Considerations for Aerosolized Antibiotics in Multidrug-Resistant Gram-Negative Pneumonia

Hospital-acquired and ventilator-associated pneumonias (HAPs/VAPs) are common infections linked with significant morbidity and mortality, particularly when caused by multidrug-resistant gram-negative bacilli (MDR GNB) such as Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacterales.^1,2 The increasing prevalence of pneumonia caused by these organisms, which often exhibit reduced susceptibility to β-lactam antibiotics, has led to a resurgence of the use of aminoglycoside or polymyxin therapies in certain applications.^2,3 However, the utility of these systemic agents in pneumonia is limited by low lung concentrations and narrow or poorly understood therapeutic indices.^3-6 These treatment barriers may ultimately contribute to inferior outcomes in critically ill patients with pneumonia.⁷ From a pharmacokinetic and pharmacodynamic perspective, aerosolized antibiotic formulations have several perceived advantages over conventional systemic therapy for treatment of MDR gram-negative pneumonia, but data remain limited. Still, aerosolized antibiotics are prescribed for nosocomial pneumonias in up to 67% of intensive care units worldwide,⁸ with tobramycin, amikacin, and colistin most frequently used.

BACKGROUND

Unlike in systemic administration, aerosolized antibiotics avoid the need for drug diffusion across the blood-alveolar barrier into the epithelial lining fluid, a process dependent on antibiotic physicochemical properties (eg, lipophilicity, molecular weight, protein binding) and patient-specific characteristics (eg, tissue permeability, renal function) that may complicate target-site penetration.⁹ Aminoglycosides and polymyxins have been found to poorly concentrate in lung tissue of humans and large animals due to compound hydrophilicity and/or poor lung tissue binding properties.^4,5 Direct antibiotic administration through inhalation allows for higher parenchymal concentrations and maximal antibiotic exposures needed for pharmacokinetic/pharmacodynamic optimization, with limited systemic drug exposure and risk for toxicity.^9,10 Aerosolization technique (eg, nebulization, metered or dry powder inhaler) and availability of inhalation powder formulations have also been shown to impact the efficiency of aerosolization.¹⁰

Elevated minimum inhibitory concentrations (MICs) of MDR GNB and poor lung concentrations achieved by systemic aminoglycosides and polymyxins require aggressive dosing strategies to effectively treat severe pneumonia.^4,6,9 Prolonged high-dose exposures of these antibiotics may ultimately potentiate the risks of toxicities; some literature suggests the prevalence of nephrotoxicity to be 43% to 58% with either antibiotic class.^11,12 To avoid these issues related to systemic use, some clinicians have used aerosolized aminoglycosides and polymyxins as adjunctive treatment in MDR GNB pneumonia with some success.

CLINICAL DATA

The majority of published aerosolized antibiotic data in nosocomial pneumonia are limited by comparisons of heterogeneous antibiotic and dosing regimens, questionable pneumonia diagnostic criteria, nonstandard endpoint definitions, and small patient samples.^10,13 Furthermore, many studies used variable aerosolization techniques and were not designed to assess differences in efficacy for patients receiving adjunct inhaled antibiotics. These concerns ultimately make study results difficult to extrapolate to the general population, although the theoretical benefits of inhaled antibiotic administration remain valid. Most studies to date have assessed aerosolized tobramycin or colistin, both available as powdered formulations for inhalation, as adjunct therapy to systemic therapy (ie, inhaled drug combined with the intravenous [IV] drug formulation), and typically in combination with a β-lactam, although a few trials describe an inhaled antibiotic as a single agent used in combination with another antibiotic class. Although some data suggest no difference in outcomes,^10,13,14 several recent studies have found treatment success with aerosolized antibiotics in MDR gram-negative pneumonia.^15-17

Tumbarello et al performed a matched retrospective analysis of patients receiving aerosolized colistin plus IV colistin (n = 104) to IV colistin alone (n = 104) in microbiologically confirmed MDR GNB VAP and found significant improvement in clinical cure at the end of therapy (P = .03) and decreased duration of mechanical ventilation (P = .001) in the adjunct aerosolized colistin group.¹⁵ Similarly, a retrospective study performed by Doshi et al found significant improvement in clinical cure at the end of therapy (P = .033) when adding aerosolized colistin to IV colistin (n = 35) compared with IV colistin alone (n = 33) for MDR GNB pneumonia with high-quality cultures.¹⁶

Hassan and colleagues performed a randomized trial comparing the efficacy of nebulized amikacin with piperacillin/ tazobactam (n = 86) to IV amikacin with piperacillin/ tazobactam (n = 47) in post—cardiac surgery patients with HAP or VAP caused by microbiologically confirmed MDR GNB.¹⁷ Efficacy was defined as clinical cure evaluated on day 7 of amikacin initiation: normalized body temperature, total leukocyte count less than 10,000/mL, absence of purulent secretions, and improvement of radiological findings, in addition to PaO2/FiO2 greater than 250 in patients with VAP. Clinical cure was significantly higher in the nebulized group (P = .002), and this association was retained in a stratified analysis by isolated organism. Patients receiving IV amikacin also developed acute kidney injury more frequently than the nebulized group (P = .0232). Although these data are interesting, another recent randomized trial by Kollef et al found no differences (P = .70) in the clinical pulmonary infection score for patients with GNB VAP receiving an amikacin/fosfomycin inhalation system (n = 71) in addition to standard antibiotics compared with a control group (n = 72).¹⁴

SAFETY AND ADVERSE EFFECTS

Aerosolized antibiotics are generally well tolerated and display a good safety profile, with the most common adverse effects identified as bronchospasm and wheezing.^10,13 The limited systemic antibiotic exposure achieved with aerosolization has resulted in no data identifying associations with nephrotoxicity in humans. Hypotension and fatal respiratory distress have been documented in patient cases where parenteral powder formulations were used for inhalation and thus should be avoided.^18,19 Prior to the development of inhalation formulations, antibiotics were extemporaneously compounded from IV powder or solution and subsequently aerosolized, which was found to induce bronchospasm and pneumonitis potentially related to the presence of preservatives in the IV powder or solution.²⁰ Inhaled antibiotic formulations do not contain preservatives.¹³

FUTURE DIRECTIONS AND CONCLUSIONS

The optimal patient population for aerosolized antibiotic therapy remains controversial. The 2016 Infectious Diseases Society of America and the American Thoracic Society guidelines on the management of HAP and VAP provide narrow recommendations for aerosolized antibiotic use in patients with documented MDR gram-negative infections susceptible to only aminoglycosides and colistin (weak recommendation, low-quality evidence) and in combination with systemic therapy.²¹ Although the use of concomitant systemic aminoglycoside or colistin therapy may negate the main advantages of aerosolized antibiotics (ie, high lung drug exposure and minimal risk of toxicity), the low systemic antibiotic concentrations achieved after inhalation suggest use as monotherapy is likely not appropriate in critically ill patients with MDR GNB pneumonia at risk for seeding extrapulmonary foci.

Controversy also remains in regard to the utility of, or warranted duration of, combination therapy in MDR GNB infections.³ However, in select populations with HAP/VAP (eg, critically ill patients, high institutional prevalence of MDR GNB), it would seem reasonable to utilize at least 1 dose of systemic antibiotics in combination with inhaled formulations until respiratory culture susceptibilities have resulted, as aminoglycoside- or colistin-associated nephrotoxicity develops after roughly 6 days of therapy.^11,12

The lack of therapeutic options for lower respiratory tract infections caused by emerging bacterial pathogens represents a major threat to humanity.² Fortunately, the landscape for new antibiotics targeted toward MDR GNB is promising.²² New data surrounding recently developed antibiotics suggest they achieve adequate pulmonary concentrations and are effective compared with conventional regimens.^23,24 As more efficacious and less toxic antibiotics are developed, the role for aminoglycoside and polymyxin therapies, including aerosolized formulations, may be regulated for use in other populations, such as patients with cystic fibrosis.

Dr. Veve is a clinical assistant professor at the University of Tennessee Health Science Center College of Pharmacy and an infectious diseases specialist at the University of Tennessee Medical Center in Knoxville, Tennessee. He received a PharmD at the Albany College of Pharmacy, in Albany, New York, and completed a PGY1 pharmacy practice residency at Henry Ford Hospital in Detroit, Michigan, and an infectious diseases pharmacotherapy fellowship at Wayne State University/Henry Ford Hospital, also in Detroit.

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