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Recurrent Pneumococcal Bacteremia
Risk Factors and Outcomes
Glenn S. Turett, MD;
Steve Blum, PhD;
Edward E. Telzak, MD
Arch Intern Med. 2001;161:2141-2144.
ABSTRACT
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Background Recurrent pneumococcal bacteremia receives infrequent mention in the
literature, usually in association with patients who are immunocompromised.
Objective To examine recurrent cases of pneumococcal bacteremia to determine risk
factors and outcomes (mortality rates and emergence of resistance) associated
with recurrences.
Methods We retrospectively reviewed all cases of pneumococcal bacteremia identified
by our microbiology laboratory from January 1, 1992, through December 31,
1996. Demographic, clinical, and laboratory data were abstracted.
Results There were 462 bacteremic episodes in 432 patients; 23 of these patients
had 30 recurrent episodes. The 5.3% recurrence rate (23/432) is greater than
that previously described. The median time to recurrence was 200 days. The
mean age of patients with recurrences was 34 years, 70% were women, all were
black or Hispanic (in near equal numbers), and 87% were infected with the
human immunodeficiency virus (HIV). Human immunodeficiency virus infection,
coexistent cancer, and female sex were independent predictors of recurrence.
Only patients who were HIV-infected had multiple recurrences. Isolates from
recurrent bacteremias were more likely to be penicillin-resistant than were
initial bacteremic isolates (relative risk, 2.0; P
= .16). Patients with recurrences had a higher (although not statistically
significant) mortality rate than those without recurrences (22% vs 16%; P = .33). There was an inverse relationship between severity
of illness and likelihood of recurrence.
Conclusions Rates of recurrent pneumococcal bacteremia may be higher than previously
reported. In patients with recurrent pneumococcal bacteremia, the presence
of an underlying immunodeficiency should be investigated.
INTRODUCTION
RECURRENT pneumococcal bacteremia is an uncommon event. Although most
reports1-4
in the literature are of isolated cases, recently some larger case series5-7 have been described.
Episodes of recurrent pneumococcal bacteremia have been reported primarily
in patients with underlying immunodeficiencies.1-2,4-7
The increased incidence of invasive pneumococcal disease in patients infected
with human immunodeficiency virus (HIV) is well documented,8-16
but there are only limited references5-7,11, 17-19
relating HIV infection and recurrent pneumococcal disease. Our medical center
serves a community with one of the highest rates of HIV infection in the United
States.20 In reviewing our overall experience
with pneumococcal bacteremias during 5 years, we observed a higher rate of
recurrence than that previously reported and a marked association between
HIV infection and recurrences. We looked to determine what other variables
besides HIV infection were associated with recurrent pneumococcal bacteremia
and what effect recurrences had on mortality rates and on emergence of penicillin
resistance.
PATIENTS AND METHODS
Bronx-Lebanon Hospital Center is an acute-care facility serving an inner-city
patient population of nearly half a million in the south Bronx, NY. All episodes
of pneumococcal bacteremia between January 1, 1992, and December 31, 1996,
were identified by retrospective review of microbiology records. Hospital
inpatient and outpatient records were reviewed, and demographic, clinical,
and laboratory data were abstracted on all identified patients. A description
of this entire cohort and predictors of mortality have been previously published.21
Recurrent pneumococcal bacteremia was defined as the presence of Streptococcus pneumoniae in the blood at least 4 weeks
after initial isolation and following a course of therapy with antibiotics
that had in vitro activity against the initial isolate and evidence of a clinical
response. Severity of illness was graded as severe or not severe based on
clinical status and arterial blood gas measurements; illness was deemed severe
if there was need for intensive care unit evaluation, hemodynamic instability,
or an arterial PO2 of less than 50 mm Hg.
In vitro susceptibility of the isolates to penicillin was initially
determined using the oxacillin sodium disk diffusion test. If resistance was
found by this method, a minimal inhibitory concentration was subsequently
determined using the E-test. Levels of resistance to penicillin were defined
according to criteria of the National Committee for Clinical Laboratory Standards.22
The main outcomes of interest were episodes of recurrent pneumococcal
bacteremia, emergence of penicillin resistance, and mortality.
Statistical analyses included bivariate and multivariate analyses of
the effects of all variables on recurrent pneumococcal bacteremia. The  2 or Fisher exact test (for expected cell frequencies <5) was used
for bivariate examination of categorical data, and forward stepwise logistic
regression techniques were used to determine the effects of continuous and
categorical variables (with P .10 on bivariate
analysis) on recurrent episodes of pneumococcal bacteremia. Also, the relationships
between recurrences and penicillin resistance and recurrences and mortality
rates were explored using similar statistical methods.
RESULTS
During the study, there were 462 episodes of pneumococcal bacteremia
in 432 patients. Twenty-three patients had 30 episodes of recurrent bacteremia:
17 had single recurrences, 5 had 2 recurrences, and 1 patient had 3 recurrences.
Overall, 5.3% of the patients (23/432) had recurrent pneumococcal bacteremia.
The median time to recurrence was 200 days (range, 32-1196 days). All 6 patients
with multiple recurrences were HIV-infected. Patients with a first recurrence
were almost 5 times more likely to have another recurrence compared with the
likelihood of recurrence for the entire group (multiple recurrence rate/initial
recurrence rate = 6/23 divided by 23/432 = 4.9).
Table 1 compares demographic
and clinical characteristics of the patients with and without recurrent pneumococcal
bacteremia and shows the statistical associations between the different variables
and recurrences using bivariate analysis. Documented HIV infection, coexisting
cancer, and female sex were the only characteristics significantly associated
with recurrent pneumococcal bacteremia. Age, race, ethnicity, CD4+
cell count, trimethoprim-sulfamethoxazole use among those known to be HIV-infected,
chest roentgenogram findings, involvement of other sterile sites, presence
of underlying disease (other than HIV infection), and penicillin resistance
were similar in the 2 groups and were not associated with recurrences (P .30 for all variables). In those patients without
severe manifestations of disease on presentation, there was a trend toward
developing recurrent pneumococcal bacteremia, compared with those presenting
with severe manifestations of disease (7% vs 2%, P
= .06).
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Table 1. Characteristics at the Time of Their Initial Bacteremic Episodes
of Patients Ultimately With (n = 23) and Without (n = 409) Recurrent Pneumococcal
Bacteremia*
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Table 2 demonstrates the
results of the forward multiple stepwise logistic regression analysis to determine
factors independently associated with recurrent pneumococcal bacteremia. Coexistent
cancer, HIV infection, and female sex all remained independent predictors
of recurrence.
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Table 2. Forward Stepwise Logistic Regression Analysis to Determine
Factors Independently Associated With Recurrent Pneumococcal Bacteremia
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To try to understand the association between female sex and recurrence,
further bivariate analyses were done on all variables according to sex. Women
were younger, less severely ill on presentation, and had higher CD4+ cell counts among those who were HIV-infected. None of these findings
explain the increased recurrences seen in women.
The mean and median ages of the patients infected with HIV who had recurrences
were 30 and 32 years, respectively. This was significantly lower than the
mean of 36 years and the median of 39 years for the patients with HIV without
recurrences (P = .049). The mean age of the 3 patients
without HIV infection who had recurrences was 63 years. Two of these patients
had multiple myeloma, and the third had cirrhosis of the liver.
Five (22%) of the 23 patients with recurrences died, compared with 67
(16%) of 409 patients with single bacteremic episodes (P = .33). Isolates from recurrent bacteremias were twice as likely
to be penicillin-resistant than were isolates from initial bacteremias (13.3%
[4/30] vs 6.7% [29/432]; relative risk, 2.0; P =
.16).
COMMENT
In this study, HIV infection, cancer, and female sex were each independent
predictors of recurrent pneumococcal bacteremia. Others have previously described
the association between cancer,5-7
HIV infection,6, 17-19
and recurrent pneumococcal bacteremia. However, the association between female
sex and recurrent pneumococcal bacteremia has not been previously noted, and
this finding remains unexplained, despite extensive analysis.
Our series of 23 patients with recurrent pneumococcal bacteremia is
among the largest reported to date; previous descriptions ranged from isolated
case reports to series of up to 15 patients.1-7,17
A recent article from San Francisco, Calif,19
that examined the relationship between HIV and invasive pneumococcal disease
described 28 patients who were HIV-infected who had recurrent pneumococcal
bacteremia, with a rate of recurrence of almost 15%. However, these authors
defined recurrent disease as "isolation of S. pneumoniae from a normally sterile site more than 7 days after the original episode,"19(p183) although the actual mean, median, and/or range
of times to recurrence were not reported. By using such a short interval between
initial and subsequent isolation as the criterion for recurrence, some episodes
classified as recurrent may actually have been persistent initial infections.
Our definition of recurrence is more stringent and is more consistent with
that in the literature (eg, infection-free for 30 days between episodes,6 or 22-947 days [mean, 268 days; median, 180 days]
between episodes7). The 5.3% overall rate of
recurrent pneumococcal bacteremia we observed is greater than the 1.5% to
4.1% rates previously reported.5-7,17
One possible explanation for our increased rate of recurrence is the greater
proportion (48%) of patients who were HIV-infected in our cohort compared
with the 7% to 33% seen in the other series.5-7,17
Frankel et al17 noted a greater relative risk
of recurrent pneumococcal bacteremia with HIV than we did (15 vs 7.3). Redd
and associates11 found an increased risk (relative
risk, 1.6) that did not reach statistical significance (P = .11).
Our 22% mortality associated with recurrent bacteremias was not significantly
higher than the 16% seen during initial episodes (P
= .33). Rodriguez-Creixems et al,6 in reviewing
their 10-year experience with recurrent pneumococcal bacteremia, noted a mortality
of 47%. Like our patients, all of theirs were immunosuppressed with malignancies,
HIV infection, or cirrhosis. Their mean age was 52 years. On multivariate
analysis, they found multiple myeloma to be the only clear predictor of recurrent
bacteremia. The younger mean age (34 years) in our patients with recurrences
may in part explain the lower mortality rate we saw compared with that of
Rodriguez-Creixems et al.
Patients in our cohort with recurrences were twice as likely to be infected
with resistant pneumococcus as those with single episodes. This is not unexpected
considering all had recently been hospitalized and received antibiotics (primarily  -lactams),
factors previously associated with penicillin-resistant pneumococci.23-25 Similarly, Rodriguez-Creixems
et al6 found penicillin resistance to be more
common among their recurrent cases, although also not statistically significantly
so.
Those patients without severe illness were more likely to have recurrences,
and this finding approached statistical significance (P = .06). This inverse relationship between severity of illness and
recurrence (relative risk, 0.3) may be explained by the fact that severe illness
was an independent predictor of mortality in the entire cohort with pneumococcal
bacteremia; 56% of those presenting with severe manifestations of disease
died, compared with only a 3% mortality in those not presenting with severe
manifestations of disease.21 So, if one did
not survive a first episode of pneumococcal bacteremia, he or she would not
have the opportunity to develop recurrent bacteremia.
One drawback of this study was that no serotyping of pneumococcal isolates
was done. Hence, we were unable to distinguish if these recurrences represented
relapses or reinfections. Also, the rate of recurrent pneumococcal bacteremia
described herein is greater than that in most previous reports, but it is
likely that this rate is an underestimate because it includes only those patients
who returned to and were evaluated at our institution. It is probable that
some patients, of whom we were unaware, presented to other institutions with
recurrent disease.
This series of patients with recurrent pneumococcal bacteremia confirms
the previously reported associations with coexistent cancer and HIV infection,
and illustrates the newly found association with female sex and the inverse
relationship with severity of illness. More than 1 recurrence appears suggestive
of HIV infection. When caring for a patient with recurrent pneumococcal bacteremia,
clinicians should explore the possibility of an underlying immunocompromising
condition, offer HIV testing, search for an occult malignancy, and look for
other immunodeficiencies.
AUTHOR INFORMATION
Accepted for publication February 22, 2001.
Presented as a poster at the 38th Annual Meeting of the Infectious Diseases
Society of America, New Orleans, La, September 8-9, 2000.
Corresponding author: Glenn S. Turett, MD, Section of Infectious
Diseases, Department of Medicine, Saint Vincents Hospital and Medical Center,
Cronin Bldg, Room 1003, 153 W 11th St, New York, NY 10011 (e-mail: gsturett{at}onebox.com).
From the Section of Infectious Diseases, Department of Medicine, Saint
Vincents Hospital and Medical Center, New York (Dr Turett); and the Division
of Infectious Diseases, Department of Medicine, Bronx-Lebanon Hospital Center,
Albert Einstein College of Medicine, Bronx (Drs Blum and Telzak), NY.
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