Epidemiology and clinical spectrum of pneumococcal infections: an Israeli viewpoint

Journal

of Hospital

Infection

(1995)

Epidemiology pneumococcal M. Yigla*f,

29, 57-64

and clinical spectrum of infections: an Israeli viewpoint

R. Finkelstein*$, N. Hashman& and D. Merzbachs

P. Greens,

L. Cohn5

*Department of Internal Medicine; tDivision of Pneumology; Slnfectious Diseases Unit; and $Clinical Microbiology, Rambam Medical Center, Technion, Israel Institute of Technology, Haifa, Israel Accepted for publication

2 September

1994

Summary:

We performed a prospective study of consecutive pneumococcal infections documented during a six-month period in our clinical microbiology laboratory. A total of 59 cultures obtained from clinically significant specimens of 58 patients were positive for Streptococcus pneumoniae. Relative penicillin resistance occurred in 14 strains (24%) and only one (1.7%) was highly resistant to penicillin (minimum inhibitory concentration = 2.0 pg ml-‘). Resistance to common alternative drugs was not found. Serotypes were of a wide variety, however types 1, 7 and 14 predominated (60% of all blood culture isolates). Twenty-three patients with community-acquired infection required hospitalization. Nosocomial pneumonia developed in three additional cases (14%). Invasive disease was diagnosed in 24 patients with pneumonia representing the most common infection (22 patients). Pneumonia was characterized by a high incidence of serious underlying diseases (82%) and associated bacteraemia (68%). Compared with controls, patients with penicillin-resistant pneumococcal pneumonia had a significantly higher incidence of previous hospitalizations and use of antibiotics (57 vs. 7%, P= 0.02). The overall case fatality rate was high (36%) and did not differ significantly between patients with pneumonia due to resistant and susceptible strains. The epidemiology and clinical spectrum of serious pneumococcal infections in Israel is similar to those described in many parts of the world, but high level resistance to penicillin and to other alternative drugs is still rare.

Keywords: Streptococcuspneumonaie;

penicillin

resistance;

pneumonia;

Israel

Introduction and preventive advances in the past 50 infections remain a problem of major importance. Streptococcus pneumoniae continues to be the leading cause of communityacquired pneumonia, the second most common pathogen in bacterial meningitis, and the aetiological agent in more than a half of children with otitis Despite

significant

therapeutic

years, pneumococcal

Correspondence Haifa, Israel. 01956701/95/010057+08

to:

Dr

R.

Finkelstein,

Rambam

Medical

$OS.OO/O

Center,

Infectious

Diseases

0 1995 The Hospital

57

Unit,

Infection

31096

Society

58

M. Yigla

et al.

media.’ Resistance to penicillin is widespread and is rapidly increasing worldwide.’ In addition, the mortality rate from serious infections remains almost unchanged, despite antibiotic therapy.3’4 The present study was designed to characterize the clinical aspects and epidemiology of pneumococcal infections in the setting of a general tertiary care hospital in Israel. Patients and methods From November 1989 to April 1990 all significant isolates of S. pneumoniae obtained from patients referred to the Rambam Medical Center were subjected to prospective epidemiological and clinical analysis. This 950bed teaching institution serves a population of 500 000 people and is the referral center of much of northern Israel. Hospitalized patients with clinical infection and with at least one positive culture for S. pneumoniue were evaluated and followed prospectively throughout hospitalization. The study was non-interventional, and patients were managed and treated according to their attending physicians’ decisions. Patients were categorized by source of infection, pattern of pneumococcal susceptibility to antibiotics, previous hospitalization and use of antibiotics during three months prior to admission, the presence of underlying diseases and an initial critical condition. We defined an initially critical condition as including two or more of the following factors associated with a poor prognosis:’ (1) severe underlying disease (e.g. advanced cancer or advanced chronic liver disease); (2) age of 75 years or more; (3) leukopenia [white cell blood count (WBC) below SOOO]; (4) shock (systolic blood pressure below 90 mmHg in association with peripheral hypoperfusion); and (5) involvement of more than one pulmonary lobe. Pneumonia was diagnosed by the presence of clinical findings compatible with a lower respiratory tract infection and a new pulmonary infiltrate on chest radiography. The aetiology of pneumonia was established by following criteria: sputum Gram stain showing more than 2.5 WBC/high power field, numerous Gram-positive cocci and a sputum and/or blood culture positive for S. pneumoniae. Pneumococcal infection in other sites (meningitis, peritonitis, otitis media) was defined by the presence of compatible clinical and laboratory findings in addition to the isolation of S. pneumoniae from one of the above-mentioned specific sites. An infection was considered to be hospital acquired when the signs and symptoms developed 72 h or more after admission for an unrelated illness. Microbiological studies Isolates were identified by standard methods.6 Serotyping was performed by the Central Streptococcal Reference Laboratory of the Ministry of Health in Jerusalem, for blood isolates only, using standard antisera (Statens Seruminstitut, Copenhagen, Denmark). Antibiotic susceptibility testing was routinely performed according to the disc-diffusion technique7 in

Pneumococcal

infections

59

in Israel

Miiller-Hinton agar supplemented with 5% lysed horse blood. For testing susceptibility to penicillin, a 1 pg oxacillin disc was used initially. Isolates showing a zone of inhibition of ~20 mm were considered to have decreased sensitivity to penicillin. The minimum inhibitory concentration (MIC) was determined according to a macrodilution method* in Miiller-Hinton broth supplemented with 5% lysed horse blood, MgClz lOmgl-’ and CaCl, 20 mgll’ at appropriate antibiotic concentrations. Inocula were obtained by suspending an overnight growth on an agar plate in trypticase soy broth and adjusting to a turbidity of 0.5 McFarland standard. Cultures were diluted to produce a final concentration of approximately 10’ cfu ml-‘. The MIC value was defined as the lowest concentration of antibiotic that prevented macroscopic growth after 18-24 h of incubation at 35°C. An isolate was defined as susceptible to penicillin when MIC values were ~0.1 pg ml-‘; relatively resistant when MIC values were between 0.1-1.0 pg ml-‘; and highly resistant to penicillin when MIC values were >l*O pg ml-‘. Further MIC value determinations for chloramphenicol, cefotaxime and vancomycin were performed for all non-susceptible isolates.

Statistical

evaluation

Fisher’s exact test was used to compare sample proportions. CO.05 was considered statistically significant.

A

P value of

Results During the study period 59 pneumococcal isolates were made from 58 patients. The sources of these isolates are shown in Figure 1. The most common source of isolation was the sputum (17 cases), followed by blood (15 cases). Twenty-three patients with community-acquired infection required hospitalization: otitis media was diagnosed in two, meningitis in one, spontaneous bacterial peritonitis in one and pneumonia in 19. Nosocomial infection was diagnosed in three patients with bacteraemic pneumonia and multiple trauma who were treated in the intensive care unit. The 22 patients with pneumonia were the subject of a separate evaluation. The mean age of these patients was 60.2 years (range l-90 years) and the male:female ratio was l-75. One or more serious underlying diseases were found in 18 cases (82%), bacteraemia in 15 (68%); and the case-fatality rate was 36.3%. A wide range of serotypes was isolated and their distribution is presented in Table I. Types 1, 7 and 14 were most frequently isolated (60%). There was a good correlation between the disc-diffusion and macrodilution susceptibility tests; nevertheless, two isolates showing decreased susceptibility to penicillin by the disc method were sensitive as judged by MIC values (MIC value = 0.03 pg ml-’ and 0.06 mg ml-‘). Relative resistance to penicillin was demonstrated in 14 of the 58 strains isolated during the study period (24.1%) and only one (1.7%) was highly resistant (MIC value = 2 pg ml-‘). This strain was isolated from a purulent ear discharge in a child

M. Yigla et al.

60 Cerebrospl

fluid \

“4’

Nose 9 Figure 1. Sources of 59 isolates of Streptococcus pneumoniae a six-month period at Rambam Medical Center.

obtained

from 58 patients over

Table I. Serotype distribution of the 15 blood isolates of Streptococcus pneumoniae Serotype

No. of isolates (%)

: :: 1: 15

3 1 1 3 1 3 2 1

18

(20) (6.7) (6.7) (20) (6.7) (20) (13) (6.7)

relapsing after an initial episode (not evaluated in this study) of otitis media and bacteraemia treated with penicillin G. All 15 strains were susceptible to chloramphenicol, cefotaxime, and vancomycin. Table II summarizes the clinical characteristics of seven cases of pneumonia caused by penicillinresistant (PR) pneumococci, compared with 15 controls having penicillinsensitive (PS) S. pneumoniue. Patients included in both groups were similar in terms of age, sex and underlying diseases. However, as compared with controls, cases had a significantly higher incidence of previous hospitalization (57 vs. 6*6%, P=O-02) and previous use of antibiotics (57 vs. 6*6%, P=O-02). Bacteraemia and the presence of an initial critical illness were most common among patients with pneumonia due to susceptible

Pneumococcal Table

II.

infections

in Israel

61

Clinical characteristics of seven cases of pneumonia due to penicillin-resistant pneumococci and 15 controls with pneumonia due to susceptible strains Cases

than one underlying

P values NS NS

Age (mean) Sex (male:female) Underlying conditions (patients)* Diabetes mellitus Chronic obstructive lung disease Cirrhosis Muscular distrophy Organic mental syndrome Steroid therapy Multiple trauma Cerebral vascular accident Congestive heart failure Malignancy Total (%) Previous hospitalization (%) Previous antibiotic therapy (%) Nosocomial infection (%) Bacteraemia (%) Initial critical condition (%) Mortality (%) * Some patients had more NS, non-significant.

Controls

2 2

1 :

: 2 2

-

:

-

1 -

2 2

-7

6 4 4 1 3 1 3 condition

(85) (57) (57) (14) (43) (14) (43)

1; 1 1 2 12 6 5

(80) (7) (7) (13) (88) (40) (33)

NS 0.02 0.02 NS NS ::

or disease.

strains (88 vs. 43%, and 40 vs. 14%, respectively); however these figures did not achieve statistical significance. Antibiotics initially chosen for treatment were also similar in both groups and were not changed in any patient, irrespective of the results of susceptibility tests. Patients with PR pneumococcal pneumonia were treated with penicillin G (two cases), cefazolin (two cases), piperacillin (one case) and tetracycline (one case). The overall mortality rate was slightly higher among patients infected with PR pneumococci, but this was not statistically significant (43 vs. 33%, P= O-5). Five patients (two cases and three controls) died during the first 48 h of hospitalization. One patient in each group died before antibiotics were started. Only one of the three nosocomial isolates had decreased sensitivity to penicillin. The serotype pattern of S. pneumoniae was similar for both groups. None of the cases or controls had previously undergone immunoprophylaxis with pneumococcal polyvalent vaccine. Discussion

S. pneumoniae remains a significant cause of morbidity and mortality at all ages. Therefore, considerable efforts continue to characterize the clinical and epidemiological spectrum of pneumococcal disease in many parts of the world. Invasive pneumococcal infections in Israel are common and carry considerable morbidity;g nevertheless, clinical data are still scanty.

62

M. Yigla

et al.

Previous studies have focused on the high prevalence of penicillin resistance in clinical isolates examined in reference laboratories,” and in nasal specimens from healthy children;” or have emphasized the unchanging mortality rate of pneumococcal bacteraemia.3 Our study, starting with the isolation of pneumococci from consecutive clinical specimens and following with a prospective clinical evaluation of hospitalized patients, represents a different approach to the problem of pneumococcal disease. The incidence of pneumococcal infection and bacteraemia found during this six-month period were 1.4 and 0.8 per 1000 hospitalizations, respectively, which is similar to that previously reported elsewhere.“‘i3 As might be expected pneumonia was the most common serious infection, but the 68% of patients with pneumonia who showed bacteraemia was surprisingly high, although such figures have been previously reported.” This certainly overestimates the true incidence of bacteraemia associated with pneumococcal pneumonia and may represent a diagnostic trend found in any large, general emergency care hospital where the common scenario of elderly, uncooperative and critically-ill patients and busy doctors leads to the sputum examination being underused as a tool for the diagnosis of pneumonia. Isolates of S. pneumoniue in our hospital were of a wide variety of serotypes, many of them the same as those described in other series in Israel9”o and other parts of the world.‘2~‘~‘6 Recent surveys on antibiotic susceptibility indicate that the prevalence of antimicrobial resistance among isolates of S. pneumoniue is increasing in many countries. A high prevalence of resistance, particularly to penicillin, has been reported in South Africa, Spain, France and Hungary.“17 In our hospital 25.8% of pneumococci have a decreased susceptibility to penicillin: 24.1% show intermediate resistance, and 1.7% high level resistance. Resistance to common alternative drugs was not found. These figures, which are similar to those previously reported from other areas of Israel,‘&” show that the prevalence of relative penicillin resistance in Israel remained high, but unchanged in the last decade. However, and in contrast to series from other parts of the world,15-17 high level resistance to penicillin and resistance to other common alternative drugs are still rare. Oxacillin disc testing remains suitable for testing pneumococci with decreased susceptibility to penicillin. However, and as recently reported,‘* a few oxacillin-resistant isolates may be sensitive to penicillin by determination of the MIC value. Although the clinical relevance of these observations is not clear, they emphasize the importance of MIC value determination for epidemiological reports. Some conditions such as previous antibiotic therapy, previous hospitalization, previous pneumonia, and nosocomial infection have been identified as risk factors associated with PR pneumococcal pneumonia and non-pneumonic pneumococcal infection.“‘* In the present series, recent hospitalization and previous use of antibiotics were significantly more

Pneumococcal

infections

in Israel

63

common among patients with PR pneumococcal infections than among controls. Whether these infections carry a worse prognosis than that of infections caused by susceptible organisms remains to be established. Pallares et ~1.’ have shown a higher mortality rate among patients with bacteraemic PR pneumococcal pneumonia, but this was attributable, at least in part, to a higher incidence of associated critical illness. In our study the incidence of serious underlying diseases, bacteraemia and initially critical illnesses among patients with PR pneumococcal pneumonia did not differ significantly to that among patients with infection caused by susceptible organisms, and the mortality was similar in both groups. Controversy over the treatment of serious pneumococcal infections caused by less susceptible strains cannot be addressed in this study because of the small number of patients and the fact that most fatalities occurred in the first 48 h of hospitalization. The observation was made by Austrian and Gold 30 years ago that serious pneumococcal infections are associated with significant mortality despite effective antimicrobial therapy.” Our study shows that most aspects of the epidemiology and clinical spectrum of pneumococcal infections in Israel are similar to those published over the last decade in many parts of the world. In contrast, high level resistance to penicillin and to alternative drugs still appears to be rare.

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17.

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