bioavailability, oral fluoroquinolones, trimethoprim-sulfamethoxazole, minocycline, and linezolid should be used whenever possible. Due to toxicity risk, colistin and chloramphenicol are reserved for life-threatening, highly resistant infections. Additional combinations of two or three drugs may be used for highly resistant organisms based on synergy studies that test susceptibility of different antibiotic combinations.

Inpatient treatment of MRSA can consist of IV vancomycin or oral agents as described above, depending on the severity of infection and concomitant organisms. Vancomycin IV may also be converted to oral step-down therapy upon discharge.

Chronic maintenance antibiotic therapy may be used in patients with Pseudomonas colonization in an attempt to prevent bacterial overgrowth. However, long-term systemic antibiotics are not recommended due to emergence of resistance.1 Chronic or rotating inhaled-antibiotic maintenance therapy is used for suppressing P aeruginosa colonization. Inhaled tobramycin (TOBI) is typically administered to patients 6 years of age and older in alternating 28-day cycles of 300 mg nebulized twice daily, followed by a 28-day washout period to minimize development of resistance. Long-term intermittent administration improves pulmonary function, decreases microbial burden, and reduces the need for hospitalization for IV therapy.25,26 Due to minimal systemic absorption, pharmacokinetic monitoring is not necessary with normal renal function. Lower doses of nebulized tobramycin solution for injection have been used in younger children, and studies are underway using 300 mg twice daily in children under age 6 years. Nebulized colistin using the IV formulation may be an option in patients with tobramycin-resistant strains or intolerance to inhaled tobramycin, but pre-treatment with albuterol is necessary due to increased riskofbronchoconstriction.1,5 Inhaled antibiotics are typically stopped during an acute exacerbation requiring IV therapy. Drug delivery is reduced with increased sputum production, and concomitant use of IV aminoglycosides may increase risk of toxicity.

Pharmacokinetic Considerations

CF patients have larger volumes of distribution for many antibiotics due to an increased ratio of lean body mass to total body mass and lower fat stores. CF patients also have an enhanced total body clearance, although the exact mechanism has not been determined. Increased renal clearance, increased glomerular filtration rate, decreased protein binding, increased tubular secretion, decreased tubular reabsorption, extrarenal elimination, and increased metabolism have all been proposed as possible reasons for the increased clearance.

Table 16-3 Pharmacokinetic Goals in Cystic Fibrosis

Because of these pharmacokinetic changes, higher doses of aminoglycosides are needed to achieve target serum levels and promote adequate tissue penetration. Higher doses of P-lactam antibiotics are also needed to achieve and sustain levels above the MIC. Trimethoprim-sulfamethoxazole displays enhanced renal clearance and hepatic metabolism in the CF population. Fluoroquinolones and vancomycin have fewer pharmacokinetic deviations in the CF population; however, higher doses are typically

needed to attain inhibitory serum and tissue concentrations against CF pathogens.

Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased renal clearance. Reasons may include concomitant use of nephrotoxic medications, presence of diabetic neph-ropathy, history oftransplantation (immunosuppressant use and/or procedural hypox-ic injury), age-related decline in renal function in adult patients, and multiple lifetime exposures to aminoglycosides. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to appropriate dosing.

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