CITATION: Saiman L. 1996. Multidrug-resistant organisms in cystic fibrosis--an increasingly important problem. APUA Newsletter 14(3):1,5-6.


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Multidrug-resistant organisms in cystic fibrosis--an increasingly important problem
Lisa Saiman, Columbia University, New York, New York, USA

Enormous progress has been made in understanding the basic genetic defect of cystic fibrosis (CF) and in caring for patients with CF. This improved care has lengthened life expectancy so that a patient born today can expect to live into his or her fifth decade. Indeed, the number of adult patients with CF has increased fourfold from 1969 (8%) to 1990 (33%).1 However, the day-to-day management of chronic pulmonary infection remains difficult, particularly with the emergence of multidrug-resistant Pseudomonas aeruginosa. Respiratory failure continues to be the most frequent cause of death in CF patients.

Young children with CF are colonized early in life with
Staphylococcus aureus, non-typeable Haemophilus influenzae, or less commonly, Klebsiella pneumoniae, organisms that still respond readily to the appropriate antibiotics. By age 26, 81% of patients with CF in the US are colonized or infected with P. aeruginosa.2 Once colonization with P. aeruginosa has occurred, it is rare that this organism is eradicated from the respiratory tract of patients with CF. The pathogenesis of Pseudomonas infection in CF is not fully understood but seems to be a combination of the unique properties of the organism, the unique milieu of the CF lung and the exuberant host immune response.

Antibiotic therapy is the mainstay of treatment of pulmonary exacerbations in patients with CF. Increasingly, antibiotics are also being used prophylactically to prevent colonization and to reduce the bacterial burden of chronically colonized patients. An unfortunate consequence of repeated courses of antipseudomonas antibiotics is the emergence of strains that are more and more resistant. While there is no universal definition for multiple-antibiotic resistance, a panel of international CF experts recently agreed that a
P. aeruginosa isolate from a patient with CF can be defined as multidrug resistant if it is resistant to all agents in two or more of the following classes of antibiotics: the ß-lactams (including imipenem and aztreonam), the aminoglycosides (specifically tobramycin) or the quinolones (generally ciprofloxacin).3 Identification of the organism in at least 2 separate sputum specimens is needed to confirm that a patient is infected with a multidrug-resistant strain. This is a clinically relevant definition in that therapeutic options for these patients are limited to one or no antimicrobial agents. The number of patients with CF infected with multidrug-resistant strains is unknown, however.

In recent years, other opportunistic gram-negative pathogens have been recovered from the sputum of patients with CF that appear to play a variable role in lung disease. At present, 3.2% of patients in the US are infected with
Burkholderia (formerly Pseudomonas) cepacia.1 While the clinical course associated with B. cepacia varies, in about 20% of patients, infection with this pathogen is associated with rapid deterioration and even death. Burkholderia cepacia is highly resistant to antibiotics, and finding the most effective treatment regimens is extremely difficult.

Less is understood about the epidemiology and clinical significance of other gram-negative organisms, such as
Stenotrophomonas (formerly Xanthomonas) maltophilia, Alcaligenes (formerly Achromobacter) xylosoxidans and non-P. aeruginosa pseudomonads. Methicillin-resistant S. aureus and non-tuberculous mycobacteria have also become of concern. These species tend to be highly resistant to antimicrobial agents, and optimal therapy for patients with CF colonized or infected with these organisms is not known.

Referral Center Established
In April 1991, a referral center was established at Columbia University (Department of Pediatrics, Columbia University, 650 W 168 Street, BB4-427, New York, NY 10032; 212-305-1991) to develop rational strategies for antibiotic treatment of multidrug-resistant
P. aeruginosa isolated from patients with CF. The center performs conventional susceptibility testing on clinical isolates of P. aeruginosa using 10 antipseudomonas drugs. Nine pairs of these drugs, designed to mix different classes of antibiotics and to reflect clinically achievable concentrations, are used in checkerboard dilutions to test for synergistic effect.4,5 From August 1991 to the present, 3000 clinical isolates have been received from CF centers across the US for testing. In a recent publication describing the center, 172 isolates from individual patients were multidrug resistant, 55% of which were resistant to all antibiotics tested.5

Evaluation of Investigational Antibiotics
The center also screens investigational antipseudomonas compounds against these isolates. Susceptibility testing with multidrug-resistant
P. aeruginosa strains from patients with CF can uncover potential deficits of investigational drugs and in so doing may offer a more accurate assessment of the potential of new agents. Thus far, several investigational antibiotics have been studied, including cefepime, a novel third-generation cephalosporin with antipseudomonas activity; tazobactam, a ß-lactamase inhibitor with affinity for the ß-lactamase of P. aeruginosa, paired with piperacillin; and three investigational quinolones. Studies with meropenem and temocillin are underway.

Mechanisms and Epidemiology of Antibiotic Resistance
The referral center endeavors to centralize and standardize studies of multidrug-resistant strains from a wide geographic area, thereby identifying patterns and trends in the development of resistance. Just as the improved survival of patients with CF has paralleled the development of antipseudomonas antibiotics, the patterns of identified resistance may reflect the use of each antibiotic class in the general population. While organisms may be susceptible initially (Table), significant resistance has been found to the ß-lactam drugs, which have been used for 3 decades. Patterns of resistance in CF isolates may be increasingly relevant to non-CF-related isolates of
P. aeruginosa, as evidenced by a recent study from 5 American medical centers.6

Studies of aminoglycoside-resistant strains have shown that a permeability mutation (diminished uptake) is the most common mechanism of resistance and that the aminoglycoside-modifying enzyme AAC(6')-II is most common in
P. aeruginosa isolates.7 We found that more than 95% of isolates resistant to conventional tobramycin levels (MIC ³ 4 µg/ml) could be inhibited by high-dose tobramycin (100 or 200 µg/ml), such as achieved by aerosol therapy.5 Further, we found that the combination of amikacin and ceftazidime was additive or synergistic in all strains with AAC(6')-II.

Resistance to fluoroquinolones often develops during therapy, but reversion to a susceptible phenotype can occur when therapy is stopped.
8 This finding suggests that prolonged courses of ciprofloxacin should be avoided.

Susceptibility and synergy studies on non-pseudomonas species. The nosocomial pathogens
B. cepacia, S. maltophilia, and A. xylosoxidans are becoming increasingly prevalent in patients with CF. Generally multidrug resistant, little is known about the optimal management of these organisms in these patients. To date, we have received 150 B. cepacia strains and 100 S. maltophilia strains from clinicians requesting suggestions for treatment and are in the process of improving the susceptibility and synergy panels for these species.

Multidrug Resistance in Patients with CF Undergoing Lung Transplantation
Patients with CF are more commonly becoming candidates for lung transplantation. Therefore, treatment of multidrug-resistant organisms in patients with CF before and after lung transplantation has become a major challenge; no standard protocol has been set yet. Because bacteremia and pneumonia with
P. aeruginosa are serious threats to patients with CF after transplantation, infection in these immunosuppressed hosts can be life threatening. Therefore, the prevalence of bacterial colonization and infection in patients with CF, particularly with multidrug-resistant organisms, raises many issues with regard to the appropriateness and viability of lung transplantation. Modified susceptibility and synergy panels have been and will be used by our center to generate therapeutic options for transplantation patients. More data regarding current infectious disease management are needed to follow the outcome of lung transplantation in CF patients infected with multidrug-resistant pathogens and to develop pre- and posttransplant prophylactic antibiotic therapy regimens.

Developments in Therapies for CF
Innovative ways to use currently available antibiotics to provide adequate treatment for patients with CF are needed as development of new antibiotics progresses slowly. Using
antibiotics in combination seems to provide synergism and perhaps slows the emergence of resistance, especially when the two antibiotics have different mechanisms of action. The clinical data supporting this practice, however, are limited.
9
Alternative means of administering drugs, such as by aerosol, have recently seen renewed interest. In contrast to intravenous administration, aerosolized aminoglycosides deliver high levels of antibiotic directly to the lungs without toxicity. For this reason, susceptibility testing for tobramycin in our center includes concentrations of 100 and 200 µg/ml. Similarly, aerosol colistin, which is widely used in Europe and in some centers in North America, has been shown to be safe and without the side effects associated with intravenous colistin.
10 However, optimal dosage and delivery systems have not been studied.

Adjuvant Therapies
Several adjuvant therapies have resulted from the increased understanding of the molecular and genetic causes of CF, offering patients and their families hope for improved medical management and perhaps in time a possible cure. Designed to normalize pulmonary secretions, relieve airway obstruction and decrease inflammation, these agents may reduce bacterial load and injurious products of infection and inflammation, improve clearance of secretions from the lung, increase pulmonary function, facilitate antibiotic penetration into the secretions and restore opsonophagocytosis of infectious organisms.

The simplest of all adjuvant therapies that may effectively combat infection is mechanical clearance of secretions from the airways. Other agents under investigation include amiloride, the extracellular triphosphate nucleotides ATP and UTP, recombinant human DNAse, antiproteases and ibuprofen. Gene therapy is the ultimate hope for correcting the deficits in the CF lung.

The impact of theses therapies on the microbiology of CF is unknown. It is likely that despite numerous advances in the management of patients with CF, with increased longevity and improved quality of life, infection with multidrug-resistant organisms will still occur and therapeutic strategies for treatment will continue to be necessary.

References

  1. Cystic Fibrosis Foundation National Registry. Cystic Fibrosis Foundation, Bethesda, Md., 1995.
  2. FitzSimmons SC. J Pediatr 1993;122:1-9.
  3. Cystic Fibrosis Foundation. Consensus Conferences: Concepts in Care. 1994;Vol. V(Sect. 1):1-26.
  4. Saiman L, Niu WW, Prince A, et al. Pediatr Pulmonol 1991;56:279.
  5. Saiman L, Mehar F, Niu WW, et al. Clin Infect Dis 1996;23:532-7.
  6. Jones RN, Pfaller MA, Fuchs PC, et al. Diagn Microbiol Infect Dis 1989;12:489-94.
  7. Shaw KJ, Hare RS, Sabatelli FJ, et al. Antimicrob Agents Chemother 1991; 35:2253-61.
  8. Diver JM, Schollaardt T, Rabin HR, et al. Antimicrob Agents Chemother 1991;35:1538-46.
  9. Stratton CW, Tansk F. J Antimicrob Chemother 1987;19:413-6.
  10. Jensen T, Pedersen SS, Garne S, et al. J Antimicrob Chemother 1987;19:831-8.
 

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