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437 Risk Factors for Isolation of Streptococcus pneumoniae with Decreased Susceptibility to Penicillin G from Patients Infected with Human Immunodeficiency Virus J. L. Meynard, F. Barbut, L. Blum, M. Guiguet, C. Chouaid, M. C. Meyohas, o. Picard, J. C. Petit, and J. Frottier From the Service des Maladies Infectieuses et Tropicales, Service de Microbiologie, Service de Medecine Interne, and Service de Pneumologie, H6pital Saint-Antoine; Institut National de la Sante et Recherche Medical Unite 263, Paris, France We conducted a retrospective study of all hospitalized human immunodeficiency virus (HIV)infected patients from whom a strain of Streptococcus pneumoniae was isolated (n = 45) between January 1992 and September 1994, in order to determine the clinical manifestations and outcome of and risk factors for infection by S. pneumoniae with decreased susceptibility to penicillin G. Such strains were isolated from 14 patients (31%), of whom 8 had pneumonia, 2 had bronchial superinfection, 2 had sinusitis, and 2 were colonized. All infected patients made a clinical recovery regardless of the MIC of the isolate. Indexes of HIV disease stage (CD4+ cell count and p24 antigenemia), antiretroviral treatment, and hospital admission in the previous 3 months did not influence the susceptibility of the isolates. For HIV-infected patients, treatment with antibacterial agents-particularly trimethoprim-sulfamethoxazole-in the previous 3 months is associated with an increased risk for isolation of S. pneumoniae with decreased susceptibility to penicillin G (relative risk, 5.0; 95% confidence interval, 1.9-13.3). Infection by HIV has various effects on physiological mechanisms of cellular and humoral immunity and predisposes patients to bacterial infections [1]. Several studies have shown that Streptococcus pneumoniae is the main cause of lower respiratory tract infections in HIV ~infected adults [2]. For example, the incidence of pneumococcal pneumonia is 5.5 to 17.5 times higher in patients with AIDS than in the general population in Boston and New York [3, 4]. Clinical manifestations are similar to those in the general population of patients with pneumococcal pneumonia, although two features, the recurrent and the bacteremic nature of the infection, have been highlighted by certain authors [2-4]. There have been reports of increased mortality associated with bacteremic forms of S. pneumoniae infection in patients with AIDS [5]. Resistance to penicillin has increased greatly in the last few years among clinical S. pneumoniae isolates in many countries. In France, the estimated incidence of S. pneumoniae with decreased susceptibility to penicillin (PRP; herein the abbreviation refers to both penicillin-resistant strains and those with decreased susceptibility to the drug) was 17% in 1990 and 25.1 % in 1994 [6]. An epidemiological survey designed to identify risk factors for acquiring PRP has shown that HIV infection multiplies the risk of invasive infection by a factor of > 3 [7]. The aims of Received 6 July 1995; revised 31 October 1995. Reprints or correspondence: Dr. Jean-Luc Meynard, Service des Maladies Infectieuses et Tropica1es, H6pita1 Saint-Antoine, 184 rue du Faubourg SaintAntoine, 75012 Paris, France. Clinical Infectious Diseases 1996;22:437-40 © 1996 by The University of Chicago. All rights reserved. 1058--4838/96/2203 -0006$02.00 this study were (1) to determine the clinical manifestations, treatment, and outcome of infections due to PRP in HIV-infected patients and (2) to identify these patients' risk factors for acquiring PRP. Patients and Methods Patients Charts of all HIV-infected patients admitted to three units in the Saint-Antoine Hospital between January 1992 and September 1994 and from whom S. pneumoniae was isolated (n = 45) were reviewed. The following variables were recorded: age, sex, risk factor for HIV infection, smoking status, CD4+ and CD8+ cell counts, neutrophil counts, p24 antigen status, pentamidine inhalation, antibiotic therapy and admission to a hospital during the previous 3 months, antiretroviral treatment, the sites from which the organism was isolated, clinical manifestations, recurrence of the infection, treatment, and outcome. The CD4+ and CD8+ cell counts cited are those measured within 3 months of isolation of the bacterium or during the infectious episode. Neutrophil counts are those measured within 24 hours of isolation of the bacterium. Clinical manifestations were classified as sinusitis (radiological diagnosis), bronchial superinfection (cough, expectoration, fever, and no evocative radiological images), pneumonia (fever and evidence of a local or diffuse infiltrate on chest roentgenography), and colonization (isolation of organisms from respiratory tract specimens; no radiological abnormalities or fever). Methods Antimicrobial susceptibility testing was done with an agar disk diffusion method (Mueller-Hinton agar containing 5% 438 cm Meynard et al. 1996; 22 (March) Table 1. Clinical and laboratory findings for 14 patients infected or colonized by S. pneumoniae with decreased susceptibility to penicillin G (group 1). Patient no. First isolation (F) or relapse (R) No.ofCD4 cells per mm3 Isolation site Diagnosis I 2 3 4 5 3 3 25 294 2 BA BA, SP BC BA BA PN PN PN PN PN F R F F F 6 7 8 9 127 92 BA BC, SP BA SP BA SP BA SP BC SI bronch PN PN Sinusitis SI bronch Col Col Sinusitis PN F R F F F R F F F 10 II 12 13 14 11 18 3 25 40 10 150 Treatment Amox (6 g/24 h) Teico (6 mg/[kg' 24 h]) Amox (6 g/24 h) Amox (3 g/24 h) Ctax (3 g124 h), Teico (6 mg/[kg' 24 h]) Amox (6 g124 h) Ctax (4 g/24 h) Prist (3 g/24 h) Cfix Amox (2 g/24 h) None None Prist (3 g/24 h) Amox (6 g124 h) MIC (j-tg/mL) 2 2 1.5 1.5 2 1.5 2 1.5 0.1 0.5 0.5 0.25 0.25 0.2 Serotype ND 23 F 23 14 6 23 F 23 F 23 F 23 F ND ND ND 23 23 NOTE. The outcome was favorable for each patient. Amox = amoxicillin; BA = bronchial aspirate; BC = blood (culture); Cfix = cefixime; Col = colonization; Ctax = cefotaxime; ND = not determined; PN = pneumonia; Prist = pristinamycin; SI bronch = bronchial superinfection; SP = sputum specimen; Teico = teicoplanin. horse blood, incubated for 18 hours at 37°C in air containing 5% CO2 ), according to the recommendations of the Comite de l'Antibiogramme de la Societe Fran<;aise de Microbiologie [8]. Resistance of S. pneumoniae to penicillin G was suspected if the diameter of the zone of inhibition around the 5-l1g oxacillin disk was :::;25 mm. Resistance was confirmed by determination of MIC by the Etest method (AB BIODISK, Solna, Sweden) [9]. Isolates were designated as susceptible (MIC, <0.06 I1g/ mL), intermediately resistant (MIC, 0.12-1 I1g/mL), or highly resistant to penicillin G (MIC, > 1 I1g/mL) [8]. Serotyping. The serotypes of S. pneumoniae isolates with decreased susceptibility to penicillin G were determined at the Centre National de Reference des Pneumocoques (Dr. Geslin, Creteil, France) by a latex agglutination method (immune serum provided by the Statens Seruminstitut, Copenhagen). Statistical analysis. Fisher's exact test was used for qualitative variables, and Wilcoxon's test was used for continuous variables. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated to identify which factors were most related to PRP acquisition. Stratified analysis was then carried out with the Mantel-Haenzel estimate. The statistical analysis was performed with the SAS software package (SAS Institute, Cary, NC). Results Between January 1992 and September 1994, S. pneumoniae was isolated from 45 individual patients. PRP were isolated from 14 patients (group 1), and strains of S. pneumoniae that had normal susceptibility to penicillin G were isolated from 31 patients (group 2). In group I (table I), 8 patients (57%) had pneumonia (3 of whom had positive blood cultures), 2 had bronchial superinfection, 2 had sinusitis, and 2 were simply colonized. S. pneumoniae that was highly resistant to penicillin G was isolated from 8 patients (57%), of whom 7 had pneumonia (blood cultures were positive for 2) and I had bronchial superinfection. Serotype 23 was the most common, accounting for 80% of isolates in group I whose serotypes were identified. Clinically, infection resolved regardless of resistance to penicillin G. Pneumonia was treated with amoxicillin (3-6 g/24 h; n = 4), teicoplanin (6 mg/[kg' 24 h]; n = 2), pristinamycin (3 g/24 h; n = 1), or cefotaxime (3 or 4 g/24 h; n = I). The 14 patients from whom PRP were isolated all had a strain that was resistant to trimethoprim-sulfamethoxazole (TMP-SMZ), except for one patient who was not receiving TMP-SMZ. In group 2 (n = 31), 18 patients had pneumonia (12 of whom had positive blood cultures), 9 had bronchial superinfection, and 4 were colonized. Clinically, infection resolved in all 27 patients infected. The 31 penicillin-susceptible S. pneumoniae isolates were susceptible to TMP-SMZ in all but 2 cases (1 of the 2 patients was receiving TMP-SMZ). As shown in table 2, demographic data and the distribution of the risk factors for HIV infection were comparable between the two groups, as were CD8 + cell counts and frequency of qualitative p24 antigenemia. The median CD4+ cell count was lower in the group of patients from whom a resistant strain was isolated, although not significantly so. The distribution of the different types of infection (pneumonia, bronchial superinfection, sinusitis) and the numbers of patients colonized were comparable in groups I and 2, as were the numbers of patients cm S. pneumonia with Decreased Susceptibility to Penicillin G 1996;22 (March) 439 Table 2. Comparison of patients from whom S. pneumoniae with decreased or normal susceptibility to penicillin G were isolated. Susceptibility to penicillin G Characteristics of and data regarding patients No. (%) of males Age (y), median (range) No. (%) of smokers No. (%) addicted to drugs Median cell count per mm 3 (range) CD4 CD8 WBC PMN No. (%) with p24 antigen No. (%) with positive blood culture No. (%) relapsing During the previous 3 mo: Admission to hospital Treatment with Pentamidine aerosol Antiretroviral agents Antibiotic(s) ,B-Lactam agents TMP-SMZ NOTE. PMN =: Decreased =: 14) (%) (n (n 10 (71) 33.5 (23-59) 12 (86) 3 (21) 22 33 22 13 25 (2-294) 391.5 (164-2,020) 4,325 (1,100-10,900) 2,100 (660-9,047) 6 (43) 48 548 5,050 3,180 11 Nonnal =: 31) (%) P value (71) (27-60) (71) (42) 1 .48 .45 .31 (1-807) (30-1,822) (1,700-15,500) (1,224-12,400) (35) .09 .42 .24 .06 .74 3 (21) 3 (21) 12 (39) 1 (3) .32 .08 3 (21) 7 (23) .63 2 9 13 4 10 14 14 9 2 5 (14) (64) (93) (29) (71) (45) (45) (29) (6) (16) .09 .34 <.001 .06 <.001 polymorphonuclear neutrophil. whose blood cultures were positive, relapse rates, and neutrophil counts at the time of infection. Whatever the susceptibility of the strain, 20% of all patients had been admitted to a hospital in the previous 3 months. Patients from whom a resistant strain was isolated had received more antibiotics (of all types) than had patients from whom a susceptible strain was isolated (93% vs. 29%; P < .001), particularly with regard to ,B-lactam agents (29% vs. 6%; P = .06) and TMP-SMZ (71 % vs. 16%; P < .001). The relative risks for isolation of a resistant strain associated with administration of any antibiotic, a ,B-lactam agent, or TMP-SMZ were 13.6 (95% CI, 1.9-95.3),2.6 (95% CI, 1.25.2), and 5 (95% CI, 1.9-13.3), respectively. The relative risk associated with TMP-SMZ intake was not modified after adjustment for CD4+ cell count «50/mm 3 vs. >50/mm 3 ) (adjusted RR, 4.4; 95% CI, 1.6-7) or for hospital admission during the previous 3 months (adjusted RR, 4.9; 95% CI, 2.1-11.7). Among the patients who had not received a ,B-lactam antibiotic (n = 39), administration of TMP-SMZ was associated with an increased risk of infection with PRP (RR, 10.2; 95% CI, 2.6-40.6). As only six patients had previously been treated with ,B-lactam antibiotics (of whom four had also received TMP-SMZ), the role, if any, played by TMP-SMZ in acquisition of a strain of PRP could not be detected. Discussion Because of the effects of HIV on cellular and humoral immunity, the risks of bacterial infection are increased in HIV-infected patients [1]. The respiratory tract is a primary site of infection [2]. Many authors have highlighted the frequency of S. pneumoniae infections and their tendency to be bacteremic and recurrent in HIV-infected patients [2, 5, 10, 11]. Strains of S. pneumoniae with decreased susceptibility to penicillin G have been emerging in France over recent years [6], and HIV infection is considered a risk factor for infection by PRP [7]. Most studies on the interaction between S. pneumoniae and HIV infection have been done in the United States, where resistance to penicillin G is considerably less frequent than in Europe [12]. Our study confirms the frequency ofinfection due to PRP in HIV-infected subjects. Of the 45 such patients from whom S. pneumoniae was isolated between January 1992 and September 1994, the isolates of 14 (31 %) were PRP. During the same period the frequency of isolation of PRP in the general population of Saint-Antoine Hospital was 19%. Only previous antibacterial therapy in general-and TMPSMZ or ,B-lactam therapy in particular-emerged as a risk factor for acquisition of PRP by these HIV-infected patients. Administration ofTMP-SMZ remained a risk factor for acquisition of PRP after adjustment for the CD4+ count and recent (prior) admissions to a hospital. 440 Meynard et al. Contrary to the case with ,B-lactam antibiotics [13], the mechanism of resistance to TMP-SMZ has not been clearly defined. It appears to be related to the production of an abnormal enzyme, dihydrofolate reductase, with abnormally high affinity for TMP [14]. All 14 strains of PRP isolated were resistant to TMP-SMZ, with the exception of one isolated from a patient who was not receiving TMP-SMZ. Conversely, all the strains susceptible to penicillin G were also susceptible to TMP-SMZ, with the exception of two, one of which was isolated from a patient receiving TMP-SMZ. We hypothesize that TMP-SMZ may protect against bacterial infections, particularly those due to susceptible S. pneumoniae. Because of their immunodeficiency, HIV-infected patients are more likely to be infected by strains with decreased susceptibility to penicillin G, which are generally less virulent. Patients infected by HIV also have specific features ofimmunodeficiency that increase the risk of pneumonia and bacteremia due to S. pneumoniae serotypes that are not virulent but are often multiresistant; indeed, they have been shown to have increased oropharyngeal colonization [15], reduced antibodydependent cytotoxic responses involving local IgA production and alveolar macrophage activity [16], reduced IgG 2 responses to polysaccharide antigens [17], and abnormal complement activation [18]. Another hypothesis is that administration of TMP-SMZ may directly induce the emergence of TMP-SMZ-resistant mutants. The genes coding for sulfonamide and TMP resistance in these strains are physically close to the genes encoding penicillinbinding proteins 2x and 2b, which are the first to be altered in the penicillin-resistant strains [19], and this circumstance may explain the high frequency of resistance to sulfonamide and TMP among these strains. Long-term use of the TMP-SMZ combination may thus promote the selection of penicillin-resistant pneumococci. Conclusions This study confirms the high frequency of PRP infection and colonization in HIV-infected patients. However, the clinical manifestations and outcome were similar to those for patients infected with penicillin-susceptible strains. Recent antibiotic therapy, especially with TMP-SMZ, appears to predispose HIV-infected patients to infection by S. pneumoniae strains with decreased susceptibility to penicillin. Acknowledgment The authors are deeply indebted to Dr. P. Geslin for serotyping strains of Streptococcus pneumoniae with decreased susceptibility to penicillin G. cm 1996; 22 (March) References 1. Simberkoff MS, Leaf HL. Bacterial infections in patients with HIV infection. In: Wormser GP, ed. AIDS and other manifestations of HIV infection. New York: Raven Press, 1992:269-75. 2. Janoff EN, Breiman RF, Daley CL, Hopewell PC. 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