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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*
Characteristics at the Time of Their Initial Bacteremic Episodes of Patients Ultimately With (n = 23) and Without (n = 409) Recurrent Pneumococcal Bacteremia*
Table 2. 
Forward Stepwise Logistic Regression Analysis to Determine Factors Independently Associated With Recurrent Pneumococcal Bacteremia
Forward Stepwise Logistic Regression Analysis to Determine Factors Independently Associated With Recurrent Pneumococcal Bacteremia
1.
Matter  LWilhelm  JAAngehrn  WSkvaril  FSchopfer  K Selective antibody deficiency and recurrent pneumococcal bacteremia in a patient with Sjogren's syndrome, hyperimmunoglobulinemia G, and deficiencies of IgG2 and IgG4. N Engl J Med. 1985;3121039- 1042Article
2.
Gelfand  EWRao  CPMinta  JOHam  TPurkall  DBRuddy  S Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia. Am J Med. 1987;82671- 675Article
3.
Lee  WAustrian  RWeiser  JN Recurrent pneumococcal bacteremia in normal children. Pediatr Infect Dis J. 1994;13231- 233Article
4.
Kuhls  TLViering  TPLeach  CTSteele  MIHaglund  LAFine  DP Relapsing pneumococcal bacteremia in immunocompromised patients. Clin Infect Dis. 1992;141050- 1054Article
5.
Gransden  WREykyn  SJ Recurrent pneumococcal bacteremia. Clin Infect Dis. 1992;151072- 1073Article
6.
Rodriguez-Creixems  MMunoz  PMiranda  EPelaez  TAlonso  RBouza  E Recurrent pneumococcal bacteremia: a warning of immunodeficiency. Arch Intern Med. 1996;1561429- 1434Article
7.
Coccia  MRFacklam  RRSaravolatz  LDManzor  O Recurrent pneumococcal bacteremia: 34 episodes in 15 patients. Clin Infect Dis. 1998;26982- 985Article
8.
Simberkoff  MSSadr  WESchiffmen  GRahal  JJ Streptococcus pneumoniae infections and bacteremia in patients with acquired immunodeficiency syndrome, with report of a pneumococcal vaccine failure. Am Rev Respir Dis. 1984;1301174- 1176
9.
Polsky  BGold  JWMWhimbey  E  et al.  Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1986;10438- 41Article
10.
Witt  DJCraven  DEMcCabe  WR Bacterial infections in adult patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Am J Med. 1987;82900- 906Article
11.
Redd  SCRutherford III  GWSande  MA  et al.  The role of human immunodeficiency virus infection in pneumococcal bacteremia in San Francisco residents. J Infect Dis. 1990;1621012- 1017Article
12.
Rodriguez-Barradas  MCMusher  DMHamill  RJDowell  MBagwell  JTSanders  CV Unusual manifestations of pneumococcal infection in human immunodeficiency virus–infected individuals: the past revisited. Clin Infect Dis. 1992;14192- 199Article
13.
Janoff  ENO'Brien  JThompson  P  et al.  Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis. 1993;16749- 56Article
14.
Hirschtick  REGlassroth  JJordan  MC  et al.  Bacterial pneumonia in persons infected with the human immunodeficiency virus. N Engl J Med. 1995;333845- 851Article
15.
Garcia-Leoni  MEMoreno  SRodeno  PCercenado  EVicente  TBouza  E Pneumococcal pneumonia in adult hospitalized patients with the human immunodeficiency virus. Arch Intern Med. 1992;1521808- 1812Article
16.
Plouffe  JFBreiman  RFFacklam  RR Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. JAMA. 1996;275194- 198Article
17.
Frankel  REVirata  MHardalo  C  et al.  Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis. 1996;23577- 584Article
18.
Gilks  CFOjoo  SAOjoo  JC  et al.  Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet. 1996;347718- 723Article
19.
Nuorti  JPButler  JCGelling  LKool  JLReingold  ALVugia  DJ Epidemiologic relation between HIV and invasive pneumococcal disease in San Francisco County, California. Ann Intern Med. 2000;132182- 190Article
20.
Ernst  JAmaral  LJanseen  R Seroprevalence rates of HIV infection at Bronx-Lebanon Hospital Center, 1988-1991.  Program and abstracts of the 8th International Conference on AIDS1992; Amsterdam, the Netherlands
21.
Turett  GBlum  SFazal  BJustman  JTelzak  E Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence. Clin Infect Dis. 1999;29321- 327Article
22.
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Susceptibility Testing, Sixth Informational Supplement (M100-S6).  Villanova, Pa National Committee for Clinical Laboratory Standards1995;
23.
Meynard  JLBarbut  FBlum  L  et al.  Risk factors for isolation of Streptococcus pneumoniae with decreased susceptibility to penicillin from patients infected with human immunodeficiency virus. Clin Infect Dis. 1996;22437- 440Article
24.
Nava  JMBella  FGarau  J  et al.  Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study. Clin Infect Dis. 1994;19884- 890Article
25.
Pallares  RGudiol  FLinares  J  et al.  Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med. 1987;31718- 22Article
Original Investigation
September 24, 2001

Recurrent Pneumococcal BacteremiaRisk Factors and Outcomes

Author Affiliations

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.

Arch Intern Med. 2001;161(17):2141-2144. doi:10.1001/archinte.161.17.2141
Abstract

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.

RECURRENT pneumococcal bacteremia is an uncommon event. Although most reports14 in the literature are of isolated cases, recently some larger case series57 have been described. Episodes of recurrent pneumococcal bacteremia have been reported primarily in patients with underlying immunodeficiencies.1,2,47 The increased incidence of invasive pneumococcal disease in patients infected with human immunodeficiency virus (HIV) is well documented,816 but there are only limited references57,11,1719 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 χ2 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).

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.

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,57 HIV infection,6,1719 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.17,17 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.57,17 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.57,17 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 β-lactams), factors previously associated with penicillin-resistant pneumococci.2325 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.

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Article 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@onebox.com).

References
1.
Matter  LWilhelm  JAAngehrn  WSkvaril  FSchopfer  K Selective antibody deficiency and recurrent pneumococcal bacteremia in a patient with Sjogren's syndrome, hyperimmunoglobulinemia G, and deficiencies of IgG2 and IgG4. N Engl J Med. 1985;3121039- 1042Article
2.
Gelfand  EWRao  CPMinta  JOHam  TPurkall  DBRuddy  S Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia. Am J Med. 1987;82671- 675Article
3.
Lee  WAustrian  RWeiser  JN Recurrent pneumococcal bacteremia in normal children. Pediatr Infect Dis J. 1994;13231- 233Article
4.
Kuhls  TLViering  TPLeach  CTSteele  MIHaglund  LAFine  DP Relapsing pneumococcal bacteremia in immunocompromised patients. Clin Infect Dis. 1992;141050- 1054Article
5.
Gransden  WREykyn  SJ Recurrent pneumococcal bacteremia. Clin Infect Dis. 1992;151072- 1073Article
6.
Rodriguez-Creixems  MMunoz  PMiranda  EPelaez  TAlonso  RBouza  E Recurrent pneumococcal bacteremia: a warning of immunodeficiency. Arch Intern Med. 1996;1561429- 1434Article
7.
Coccia  MRFacklam  RRSaravolatz  LDManzor  O Recurrent pneumococcal bacteremia: 34 episodes in 15 patients. Clin Infect Dis. 1998;26982- 985Article
8.
Simberkoff  MSSadr  WESchiffmen  GRahal  JJ Streptococcus pneumoniae infections and bacteremia in patients with acquired immunodeficiency syndrome, with report of a pneumococcal vaccine failure. Am Rev Respir Dis. 1984;1301174- 1176
9.
Polsky  BGold  JWMWhimbey  E  et al.  Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1986;10438- 41Article
10.
Witt  DJCraven  DEMcCabe  WR Bacterial infections in adult patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Am J Med. 1987;82900- 906Article
11.
Redd  SCRutherford III  GWSande  MA  et al.  The role of human immunodeficiency virus infection in pneumococcal bacteremia in San Francisco residents. J Infect Dis. 1990;1621012- 1017Article
12.
Rodriguez-Barradas  MCMusher  DMHamill  RJDowell  MBagwell  JTSanders  CV Unusual manifestations of pneumococcal infection in human immunodeficiency virus–infected individuals: the past revisited. Clin Infect Dis. 1992;14192- 199Article
13.
Janoff  ENO'Brien  JThompson  P  et al.  Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis. 1993;16749- 56Article
14.
Hirschtick  REGlassroth  JJordan  MC  et al.  Bacterial pneumonia in persons infected with the human immunodeficiency virus. N Engl J Med. 1995;333845- 851Article
15.
Garcia-Leoni  MEMoreno  SRodeno  PCercenado  EVicente  TBouza  E Pneumococcal pneumonia in adult hospitalized patients with the human immunodeficiency virus. Arch Intern Med. 1992;1521808- 1812Article
16.
Plouffe  JFBreiman  RFFacklam  RR Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. JAMA. 1996;275194- 198Article
17.
Frankel  REVirata  MHardalo  C  et al.  Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis. 1996;23577- 584Article
18.
Gilks  CFOjoo  SAOjoo  JC  et al.  Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet. 1996;347718- 723Article
19.
Nuorti  JPButler  JCGelling  LKool  JLReingold  ALVugia  DJ Epidemiologic relation between HIV and invasive pneumococcal disease in San Francisco County, California. Ann Intern Med. 2000;132182- 190Article
20.
Ernst  JAmaral  LJanseen  R Seroprevalence rates of HIV infection at Bronx-Lebanon Hospital Center, 1988-1991.  Program and abstracts of the 8th International Conference on AIDS1992; Amsterdam, the Netherlands
21.
Turett  GBlum  SFazal  BJustman  JTelzak  E Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence. Clin Infect Dis. 1999;29321- 327Article
22.
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Susceptibility Testing, Sixth Informational Supplement (M100-S6).  Villanova, Pa National Committee for Clinical Laboratory Standards1995;
23.
Meynard  JLBarbut  FBlum  L  et al.  Risk factors for isolation of Streptococcus pneumoniae with decreased susceptibility to penicillin from patients infected with human immunodeficiency virus. Clin Infect Dis. 1996;22437- 440Article
24.
Nava  JMBella  FGarau  J  et al.  Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study. Clin Infect Dis. 1994;19884- 890Article
25.
Pallares  RGudiol  FLinares  J  et al.  Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med. 1987;31718- 22Article
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