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(Chest. 2005;127:2231-2236.)
© 2005 American College of Chest Physicians

Clinical Significance of the Infection-FreeInterval in the Management of Acute Bacterial Exacerbations of Chronic Bronchitis*

Sanford Chodosh, MD, FCCP

* From the Boston University School of Medicine, Boston, MA.

Correspondence to: Sanford Chodosh, MD, FCCP, 35 Oak Hill Rd, Wayland, MA 01778-2917; e-mail: schodosh15{at}comcast.net


   Abstract
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 Abstract
Introduction
 IFI
 Incorporating the IFI in...
 Summary
 References
 
Rational and appropriate antibiotic use for patients with acute exacerbation of chronic bronchitis (AECB) is a major concern, as approximately half of these patients do not have a bacterial infection. Typically, the result of antimicrobial therapy for patients with acute bacterial exacerbation of chronic bronchitis (ABECB) is not eradication of the pathogen but resolution of the acute symptoms. However, the length of time before the next bacterial exacerbation can be another important variable, as the frequency of exacerbations will affect the overall health of the patient and the rate of lung deterioration over time. Clinical trials comparing antimicrobial therapies commonly measure resolution of symptoms in AECB patients as the primary end point, regardless of whether the exacerbation is documented as bacterial in nature. Ideally, the scientific approach to assessing the efficacy of antibiotic therapy for ABECB should include a measurement of acute bacterial eradication rates in patients with documented bronchial bacterial infection followed by measurement of the infection-free interval (IFI), ie, the time to the next ABECB. The use of these variables can provide a standard for comparing various antimicrobial therapies. As we learn more about how antibiotics can affect the IFI, treatment decisions should be adapted to ensure optimal management of ABECB for the long-term.

Key Words: acute bronchitis • acute exacerbation of chronic bronchitis • antibiotics • disease-free interval • infection-free interval


   Introduction
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 Abstract
 Introduction
IFI
 Incorporating the IFI in...
 Summary
 References
 
Chronic bronchitis (CB) is estimated to affect approximately 13 million people in the United States (nearly 5% of the total population).123 Acute exacerbation of CB (AECB) is a frequent and troublesome occurrence and accounts for significant morbidity and loss of time from work and normal activities. Even the stable symptoms of chronic cough, sputum production, and some degree of dyspnea affect the physical well being and quality of life of patients with CB. AECB increases baseline discomfort, and the frequency of exacerbations can affect declining health status and lung function over the long-term.45 Prompt diagnosis of the etiology of an AECB followed by specific therapy may decrease the duration of morbidity.6 Proper, rapid treatment may also improve the overall status of the disease process, which, if left untreated, can lead to declining pulmonary function and disability.7

The practice of treating AECB empirically with antimicrobials without first establishing a bacterial cause presents both medical and economic concerns.1 These concerns can also include antibiotic treatment for acute bronchitis in patients without underlying CB.89 Antimicrobial therapy is useful only for acute bacterial exacerbation of CB (ABECB). Although prescribing habits for treating AECB are based on results from comparative clinical trials, these studies typically include a high percentage of patients without proven bacterial infection and may provide misleading information regarding the efficacy of antibiotic therapy.310 The inclusion of large percentages of nonbacterial AECB in clinical trials dilutes the value of the clinical outcome, since many of these cases are either self-limiting or are concomitantly treated with supportive therapy. The broader medical and economic implications of the current practice include a higher overall cost for unnecessary antibiotics and a greater risk for development of bacterial resistance.811 Additionally, favoring the use of empiric antimicrobial therapy may reduce the chance of providing the appropriate specific therapy for the other possible causes of AECB.

The proper evaluation of antimicrobial therapy in ABECB depends on careful and appropriate examination of the sputum expectorated by the patients. The basis for sputum evaluation has previously been reported.612131415 However, our clinical environment does not afford the opportunity to allow careful analysis for each patient, particularly in primary care clinics, mainly due to time and constraints imposed by clinical laboratory guidelines. For this reason, numerous treatment strategies have been published based on limited evidence-based methodology to determine a rational course of treatment.161718 The practical aspects of these therapeutic strategies will not be covered in this report. The following discussion will examine the use of the infection-free interval (IFI) in determining the effectiveness of an antibiotic treatment for ABECB, and how the IFI may affect treatment decisions when choosing an optimal antibiotic. Comparative ABECB and AECB clinical trials that included long-term follow-ups (≥ 6 months) to measure the time until the next acute exacerbation have been included in this analysis.


   IFI
TOP
 Abstract
 Introduction
 IFI
Incorporating the IFI in...
 Summary
 References
 
Although numerous comparative clinical trials have been conducted through the years to compare antibiotic therapies for treating AECB, studies in which all or a high percentage of patients have confirmed ABECB can provide a more accurate assessment of the effectiveness of antibiotic therapy. Although these trials do not usually demonstrate significant differences between antibiotic agents for short-term efficacy (14 to 21 days after treatment ends), differentiation between treatment options may be observed when long-term follow-ups (≥ 6 months) are conducted. The IFI, defined as the time in days from the end of therapy to the onset of the next ABECB, can provide important information regarding the long-term effectiveness of antibiotic therapy.619 The IFI is distinctly different from the disease-free interval (DFI), which does not necessarily attribute the initial and/or subsequent exacerbations to bacterial causes. The concerns of using the DFI to assess antimicrobial efficacy will be described later.

Agents that prolong the IFI can offer important clinical and economic advantages.419 A decrease in the frequency of exacerbations will result in less office visits and potential hospitalizations, and a decreased use of antibiotics, lowering overall medical costs. Less antibiotic usage may also reduce the risk of resistance development as usage has been linked to the emergence of resistance.11 Studies520 have also suggested that patients with more frequent episodes of AECB experience a greater rate of lung function deterioration and worse overall health status. Additionally, patients with an early relapse after antibiotic therapy experience prolonged negative effects in overall health.21

Data from a number of clinical trials1022232425 suggest that certain antimicrobial regimens may prolong the IFI compared to other agents (Table 1 ). From these studies, the factors that seem to have importance are as follows: (1) the use of antimicrobials that, in vitro and in vivo, provide blood and tissue levels above the minimum inhibitory concentrations for all of the common bacterial pathogens in ABECB; (2) the antimicrobial should be bactericidal; (3) the acute rate of eradication of pathogens in ABECB should be at least 90%; (4) the relapse rate during therapy or within 14 to 21 days after therapy ceases should be < 10%; (5) the dosage during therapy should be the optimal amount needed to satisfy the preceding four factors; and (6) adequate supportive therapy should be included during and after antimicrobial treatment; for example, bronchodilators, enhanced sputum clearing therapies, and appropriate lifestyle modifications.


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  		Table 1.. Comparison of IFIs From Various Clinical Trials*

 
Understanding the pathophysiologic mechanisms that control the IFI remains largely hypothetical. Studies102627 suggest that patients with CB have persistent bacteria colonization, particularly Haemophilus influenzae, even after an antimicrobial regimen. Qualitative and quantitative cytologic studies of sputum obtained during stable state, at onset of an ABECB, and at the end of a successful ampicillin regimen revealed a consistent presence of bacteria in the exfoliated bronchial epithelial cells.10 The number of bronchial epithelial cells with intracellular bacteria (x 106/d) at 0, 14, and 28 days after initiating a 14-day ampicillin course were 4.0 ± 1.1, 8.8 ± 1.9, and 3.1 ± 0.8, respectively (± SE). These observations suggest that the clearance of pathogens from the sputum does not ensure that the bacteria have been completely eradicated from the bronchial tissue and supports the concept of chronic mucosal infestation. A more recent report27 supports the idea of chronic colonization in COPD patients with H influenzae that may cause intermittent exacerbation. Therefore, the IFI may provide an indication of how a particular antimicrobial regimen affects the resident pathogen population present in the pulmonary tissues.

It is reasonable to hypothesize that the fewer viable pathogens remaining in the bronchial tissue after antimicrobial treatment, the longer it will require for the bacterial population to increase sufficiently to induce a new exacerbation. However, this hypothesis does not exclude the possibility of a new pathogen inducing an ABECB episode. Sethi et al28 followed up 81 patients with CB over 56 months and showed that isolation of a new strain of H influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis was associated with a significantly increased risk of an exacerbation. In a prospective study26 of 48 patients with a purulent exacerbation and positive sputum culture finding (H influenzae in 27 patients), 17 patients had persistently positive sputum culture findings even after 10 days of cefuroxime axetil therapy. These patients exhibited significantly higher sputum inflammatory markers than those patients who had bacterial eradication. This study provides evidence for the role of bacteria in bronchial inflammation during an exacerbation and after resolution, and supports evidence associating bacterial load with airway inflammation.29

When IFI data are assessed along with acute resolution rates and early relapse rates, distinctions between antimicrobial treatments may be noted that are not detected when only short-term outcomes are measured. Double-blind, crossover designed trials provide the advantage of largely eliminating the variability of response between patients commonly seen in parallel-assignment designed studies.102425 This is particularly important for ABECB clinical trials, since the severity of disease and the frequency of ABECB can vary considerably among patients with CB.

The IFI can significantly improve the ability to compare efficacy between antimicrobials, or between different dosage regimens of a single antimicrobial (Table 1). An early study10 comparing trimethoprim/sulfamethoxazole (TMP/SMX) with ampicillin demonstrated similar rates of acute resolution, but markedly different IFIs (62 days vs 96 days for TMP/SMX and ampicillin, respectively). Differences between dosages of the same drug are also detectable. In various studies2224 of ciprofloxacin, 500 mg bid resulted in a mean IFI of approximately 145 days, whereas 750 mg bid resulted in an IFI of > 200 days, although the acute eradication and clinical improvement rates were similar with both dosages.

When an antimicrobial is clearly inferior to other effective antimicrobials based on a poor acute response rate and a high percentage of treatment failures, the mean IFI is invariably short. In studies with cephalexin and cefaclor, acute cure rates (80% and 69%, respectively) were poor and the IFIs were very short (38.4 and 19.1 days, respectively).25 This is not surprising considering that treatment failures are counted as 0 days for the IFI.

In addition to crossover studies, the IFI also has been measured in multicenter, double-blind, and parallel assignment investigations.2223 In order to attain adequate statistical power, the required number of ABECB patients is often significantly greater than in a crossover study. Since there are frequently time constraints for completion of multicenter studies, there is often a cut-off of 6 to 12 months of follow-up so that longer IFIs may be truncated to the maximum days allowed for follow-up, possibly resulting in an underestimation of the IFI. However, it remains to be determined the degree of the effects on the IFI still elicited 6 to 12 months after completing an antimicrobial regimen.

There are a number of limitations in the design of ABECB clinical trials that can contribute to difficulty in determining the value of antimicrobial therapy and make the measurement of the IFI impossible or unreliable. Some of these include the following: (1) imprecise diagnosis of the underlying chronic bronchial disease; (2) failure to exclude AECBs that do not have a bacterial etiology; (3) limited short-term follow-up; (4) dependency on subjective or secondary parameters rather than objective measures of infection; (5) too few subjects with bacterial infection to detect differences or real equivalence between antimicrobial regimens; and (6) study designs lacking statistical power to detect significant differences between treatments.

It is important to differentiate the IFI from the DFI, which has been reported in several studies30313233 (Table 2 ). These studies30313233 have a number of methodologic flaws. They used an end point of the time until the next AECB episode regardless of its etiology (bacterial or nonbacterial). The literature234 suggests that approximately 50% of all AECBs are nonbacterial. Subjects with initial failed treatment were excluded from the DFI group, and the proportion of the AECBs that were documented to be ABECBs were very low, similar to many short-term antibiotic studies.21734 In one example, a recently published clinical trial33 compared moxifloxacin and standard therapy for treatment of AECB with monthly assessments up to 9 months after treatment. A longer mean DFI was observed in the moxifloxacin-treated group compared to the clarithromycin-treated group (132.8 days vs 118.0 days, respectively; p = 0.03), although no difference was observed in the occurrence of a new exacerbation during the follow-up period. However, only approximately 20% of the intent-to-treat population included in the follow-up analysis had a documented bacterial infection at study entry, and bacterial causes of the subsequent exacerbation were not reported. Considering these concerns of DFI studies, the value of the DFI as an index of efficacy for an antimicrobial therapy is questionable. IFI studies designed to avoid the previously noted negative factors provide a more accurate assessment of the effectiveness of a particular antibiotic for the treatment of ABECB. However, the controlled trials3132 that have suggested an improved DFI with a quinolone have confirmed a higher bacterial eradication (particularly of H influenzae) with the respiratory quinolones.


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  		Table 2.. Recurrence of AECBs Within 9 Months After Therapy

 

   Incorporating the IFI in Future Clinical Trials
TOP
 Abstract
 Introduction
 IFI
 Incorporating the IFI in...
Summary
 References
 
The IFI, in combination with short-term clinical outcomes, can provide practical information regarding the long-term effectiveness of antibiotics in treating ABECB. However, studies must be properly designed and executed to provide an accurate assessment of the data. First, only patients with documented ABECB should be included in clinical trials measuring the effectiveness of antibiotic therapy. This is imperative when trying to measure the IFI, as a large proportion of subjects with undocumented ABECB will dilute the usefulness of the data. Second, clinical trials should include a long-term follow-up period that extends at least to 6 to 12 months after cessation of therapy to document the time of next exacerbation. Finally, the number of ABECB patients must be adequate to provide a statistically sound analysis to compare any differences or similarities between two antibiotic treatments.


   Summary
TOP
 Abstract
 Introduction
 IFI
 Incorporating the IFI in...
 Summary
References
 
The rationale for extending the duration of the IFI is straightforward. A longer IFI means fewer ABECBs suffered by the CB patient, resulting in fewer office visits and hospitalizations and decreased use of antibiotics. Additionally, a reduced frequency of exacerbations may slow the rate of lung function deterioration in these patients and improve overall health status. The economic advantages of a longer IFI can also be significant. Our understanding of the pathophysiologic basis to explain the IFI remains largely hypothetical. However, data from numerous clinical trials10222325 suggest that certain therapeutic regimens do lengthen the IFI. To more fully understand the link between antibiotics and the IFI, it is imperative that future studies evaluate ABECB separately from AECB.


   Acknowledgements
 
I would like to thank Marco P. Cicero, PhD, for editorial support.


   Footnotes
 
Abbreviations: ABECB = acute bacterial exacerbation of chronic bronchitis; AECB = acute exacerbation of chronic bronchitis; CB = chronic bronchitis; DFI = disease-free interval; IFI = infection-free interval; TMP/SMX = tri-methoprim/sulfamethoxazole

Received for publication March 17, 2004. Accepted for publication November 9, 2004.


   References
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 IFI
 Incorporating the IFI in...
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