Inhaled Antimicrobials in the Treatment of Hospital-acquired Pneumonia

Part I of II-Part Series

By Emily Cheng, PharmD Candidate, PharmD Candidate at the University of the Pacific, and Jessica C. Song, MA, PharmD, PharmD at the University of the Pacific, is Associate Editor for Infectious Disease Alert.

Emily Cheng and Jessica C. Song report no financial relationships relevant to this field of study.

Hospital-acquired pneumonia (HAP) represents the second most common nosocomial infection, accounting for 15% of all hospital-associated infections.1 Multiple parenteral antibiotic regimens have been recommended for use in the treatment of HAP patients, as illustrated in the American Thoracic Society treatment guidelines.2 However, the treatment of HAP has been complicated by the emergence of multidrug-resistant (MDR) organisms such as Pseudomonas aeruginosa and Acinetobacter baumannii.2

The use of antibiotics via inhalation as prophylaxis against chronic Pseudomonas aeruginosa pulmonary infections in cystic fibrosis patients, has been extensively reported in the medical literature.3 At present, few studies have examined the efficacy of aerosolized antibiotics in the treatment of nosocomial respiratory tract infections. Ioannidou et al conducted a meta-analysis of five randomized, controlled trials that compared inhaled (or endotracheally instilled) antibiotics (tobramycin, 3 trials; sisomycin, 1 trial; gentamicin, 1 trial) with control treatment (placebo, 4 trials; intramuscular gentamicin, 1 trial).4 Administration of aminoglycosides via the respiratory tract improved treatment success in the intention-to-treat patients (odds ratio = 2.39, 95% CI, 1.29 to 4.44).

To date, small case studies and larger studies have evaluated the efficacy of colistimethate (Coly-Mycin), amikacin, tobramycin, and ceftazidime in the treatment of HAP/VAP (ventilator-associated pneumonia) patients.5-9 In addition, aerosolized amphotericin B deoxycholate and liposomal amphotericin B (AmBisome) have been studied for use as prophylaxis against invasive Aspergillosis infections.10-12

This two-part review (part II will come in a future issue) will discuss the use of inhaled antibiotics in the treatment of HAP/VAP, along with the use of aerosolized amphotericin B for prophylaxis of invasive fungal infections in patients at high risk for acquiring these infections. Part I will highlight aerosolized colistimethate and amphotericin B. Part II will continue with a discussion on aerosolized tobramycin, amikacin, and ceftazidime.

Part I: Colistimethate and Amphotericin B

Administration of Inhaled Colistimethate and Amphotericin B (Deoxy Cholate/Liposomal)

Inhaled antibiotics may be more valuable than intravenous antibiotics in the treatment of HAP for several reasons. Direct delivery of antibiotics to the lungs results in higher concentrations at the site of infection and increased drug efficacy.5,6 Also, local administration reduces the risk of systemic toxicity. The most common adverse reaction associated with inhaled antibiotics is bronchospasm.5 Administration of a short-acting b2-agonist bronchodilator (albuterol) before inhalation therapy can mitigate this side effect.

Parenteral colistimethate is indicated for the treatment of infections caused by gram-negative bacteria, but is infrequently used because of its association with nephrotoxicity and neurotoxicity.13 European studies have primarily utilized the prodrug colistimethate sodium (Coly-Mycin) rather than colistin sodium because it is better tolerated and easier to prepare for inhalation.5,7,8 Aerosolized solution can be prepared by reconstituting one vial of colistimethate for injection in a suitable volume (usually 4-5 mL) of normal saline or sterile water and placing it into a nebulizer.13 Colistimethate studies have used a dosing range of 1.5 to 6 million IU per day (12,500 IU is equal to 1 mg), divided into 2-4 doses.5,7,8 When administered via inhalation, colistimethate is most commonly associated with bronchoconstriction, which can be prevented with pretreatment. Severe adverse effects such as nephrotoxicity and neurotoxicity are rare. There has been one reported death associated with aerosolized colistimethate. When the prodrug colistimethate is mixed with water, it undergoes hydrolysis, creating two forms of the active drug, one of which is toxic to lung tissue. The concentration of this metabolite increases with time, and can result in severe pulmonary and systemic toxicity. Thus, colistimethate for inhalation should be used within 24 hours of preparation.13 For Santa Clara Valley Medical Center's protocol on aerosolized colistin, refer to appendix I below.

Intravenous amphotericin B is indicated for the treatment of numerous fungal infections. Like colistimethate, intravenous amphotericin B is associated with systemic toxicity, which can be avoided with aerosolized formulations. Inhalation solutions of amphotericin B deoxycholate and AmBisome® can be prepared by reconstituting the vial of powder for injection with sterile water. For amphotericin B deoxycholate, solutions of 2 mg/mL and 10 mg/mL have been used for inhalation in clinical studies.10,12 AmBisome® can be reconstituted to a concentration of 5 mg/mL.11 After reconstitution, these solutions can be placed in a nebulizer for use.

Clinical Trials of Colistimethate and Amphotericin B Aerosolized colistin/colistimethate has been studied as an adjunctive measure to parenteral antibiotics in the treatment of P. aeruginosa and A. baumannii infections.

Berlana et al studied the effects of inhaled colistimethate on the clearance of causative organisms from sputum, urine, blood, and CSF.7 Concurrent systemic antibiotics were given to 73% (53 out of 80) of patients. Results showed aerosolized colistimethate to be both efficacious and safe. Michalopoulos et al studied inhaled colistimethate as an adjunct to intravenous levofloxacin, co-trimoxazole, ciprofloxacin, meropenem, tobramycin, aztreonam, or gentamicin.8 This study also found inhaled colistimethate to be beneficial in combination with IV antibiotics against MDR HAP. The details of these studies can be found in Table 1.

Inhaled amphotericin B has been studied as prophylaxis against aspergillosis in immunocompromised patients. Posaconazole is indicated for prophylaxis of Aspergillus and Candida infections in immunocompromised patients, but has been shown to interact with multiple drugs, and should be used with caution in patients with impaired hepatic function.14,15 Dubois et al studied the physiologic effects of inhaled amphotericin B after a mean of 4.98 treatments in granulocytopenic patients. They found that aerosolized amphotericin B deoxycholate is generally well-tolerated, with few mild adverse reactions such as nausea, vomiting, and cough.10

Rjinders et al performed a trial using aerosolized liposomal amphotericin B (AmBisome®) in neutropenic patients who received prior fluconazole prophylaxis.11 During the treatment period for patients given aerosolized AmBisome® and placebo, inhaled AmBisome® resulted in lower incidence of invasive Aspergillus infection (4% vs 14%, p = 0.005).

Schwartz et al conducted a study using inhaled amphotericin B deoxycholate for prophylaxis against invasive aspergillosis in patients with prolonged neutropenia. In this study, antibacterial prophylaxis was administered to some patients, and oral antifungals (amphotericin and fluconazole) were allowed for prophylaxis against Candida species. In contrast to the findings of Rjinders et al, Schwartz et al failed to demonstrate the prophylactic efficacy of aerosolized amphotericin B deoxycholate against the development of invasive Aspergillus infection. Table 2 outlines the key data regarding the efficacy of aerosolized amphotericin B as prophylaxis for invasive Aspergillus infection.

Conclusion

As MDR organisms become more prevalent in the hospital setting, inhaled antimicrobials may be considered as a treatment option. Direct administration of antimicrobials to the lungs, in combination with parenteral antimicrobials, may enhance clinical outcomes, and does not appear to be associated with systemic toxicity. Clinical studies of inhaled colistimethate show that it is beneficial against P. aeruginosa and A. baumannii pneumonia. While the studies of inhaled amphotericin have yielded mixed results, this antifungal class may still represent an option for the prevention of fungal infections in immunocompromised patients who are unable to tolerate azole antifungals or echinocandins.

References

  1. Tablan OC, et al. Guidelines for preventing health-care-associated pneumonia, 2003: Recommendations of the CDC and Healthcare Infection Control Practices Advisory Committee. Accessed on November 2, 2008. http://www.cdc.gov/ncidod/dhqp/gl_hcpneumonia.html
  2. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005:171:388-416.
  3. Lobue PA. Inhaled tobramycin: not just for cystic fibrosis anymore? Chest. 2005;127:1098-1101.
  4. Ioannidou E, et al. Administration of antimicrobials via the respiratory tract for the treatment of patients with nosocomial pneumonia: a meta-analysis. J Antimicrob Chemother. 2007;60:1216-1226.
  5. Dhand R. The role of aerosolized antimicrobials in the treatment of ventilator-associated pneumonia. Respir Care. 2007:52:866-884.
  6. Bressolle F, et al. Endotracheal and aerosol administration of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability. Antimicrob Agents Chemother. 1992:36:1404-1411.
  7. Berlana D, et al. Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. Am J Health Syst Pharm. 2005:62:39-47.
  8. Michalopoulos A, et al. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant gram-negative bacteria in patients without cystic fibrosis. Crit Care. 2005:9:R53-R59.
  9. Standridge JB, Aliff CL. Aerosolized amikacin in the treatment of Pseudomonas pneumonia in the nursing home setting. South Med J. 2001:94:244-246.
  10. Dubois J, et al. The physiologic effects of inhaled amphotericin B. Chest. 1995:108:750-753.
  11. Rjinders BJ, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled study. Clin Infect Dis. 2008:46:1401-1408.
  12. Schwartz S, et al. Aerosolized amphotericin B inhalations as prophylaxis for invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood. 1999:93:3654-3661.
  13. Information for healthcare Professionals: Colistimethate (marketed as Coly-Mycin M and generic products". 28 Jun 2007. US Food and Drug Administration. 1 Nov 2008. http://www.fda.gov/CDER/DRUG
  14. Posaconazole (Noxafil®) prescribing information. Kenilworth, NJ:Schering-Plough:2008.
  15. Cornely OA, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007:356:348-359.

APPENDIX I

Policy: Aerosolized Colistin may be used to treat acute or chronic pulmonary infections secondary to multi-drug resistant Pseudomonas aeruginosa or other susceptible bacteria refractory to conventional therapy (oral and IV medications). Aerosolized Colistin must be delivered via a closed nebulizer system or in the hood in the Respiratory Care Special Procedure Room. A Pulmonary Attending order/approval is mandatory.

Responsible Party: Respiratory Care

Action:

  1. Review patient's chart for:
    1. Admitting diagnosis
    2. Patient's history and appropriate laboratory data
    3. Order for Colistin "150 mg BID" via PARI LC PLUS Filtered Nebulizer. Order must be by Pulmonary Attending Only.
  1. Verify that the patient has signed an informed con sent form for non-FDA approved delivery of Colistin.
  1. Contact Pharmacy to inform them of order for Colistin.
  1. Obtain medication from Pharmacy. (Any questions regarding the reconstitution of the Colistin, please contact the Pharmacy).
  1. Gather equipment:
    1. Flowmeter
    2. PARI LC PLUS Filtered Nebulizer System
    3. Nose clips or aerosol mask if indicated
    4. Ordered antibiotic
    5. Hand-held nebulizer
    6. Bronchodilator
  1. Introduce yourself to the patient.
  1. Wash your hands.
  1. Check patient identification wristband.
  1. Explain procedure to patient.
  1. Assemble and check equipment for proper function.
  1. Administer Albuterol treatment via Respiratory Care Small Volume Nebulizer Procedure B7180-29. (Administer Alupent or Atrovent if contraindications to Albuterol exist).
  1. Upon completion of the bronchodilator treatment place contents of the antibiotic vial into the PARI LC PLUS Filtered Nebulizer System.
  1. Place patient in the hood in the Special Procedure Room or verify that patient is in single patient room.
  1. Perform patient assessment. Assessment to include but not limited to:
    1. Respiratory Rate
      1. Hold for Respiratory Rate ≥ 25/minute
    2. Breath sounds — aeration, wheezes, rhonchi, rales and locations in lungs
    3. Pulse (Additionally checked mid-therapy)
      1. Hold or stop therapy for:
        1. Pulse greater than 120/minute or limits ordered by physician
        2. Increase in pulse with treatment greater than 20/minute
        3. Notify MD/Nurse of these conditions and "the holding" of therapy
    4. Respiratory effort — easy, unlabored, dyspneic, SOB, use of accessory muscles, retractions
    5. Chest expansion — good, improved, equal
    6. Cough effort — good, poor, splinting
    7. Sputum — color, quantity, viscosity
    8. Patient indicated response (when possible)
    9. Subjective evaluation of response — no apparent distress, relief from SOB, tolerated well
    10. Adverse reactions
    11. Mental status/behavior — uncooperative, combative, agitated, cooperative
  1. Have patient place mouthpiece into his/her mouth and adjust flow of gas for a continuous, dense mist. (Approximately 6-8 LPM).
  1. Instruct the patient to breathe through their mouth until all the medication has been nebulized.
  1. At the end of the treatment, have the patient rinse their mouth with water.
  1. Shake out the PARI LC PLUS Filtered Nebulizer System and store in patient storage bag.
  1. Perform patient assessment as before.
  1. Chart in Medi-Serve. Charting should include but is not limited to the following:
    1. Respiratory Rate
    2. Breath sounds — aeration, wheezes, rhonchi, rales and locations in lungs
    3. Pulse
    4. Respiratory effort — easy, unlabored, dyspneic, SOB, use of accessory muscles, retractions
    5. Cough effort — good, poor, splinting
    6. Sputum — color, quantity, viscosity
    7. Patient indicated response (when possible)
    8. Adverse reactions
    9. Drug and dose administered, and how tolerate
  1. Patient must remain in closed isolation room for one hour after treatment, any person entering the room during the treatment or within one hour of the Colistin treatment must wear a TB isolation mask.
  1. Adverse reaction:
    1. Bronchospasm

Serial Dilution of Inhalation Sulfite Challenge

A serial dilution of decreasing concentrations of Colistin will be mixed by the pharmacy for the Inhalation Sulfite Challenge.

• Start with 1 mL of 150 mg/mL solution of Colistin mixed with 9 mL of normal saline (NS) to come up with 15 mg/1 mL solution. This will be sample 4.

• Withdraw 1 mL from Sample 4 and mix with 9 mL of NS to come up with 1.5 mg/1 mL solution. This will be sample 3.

• Withdraw 1 mL from Sample 3 and mix with 9 mL of NS to come up with 0.15 mg/1 mL solution. This will be sample 2.

• Withdraw 1 mL from Sample 2 and mix it with 9 mL of NS to come up with 0.015 mg/1 mL solution. This will be Sample 1.

Medication will be administered serially in increasing concentrations as follows:

  Sample 1 0.015 mg/mL
  Sample 2 0.15 mg/mL
  Sample 3 1.5 mg/mL
  Sample 4 15 mg/mL

Source

Appendix I is Santa Clara Valley Medical Center's protocol on aerosolized colistin.

Resource

  1. Hamer DH. Treatment of nosocomial pneumonia and tracheobronchitis caused by multidrug-resistant Pseudomonas aeruginosa with aerosolized colistin. Am J Respir Crit Care Med. 2000;162:328-330.