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Efficacy of Macrolides in Moderate to High Risk Community Acquired Pneumonia*

Paul Cyrus S. Adapon III, M.D., Clara Tolentino, M.D. and Adrian C. Peña, M.D.

(*From

the

Department

of

Medicine,

University

(UERMMMC), Aurora Boulevard, Quezon City)

of

the

East-Ramon

Magsaysay

Memorial

Medical

Center

ABSTRACT

Community-acquired pneumonia (CAP) ranks 4 th in all-cause morbidity and is the 3 rd leading cause of mortality in the Philippines. For elderly patients and those with severe disease admitted for pneumonia, atypical pathogens like Legionella are said to be important etiologic consideration thus the recommendation of adding erythromycin IV or alternatively an oral macrolide to the antibiotic regimen. The general objective of the study is to determine the benefit of macrolides in category III (moderate risk) and category IV (high risk) CAP. The specific objectives are: 1. To compare in-hospital mortality of patients treated

with and without macrolide; 2. To determine if addition of macrolides results in shorter length of hospitalization; 3. To determine if macrolides given within 8 hours of admission is associated with improved outcome; and 4. To determine if oral or intravenous (IV) macrolide is associated with improved outcome. Patients admitted and discharged for moderate to high-risk pneumonia at UERMMMC from January 2000 to October 2001 satisfying the criteria of the Task Force on Community-acquired Pneumonia Guideline were included in the study. If the patient requested to be discharged against medical advice (DAMA), was recently hospitalized (within

10 days) or inclusion criteria were not satisfied during the course of confinement despite an admitting impression of

CAP, these patients were excluded from the study. Demographic data (age, sex), co-morbid conditions, physical examination findings and laboratory values

such as compete blood count, chest x-ray, arterial blood gas, blood urea nitrogen, creatinine, blood sugar, liver function test were collected. The effect of macrolide therapy on duration of hospitalization and mortality is the main focus of this study. The Student’s t-test was used to analyze the length of stay of patients given macrolide and those not given any macrolide. The Chi-square (x 2 ) test was used to determine any significant difference in the proportion of mortality to improved cases between those who received a macrolide and those who did not. Fisher’s Exact test was used to analyze data for the moderate risk and high risk group of patients and any significant difference in the proportion of mortality among those who received either oral or IV macrolide. Data was entered into the program Epi-Info 2000 which was used to generate frequencies, means and t, x 2 and Fisher Exact test statistic in this study. A total of 87 patients were included in this study. Of these, 46 patients were males and 41 patients were females. The average age of patients is 65.91 years ranging from 28 to 93 years old and majority of these were at least

65 years old (60.91%). Sixty one patients

(70.1%) did not receive any macrolide while 26 (29.9%) had macrolide as

part of the antibiotic regimen. The overall mortality rate of the study is 18.39% (16 out of 87). Among those who did not receive any macrolide 18.03% (11 out of 61) died while 19.23% (5 out of 21) died who did receive a macrolide as part of the antimicrobial regimen. The average length of stay for patients who received a macrolide was 6.9 days and for the non-macrolide group, the average stay was 7.2 days. This study failed to show any advantage or additional benefit in adding a macrolide to the empiric antimicrobial regimen for patients hospitalized for moderate and high risk pneumonia. A prospective study involving a larger population of patients may be done to better evaluate the therapeutic effect of macrolides in patients hospitalized with moderate and high risk pneumonia. [Phil J Microbiol Infect Dis 2002; 31(2):64-69]

Key Words: community acquired pneumonia, macrolides, guideline

INTRODUCTION

Community-acquired pneumonia (CAP) is the most common infectious disease necessitating hospitalization. It ranks 4 th in all-leading cause morbidity and is the 3 rd cause of

mortality in the Philippines. 1 Empiric antibiotic therapy is based on the likely pathogens that have been identified in the different subsets of pneumonia. In minimal risk CAP, S. pneumoniae and

H.

influenzae are the predominant infectious agents. Atypical pathogens like C. pneumoniae and

M.

pneumoniae have also been identified. For low risk CAP, M. catarrhalis and Gram negative

(enteric) bacilli are additional pathogens to be considered, aside from those described for minimal

risk CAP. Anaerobes and Legionella sp. become significant pathogens for patients classified as having moderate risk CAP while Pseudomonas aeruginosa and Staphylococcus aureus are included in the list of pathogens to be considered in those with high risk CAP. 2 A number of antimicrobial agents have been proposed as initial empiric treatment for the 4 risk categories of CAP based on the report of the Task Force on Community-acquired Pneumonia that was initiated by the Philippine Society of Microbiology and Infectious Disease (PSMID). This serves to provide practicing physicians with a rational and manageable approach to the initial antimicrobial management of CAP in the immunocompetent adult. 2 Indeed, adherence to the CAP guidelines has been shown to produce favorable outcome. In a study of 107 patients admitted for pneumonia in a local private hospital, Carandang, et al, described overall adherence to the guidelines to be 68.2%. Adherence to guidelines was as high as 85.5% for patients with CAP III, while the mortality rate was 6.5%. 3 Their study demonstrated that majority of patients hospitalized for CAP receiving recommended antibiotics had a mortality

rate that was better than the average mortality rate described for hospitalized patients, which is an 14%. 4 Adherence to other guidelines such as the American Thoracic Society Guidelines (ATS Guidelines) which is similar to the local CAP guidelines, has also been shown to be associated with a more favor-able outcome. The study by Panaligan, et al, which included 185 patients in a teaching hospital showed over-all improvement in symptoms, lesser hospital stay and improved survival that was statistically significant if treatment was consistent with the ATS recommendations. 5 For elderly patients and those with severe disease admitted for pneumonia, atypical pathogens like Legionella are said to be important etiologic consideration thus the recommendation of adding erythromycin IV or alter-natively an oral macrolide to the antibiotic regi-men. 2 However, the therapeutic benefit of macrolides in patients with moderate to high risk pneumonia seems to produce varied results. Gleason et al, in a study of the effect of initial antimicrobial therapy involving 12,945 hospitalized elderly patients with pneumonia found that an initial treatment with a second- generation cephalosporin plus a macrolide (and 2 other regimen) was independently associated with lower 30-day mortality, 6 which supports the recommendation of this regimen. However, no antibiotic regimen produced significantly lesser hospitalization. 6 Stahl and co-investigators concluded that macrolides given within 24 hours was associated with significantly shorter length of stay though their data were inadequate to evaluate for effect on mortality rate. Furthermore, patients receiving macrolides regardless of time administered did not show any benefit in duration of hospitalization. 7

included

198 patients admitted for pneumonia. The case fatality rate was reported to be 5.5% for moderate and 20% for high risk CAP treated with recommended drugs compared to 3.5% and 37.5%, respectively, for those given other agents. 8 Surprisingly, they noted that the management of 72.2% of patients do not conform to the recommended guidelines despite the mortality rate being consistent with reported figures. 10 There was no statistical significance in mean hospital stay and case fatality rate among patients given recommend-ed and other agents. 8 Although the study of Panaligan et al showed overall advantage in terms of improvement of symptoms, lesser duration of hospital stay and lesser mortality, their data showed that there was no significant difference in hospital stay and mortality for patients categorized as moderate and high risk CAP but merely earlier improvement in symptoms for those with moderate risk CAP. 5 The reason for this discrepancy is because they noted that of the 185 patients studied, only 84 (44.41%) were found to be eligible for hospitalization. This translates to 101 patients (55.59%), though hospitalized, are actually minimal or low risk CAP which could favorably influence or dilute the figures on symptom improvement, length of hospitalization and mortality rate. Other studies have shown poor adherence to recommended guidelines and yet the documented mortality rate was well within accepted figures. 3,8,10

In the local setting, Villa, et al., did a study of 3 hospitals in Metro Manila that

The general objective of the study is to determine the benefit of macrolides in

category III (mode-rate risk) and category IV (high risk) CAP. The specific objectives are: 1. To compare in-hospital mortality of patients treated with and without a macrolide; 2. To determine if addition of macrolides results in shorter length of hospitalization; 3. To determine if macrolides given within 8 hours of admission is associated with improved outcome; and 4. To determine if oral or intravenous (IV) macrolide is associated with improved outcome.

MATERIALS AND METHODS

This is a retrospective cohort study. Patients admitted and discharged for moderate to high-risk pneumonia at UERMMMC from January 2000 to October 2001 were included in the study. Review of patients’ charts was done to ensure that they fulfilled the inclusion criteria. If the patient requested to be discharged against medical advice (DAMA), was recently hospitalized (within 10 days) or inclusion criteria were not satisfied during the course of confinement despite an admitting impression of CAP, these patients were excluded from the study.

Inclusion Criteria

A patient with cough, tachypnea, tachycardia, and fever with at least one abnormal chest finding of diminished breath sounds, rhonchi, crackles or wheeze and a radio-graphic chest examination showing new infiltrates that has no clear alternative cause is defined as a pneumonia case.

Moderate Risk CAP (any of the ff.) 2

Age 65 yrs, RR 30, PR 125, Temperature 40 o C or £ 35 o C and a chest x-ray showing multi-lobar, pleural effusion, abscess, or progression of lesion to 50% of initial within 24 hours.

High Risk CAP (any of the ff.) 2

Hypotension (SBP <90 mm Hg or DBP <60 mm Hg), altered mental status, urine output < 30 ml/hr, PaO 2 < 60 mm Hg at room air or Acute hypercapnea (PaCO 2 > 50 mm Hg) at room air.

Data Elements

Demographic data (age, sex), co-morbid conditions (diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, chronic renal insufficiency, chronic alcoholism, chronic liver disease, neurologic disease, neoplasm, immunosuppression), physical examination findings and laboratory values such as compete blood count, chest x-ray, arterial blood gas, blood urea nitrogen, creatinine, blood sugar, liver function test were collected.

Outcome Measures

The effect of macrolide therapy on duration of hospitalization and mortality is the main focus of this study. Therefore, mortality rates for the 2 groups will be determined. Duration of hospitalization or length of stay (LOS) is defined as the number of days the patient was admitted up to the date of the order by the attending physician that the patient may be discharged, i.e. date of admission up to date of “May go home” order. This is necessary since some patients admitted, although already being discharged by the attending physician, tend to overstay until payment of the hospital bill or whenever their relatives pick them up from the hospital,

unnecessarily prolonging date of discharge and subsequently confounding the findings of this study.

The impact of macrolides on the outcome of either moderate or high-risk pneumonia will also be evaluated. Patients included in this study were stratified according to severity of pneumonia (either CAP III or CAP IV) then the mortality and length of stay will be analyzed. Once a positive outcome has been noted for patients who received a macrolide as part of the antimicrobial regimen, the next step is to find out if the timing of the initial dose from admission significantly affects outcome in these patients as noted in the other studies. 5,6,7 Also, a subanalysis will be done to determine if there is a therapeutic benefit or a difference in outcome among those who were given oral as compared to IV macrolide.

Statistical analysis

The Student’s t-test was used to analyze the LOS of patients given macrolide and those not given any macrolide. The same statistical method will be used to evaluate if there is significant difference between LOS of patients who received macrolides within 8 hours and those beyond 8 hours of admission. The Chi-square (x 2 ) test was used to determine any significant difference in the proportion of mortality to improved cases between those who received a macrolide and those who did not. Fisher’s Exact test was used to analyze data for the Moderate Risk and High Risk group of patients since several values in the contingency table from these two groups was lower than 5 making the Chi-square inapplicable. This test was also used to evaluate any significant difference in the proportion of mortality among those who received either oral or IV macrolide. Data was entered into the program EpiInfo 2000 which was used to generate frequencies, means and t, x 2 and Fisher Exact test statistic in this study.

RESULTS

A total of 87 patients were included in this study. Of these, 46 patients were males and 41 patients were females. The average age of patients is 65.91 years ranging from 28 to 93 years old and majority of these were at least 65 years old (60.91%, 53 of 87 patients). Table 1 shows the associated co-morbidities of the patients studied. Chronic obstructive pulmonary disease was the most common condition seen in 21 patients (24.1%) followed by diabetes mellitus in 17 patients (19.5%) and chronic renal insufficiency in 13 patients (14.9%). A large part of patients with renal problems are due to diabetes followed by hypertension then SLE (data not shown). There were 2 patients each for chronic alcoholism and immunosuppression. The 2 patients that are on immunosuppression were diagnosed cases of systemic lupus erythematosus with active nephritis.

Table 1. Co-morbid conditions of patients

Co-morbid conditions

Macrolide

No Macrolide

Diabetes mellitus Chronic Obstructive Pulmonary Disease Congestive Heart Failure Chronic Renal Insufficiency Chronic Alcoholism Chronic Liver Disease Neoplasm Neurologic Disease Immunosuppression

4

13

7

14

3

4

2

11

0

2

0

3

3

9

3

9

1

1

the 87 patients, 21 (29.9%)

had macrolide as part of the antibiotic regimen. The overall mortality rate of the study is 18.39% (16 out of 87). Among those who did not receive any macrolide 18.03% (11 out of 61) died while 19.23% (5 out of 21) died who did receive a macrolide as part of the antimicrobial regimen (Table 2).

Majority of these patients did not receive any macrolide. Of

Table 2. Outcomes of moderate and high risk CAP patients with and without macrolide treatment

Macrolide

No Macrolide

Improved

21

50

Mortality

5

11

Total

26

61

% Improved

80.77

81.97

% Mortality

19.23

18.03

Overall Mortality rate Ave. LOS

18.39% (16/87)

6.9 (1 to 15)

7.2 (1 to 17)

With regards to duration of hospitalization, the average length of stay for patients who received a macrolide was 6.9 days. The shortest was only 1 day wherein the non-macrolide group, the average stay was 7.2 days ranging from 1 to 17 days. Sixty five patients (74.71%) belonged to the moderate risk (CAP III) category while 22 patients (25.29%) were high risk (CAP IV) pneumonia patients. The breakdown of the mortality rate is 9.23% for CAP III and 45.45% for CAP IV patients (Table 3).

Table 3. Patients in the moderate risk (CAP III) and high risk (CAP IV) pneumonia

CAP III (n=65)

 

Macrolide

No Macrolide

Mortality

2

4

Improved

17

42

 

CAP IV (n=22)

 

Macrolide

No Macrolide

Mortality

3

7

Improved

4

8

There were a total of 26 patients identified that received a macrolide. Of these, 19 received an oral macrolide while only 7 were given an IV macrolide (Table 4).

Table 4. Outcome of Oral and IV Macrolide

Macrolide (n=26)

 

Oral

IV

Mortality

4

1

Improved

15

6

DISCUSSION

Majority of the patients included in this study did not receive a macrolide (70.1%, 61 of 87 patients) but most of them were nonetheless discharged improved. Focusing our attention to the mortality rate of those patients that received a macrolide versus those who didn’t receive any as part of their antimicrobial regimen, there is only minimal discrepancy between them. In fact, the mortality rate of those who received a macrolide appears to be greater than those who did not have any macrolide. However, statistical analysis showed that there is no significant difference in the mortality rate between these 2 groups (x 2 = 0.27, df = 1, p=0.868). Analysis of these data if stratified into either moderate or high-risk pneumonia

(Table 3) also did not show any significant difference between those who did and did not receive a macrolide. (Moderate risk: Fisher Exact p value=0.5712878; high risk: Fisher Exact p value =

0.6160991).

With regards to duration of hospitalization, the average LOS for patients who received a macrolide was around 6.9 days while those who did not receive any macrolide was slightly higher at 7.3 days. But again, there was no significant difference noted in the LOS between these 2 groups (t = 0.355, t crit = ±1.684, a = 0.05). Also, this figure (Table 5) is comparable to the average LOS in the study of Esguerra, et al. This, however, does not mean that macrolides are not effective agents in infectious disease. But it does put into question the rationale of adding a macrolide to the antimicrobial regimen of patients with moderate and high risk CAP and the cost- effectiveness of such a regimen. Having found no additional benefit if macrolides were added to the antimicrobial regimen brings to mind the atypical organisms that this class of antibiotic is supposed to cover for. Do we really need to cover for these atypical pathogens? Documenting these atypical organisms is quite difficult and some would believe it more cost-effective to just treat for these atypical organisms. 3 But again, the rationale of such an approach seem to lack conclusive evidence. The mortality rate for patients hospitalized for pneumonia ranged from 6.5% to 20% as described by previous studies. However, some of these studies noted that there were patients admitted to the hospital who were actually minimal or low risk CAP and therefore do not require hospitalization and have a better likelihood of being discharged in a short period of time. These patients when included in the study would have a “dilution effect” causing an underestimation of the actual mortality rate for admissible pneumonia cases. If only those patients categorized as moderate and high risk pneumonia are taken and the mortality rate is computed the results would be as shown in table 6. The study of Esguerra et al computed their mortality rate to include only patients with moderate/high risk pneumonia producing 20% mortality rate. The overall mortality rate for hospitalized CAP patients in our study is 18.39% as previously mentioned and is comparable to the study of Esguerra et al. The mortality rate of the studies done by Panaligan et al and Villa et al were also comparable to the finding in our study if their data were extrapolated to include only moderate and high risk CAP as shown in Table 5. Data for the study of Carandang et al was not available to allow computation of the mortality rate for only moderate/high risk CAP.

Table 5. Extrapolated mortality rate and LOS results of studies on hospitalized pneumonia Philippine hospitals

from different

Study Author

Hospital

Mortality rate (CAP III + CAP IV)

Ave. Length of Stay

Panaligan, et al 5 Villa, et al 8 Carandang, et al 3 Esguerra, et al 10

UERMMMC PGH, STUH, MMC CSMC JRMMC

17.85% (15 of 84) 17.46% (18 of 157) 6.5% (?) 20% (17 of 85)

NA*

NA *

NA *

7.3 days

*Not available

We also computed the mortality rate for either moderate risk or high-risk pneumonia patients in this study. The mortality rate of moderate risk pneumonia is 9.23% (6 of 65 patients, Table 3) while that of high-risk pneumonia is 45.45% (10 of 22 patients, Table 4). If data from the other studies were stratified to only those with moderate/high risk pneumonia (thus excluding non-admissible cases and avoiding the “dilution effect”) the mortality rates for the different risk categories are seen in table 6. We can see from the table that based on local studies mentioned, moderate risk pneumonia can have a mortality rate ranging from 3.5% to 10.9%. These figures are much more stable and consistent when compared to the mortality figures for high risk pneumonia which can range from 20% to 52.38%, depicting the high variability in the outcome of patients under this

risk category. This also means that there is a 2-5 fold increase in mortality for high risk pneumonia patients compared to moderate risk pneumonia patients, which clearly underscores why patients in this risk category should be regarded as “high risk.”

Table 6. Extrapolated mortality rate of studies on hospitalized pneumonia (CAP III and CAP IV) from different Philippine hospitals.

Study Author

Hospital

Mortality rate (CAP III + CAP

IV)

Ave. Length of Stay

Panaligan, et al 5 Villa, et al 8 Carandang, et al 3 Esguerra, et al 10

UERMMMC PGH, STUH, MMC CSMC JRMMC

7.9% (3 of 38) 5.5% (3.5%)* NA** 10.9% (6 of 55)

26.08% (12 of 46) 20% (37.5%)* - NA - 52.38% (110f 21)

* Rates for those that received recommended drugs and those that were given other agents (in parenthesis) **Not available

The subanalysis of the patients who received oral macrolide compared to IV macrolide was also undertaken. There were a total of 26 patients identified that received a macrolide. Of these, 19 received an oral macrolide while only 7 were given an IV macrolide (Table 4). Statistical analysis did not show any significant difference among those who received IV macrolide from oral macrolide (Fisher Exact p-value = 0.5892369). However, since there were only 26 patients who received a macrolide, this population may be too small leading to a reduced statistical power of this study to detect minute differences in the groups being analyzed. The effect of the time that the initial dose of macrolide was admi- nistered (within 8 hours vs. beyond 8 hours) and its impact on outcome (hospitalization and mortality rate) was not anymore determined since there was no significant difference in the outcome of patients who did against those who did not receive a macrolide.

CONCLUSION

This study failed to show any advantage or additional benefit in adding a macrolide to the empiric antimicrobial regimen for patients hospitalized for moderate and high risk pneumonia. A prospective study involving a larger population of patients may be done to better evaluate the therapeutic effect of macrolides in patients hospitalized with moderate and high risk pneumonia. The study outcome mainly focused on length of stay and mortality. However, there are other measurable outcomes that could be analyzed such as timing of improvement of symptoms/well- being, re-hospitalization rate, 30-day mortality rate and complication rate. While the efficacy of macrolides in various infectious diseases have been well documented it remains to be proven that further addition of a macrolide to the antibiotic regimen of patient hospitalized with CAP would absolutely provide any advantage studies regarding the subject matter in terms of outcome. Further studies must be undertaken.

REFERENCES

1. Philippine Health Statistics, 1994. Health Intelligence Service, Department of Health, Republic of the Philippines.

2. Task Force on Community-acquired Pneumonia. The Philippine Clinical Practice Guidelines on the Diagnosis, Empiric Management and Prevention of Community-acquired Pneumonia in Immunocompetent Adults. PPGD-ID Philippine Society of Microbiology and Infectious Diseases. Volume 1 No. 2, 1998.

3. Carandang RA, Mendoza MT. A clinical practice guideline-directed surveillance study of admitted patients with community- acquired Pneumonia. Phil J Microbiol Infect Dis 2001; 30(1): p. 8-17.

4. Barlett JG, et al. Guidelines from the Infectious Disease Society of America (IDSA) Community-acquired Pneumonia: Guidelines for Management. Clin Infect Dis 1998; 26: p. 811-838.

5. Panaligan MM, Alcantara MF, Peña AC. Management of community-acquired pneumonia among in-patients in a teaching hospital: Adherence to the American Thoracic Society Guidelines. Phil J Microbiol Infect Dis 1998; 29(2): p. 55-61.

7.

Stahl JE, Barza M, Desjardin J, Martin R Eckman M. Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community -acquired pneumonia. Arch Intern Med. 1999; 159: p. 2576 -2580.

8. Villa MLA, Sumagaysay I, We M, Co V, Mendoza M, Tupasi T. Current clinical practice in the management of community- acquired pneumonia: An Appraisal. Phil J Microbiol Infect Dis. 1999; 28(4): P. 121-127.

9. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: A meta- analysis. JAMA 1996; 275(2): p. 134-140.

Esguerra PT, Panaligan MM, Andaya-Esguerra MK, Cuntapay AV, Bautista IC. Assessment of quality of care among patients with community-acquired pneumonia admitted to the Dr. Jose R. Reyes Memorial Medical Center Medical Ward. Phil J Microbiol Infect Dis. 2001; 30(3): p. 87-93.