Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae

Rev Clin Esp. 2013;213(2):88---96

Revista Clínica Española www.elsevier.es/rce

ORIGINAL ARTICLE

Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae夽 P. Cardinal-Fernándeza,∗ , G. García Gabarrotb , P. Echeverriac , G. Zumd , J. Hurtadoe , G. Rieppif a

Departamento de Medicina Intensiva, CASMU-IAMPP, Montevideo, Uruguay Departamento de Laboratorios, Ministerio de Salud Pública, Montevideo, Uruguay c Servicio de Microbiología, HCFFAA, Montevideo, Uruguay d Servicio de Medicina Intensiva, Hospital Policial, Montevideo, Uruguay e Servicio de Medicina Intensiva, Hospital Espa˜ nol «Dr. Juan José Crottogini», Montevideo, Uruguay f Cátedra de Medicina Intensiva, Hospital de Clínicas «Dr. Manuel Quintela», Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay b

Received 23 May 2012; accepted 25 September 2012 Available online 13 December 2012

KEYWORDS Pneumonia; Streptococcus pneumoniae; Epidemiology; Mortality; Serotypes; Community-acquired pneumonia

Abstract Introduction: The objectives of the present study were: (a) to describe the mortality rate and its associated variables in community-acquired pneumoniae (CAP) due to Streptococcus pneumoniae (S. pneumoniae), (b) to identify therapeutic issues to improve, (c) to describe the main serotypes of S. pneumoniae and (d) to know the potential coverage of antipneumococcal 23-valent vaccine. Materials and methods: Inclusion criteria were age >16 years-old hospitalized due to PAC. Pneumococcal PAC etiology was considered if S. pneumoniae was isolated from blood culture and/or positive capsular urinary antigen detected at hospital admission. Exclusion criteria were patients who refused participation and/or pneumococcal infection diagnosis was made within the last month before hospital admission. Results: A total of 192 patients were included, mean age 54.6 ± 19.2 years. The most frequent comorbidities were diabetes, COPD and immunosupression. There were 147 patients with bacteremia. The most frequent serotypes were 7F, 1 and 3. Beta-lactamic resistant microorganisms were not identified and only 8 (5.4%) strains were erythromycin-resistant. Potential anti-pneumococcal 23-valent vaccine coverage was 93%. Thirty-seven patients died. Variables associated with mortality were shock within the first 72 h of hospital admission (OR: 7.51; 95% CI: 2.94---19.17) and antibiotic delay ≥6 h (OR: 2.47; 95% CI: 1.00---6.17).

夽 Please cite this article as: Cardinal-Fernández P, et al. Aspectos clínicos y microbiológicos de la neumonía aguda comuni-taria a Streptococcus pneumoniae. Rev Clin Esp. 2013:213:88---96. ∗ Corresponding author. E-mail address: [email protected] (P. Cardinal-Fernández).

na, S.L. All rights reserved. 2254-8874/$ – see front matter © 2013 Elsevier Espa˜

Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae

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Conclusions: Pneumococcal pneumonia mortality was 19.3%. Septic shock and antibiotic delay ≥6 h since hospital admission were associated with hospital mortality. The most frequent serotype was 7F. The potential anti-pneumococcal vaccine coverage is almost 90%. © 2013 Elsevier Espa˜ na, S.L. All rights reserved.

PALABRAS CLAVE Neumonía; Streptococcus pneumoniae; Epidemiología; Mortalidad; Serotipos; Neumonia adquirida en la comunidad

Aspectos clínicos y microbiológicos de la neumonía aguda comunitaria a Streptococcus pneumoniae Resumen Introducción: Los objetivos fueron: (a) describir la mortalidad y sus variables asociadas en la neumonía aguda comunitaria (NAC) a Streptococcus pneumoniae (S. pneumoniae); (b) identificar aspectos terapéuticos a mejorar; (c) identificar los principales serotipos de S. pneumoniae, y (d) conocer la cobertura potencial de la vacuna antineumocócica 23 valente. Material y método: Criterio de inclusión: NAC en pacientes mayores de 16 a˜ nos. Se consideró NAC neumocócica si al ingreso hospitalario se aisló S. pneumoniae desde la sangre y/o se detectó la presencia de antígeno neumocócico capsular en orina. Criterios de exclusión: negativa al consentimiento informado o infección neumocócica en el mes previo al ingreso. Resultados: Se identificaron 192 pacientes con edad promedio de 54,6 ± 19,2 a˜ nos. Comorbilidades más frecuentes: diabetes, EPOC e inmunodepresión. Se detectaron bacteriemias en 147 pacientes. Los serotipos más frecuentes fueron: 7F, 1 y 3. Ninguna cepa fue resistente a los betalactámicos y 8 (5,4%) a la eritromicina. Cobertura potencial de la vacuna antineumocócica 23 valente: 93%. Fallecieron 37 pacientes. Variables asociadas a la mortalidad: shock en las primeras 72 h desde el ingreso al hospital (OR: 7,51; IC 95%: 2,94---19,17) y demora en el inicio de la antibioticorapia ≥6 h (OR: 2,47; IC 95%: 1,00---6,17). Conclusiones: La mortalidad de la NAC neumocócica fue del 19,3%; las únicas 2 variables asociadas a ella fueron el shock séptico y la demora ≥6 h en el inicio de la antibioticoterapia. Adicionalmente el mencionado retraso constituye el principal factor terapéutico a mejorarse en el futuro. El serotipo más frecuente fue el 7F. La cobertura potencial de la vacuna 23 valente es cercana al 90%. © 2013 Elsevier Espa˜ na, S.L. Todos los derechos reservados.

Introduction What we know Pneumococcal pneumonia represents a high number of hospitalizations and a significant healthcare expenditure in our community. However, there is no available data on what this infection represents in terms of mortality, the most frequently involved serotypes and antibiotic resistance in Latin American countries.

What this article provides This study characterizes the mortality, the most frequent serotypes and the antibiotic resistance of pneumococcal pneumonia in Uruguay over a 2-year period. It includes patients admitted to the ICU or who had positive bacteremia or a poorer prognosis; however, the study is one of the few that presents the reality of this common infection in the South American continent. The Editors

In the 19th century, the renowned Canadian physician Sir William Olser described pneumococcal pneumonia as ‘‘The Captain of the Men of Death’’. More than a century later and after extensive research, significant technological advances and investments of enormous amounts of money, the above mentioned phrase remains entirely applicable. In Spain, it is estimated that each year there are 1.6 cases of acute community-acquired pneumonia (CAP) for every 1000 inhabitants, which represents an estimated 53,000 hospitalizations and a cost of 114.8 million euros in treatment alone.1 In Uruguay, unfortunately, there is no available information specifically related to CAP; however, the latest available official data correspond to the year 2008 and reveal that respiratory infections were the third leading cause of death in the general population and represent 2890 (9.21%) of the 31,363 registered deaths.2 The importance of Streptococcus pneumoniae (S. pneumoniae) as the etiological agent in CAP is based on the fact that (a) it is the most common etiological microorganism,3,4 (b) the isolation of antibiotic-resistant strains is increasing in various parts of the world,5,6 (c) there are vaccines with proven efficacy and (d) the morbidity and mortality of pneumococcal pneumonia is high.7 From the population standpoint, the prevention of infections is one of the main objectives of virtually all health

90 systems. Among the major successes of immunoprophylaxis are the eradication of smallpox worldwide and poliomyelitis in the Americas and in Europe.8 Uruguay, a country with 3,368,595 inhabitants distributed over an area of 176,215 km2 , was the first country in South America to universally incorporate the pneumococcal vaccine for children under 5 years of age.2,9 In 2008, the administration of the heptavalent vaccine (PCV7) began; however, due to its low potential coverage (49% of the serotypes that cause invasive pneumococcal disease10 ), the vaccine was substituted by the 13-valent vaccine (PCV13). For adults and on a voluntary basis, the recommendations of the Ministry of Public Health (MSP) of Uruguay include vaccinating (with the 23-valent vaccine) individuals over 65 years of age or those belonging to risk groups (immunocompromised, splenectomized, patients with chronic obstructive pulmonary disease [COPD], diabetes, liver disease, heart failure and alcoholics).2,11 The vaccination, in addition to having an individual effect on those who receive it, may have an impact on the population. In a recent study,12 Fenoll et al. analyzed the impact of the introduction of the PCV7 vaccine for children in Spain on the prevalence of noninvasive S. pneumoniae serotypes in adults. They compared two groups of samples received in the Spanish reference laboratory for pneumococcus; the first group corresponded to the period 2000---2001 (prior to PCV7) and the second to the period 2010---2011 (post PCV7). They found a significant reduction in the serotypes contained in the vaccine but a 50% increase in the serotypes not contained in the vaccine, especially the 19A (a 294% increase) and 15A (180% increase), as well as the emergence of two new serotypes (6C and 11A). They also observed changes in the antibiotic sensitivity profile, with a significant reduction in penicillin- and cefuroxime-resistant strains. When specifically assessing the strains not included in the PCV7, the results were different, and an increase was observed in the proportion of penicillin- and/or erythromycin-resistant strains. The aims of the present study were to (a) describe the mortality and associated variables of CAP in S. pneumoniae, (b) identify therapeutic aspects that need improvement, (c) identify the main serotypes of S. pneumoniae and (d) determine the potential coverage of the 23-valent pneumococcal vaccine.

Patients and methods The present study is included within the framework of the Clinical and Genetic Research Project on Acute CommunityAcquired Pneumonia due to Pneumococcus (PICGENN), which was approved by the ethics committee of each participating center.

P. Cardinal-Fernández et al. The study included patients admitted to the ward and/or to the intensive care unit (ICU), who were over 16 years of age and were diagnosed with CAP. CAP due to S. pneumoniae was considered if, at the time of admission to the hospital, S. pneumoniae was isolated from the blood and/or the presence of pneumococcal capsular antigen was detected in urine. The study excluded patients who did not give their informed consent and/or who presented a pneumococcal infection in the month prior to hospitalization.

Patient identification The study used two strategies for recording patients: (a) each center’s microbiology laboratory reported the isolation from blood of each S. pneumoniae strain to the study’s coordinating team and (b) each ICU was visited daily to identify patients with CAP, positive urinary antigen and sterile blood cultures. For logistical reasons, it was not possible to assess patients who were admitted to the ward for CAP and who exclusively presented positive urinary antigen (sterile blood cultures). Upon identifying a potential candidate, at least one of the intensivists responsible for the research confirmed the diagnosis of CAP, requested the patient’s consent and collected the data according to predefined forms. Day 0 was considered the day of admission to the hospital. Monitoring was performed daily up to day 28 from admission in the emergency department or in the ICU (if the patient was admitted directly from the community) or at hospital discharge.

Microbiological analysis The S. pneumoniae strains were identified by each participating center’s microbiology laboratory from blood cultures obtained at hospital admission. The isolated strains were transferred to the Department of Laboratories of the MSP, the national reference center, where they performed the confirmation, the sensitivity-to-antibiotics tests and serotyping using the Quellung technique with antisera from the Statens Serum Institut (Copenhagen, Denmark). The majority of the strains were serotyped until the serotype was defined (example 6B). In some cases, definition was not possible due to a lack of specific sera (e.g., pool G). According to the recommendations and protocols of the Clinical Laboratory Standards Institute, the S. pneumoniae was considered penicillin sensitive if the minimum inhibitory concentration (MIC) was ≤2 ␮g/ml and erythromycinsensitive if the MIC was ≤0.25 ␮g/ml.13

Design

Definitions

This was a prospective, observational, cohort study. The patients were recruited during the period from January 1, 2008 to December 31, 2010 at the Police Hospital ‘‘Inspector General Uruguay Genta’’, Clinical Hospital ‘‘Dr. Manuel Quintela’’, Spanish Hospital ‘‘Dr. Juan José Crottogini’’, Armed Forces Central Hospital and in CASMU-IAMPP.

--- CAP: medical history and physical examination compatible with the diagnosis of pneumonia associated with the presence of infiltrate(s) in the chest X-rays, without hospitalization in the previous two weeks.14 --- Mechanical ventilation (MV) was defined as the need for artificial ventilator support (invasive or not) at any time

Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae

---

---

---

---

---

during hospitalization and for at least 12 h. The limit of 12 h was chosen arbitrarily a priori to exclude those patients in whom ventilator support was temporary and was due to a specific situation. MV was always performed in the ICU and was indicated by intensivists based on international recommendations.15 Septic shock was defined according to the recommendation of the Consensus Conference of ACCP/SCCM16 as a condition in which the systolic blood pressure remained below 90 mm Hg despite the administration of 20 ml/kg of fluids and was accompanied by disorders in peripheral perfusion and/or required vasoactive drugs to maintain systolic blood pressure above 90 mm Hg. Septic shock was only considered if diagnosed within the first 72 h from admission to the emergency department or the ICU, in cases where the patient was sent directly from the community. The CURB65 scale17 is a classification of severity applicable to CAP and is composed of the following variables: confusion, urea >7 mmol/l, polypnea ≥30 breaths per minute, hypotension with systolic blood pressure <90 mm Hg or diastolic blood pressure <60 mm Hg and age ≥65 years. Each variable, when present, was assigned a point. The final score was defined as the sum of all points for each patient. Refractory hypoxemia as a cause of death for the presence of, in the 6 h prior to death, a ratio of the partial pressure of oxygen and fraction of inspired oxygen (PaO2 /FiO2 ) ≤100 (with a positive final expiration pressure ≥10) and which did not improve with alveolar recruitment maneuvers and prone decubitus positioning. If the patient presented refractory hypoxemia and some other dysfunction, including shock, the cause of death was considered to be multiple organ dysfunction syndrome (MODS). The time to the start of antibiotic therapy was considered the period of time, in hours, elapsed between admission to the emergency department or ICU, if the patient was admitted directly from the community, and the administration of the first dose of the antibiotic plan. The combination of ampicillin and sulbactam was considered a single antibiotic. In terms of immunoprophylaxis, patients were considered vaccinated if they received the influenza vaccine during the previous year or received the pneumococcal vaccine in the 5 years prior to the current hospitalization.

Pathological history: (a) alcoholism: daily alcohol consumption greater than 50 g; (b) chronic liver disease: presence of portal hypertension and/or pathological or imaging diagnosis (computed tomography or ultrasound) of cirrhosis or hepatic steatosis; (c) immunosuppression: chemotherapy, radiation therapy, treatment with corticosteroids at a dosage greater than 20 mg of prednisone per day (or its equivalent) in the month prior to admission, serology positive for human immunodeficiency virus, splenectomy and pregnancy; (d) cancer (considered if the patient, at admission or during the hospitalization, showed the presence of a malignant neoplastic process); (e) ischemic heart disease: history of acute coronary syndrome and/or myocardial revascularization procedure; (f) chronic renal failure: creatinine levels prior to the current disease ≥1.40 mg/dl or chronic dialysis; and lastly, (g) the presence of COPD or

91

diabetes was considered if the patient, their physician or their medical history recorded the above mentioned condition. There are no national guidelines in Uruguay for the treatment of CAP, and therefore the great majority of physicians adhere to the 2007 recommendations of the American Thoracic Society (ATS).14

Statistical analysis Categorical variables are presented as the number of cases and percentages. Continuous variables as presented as mean and standard deviation. The antibiotic delay times were dichotomized depending on the value associated with the maximum sensitivity and specificity in the ROC curve. The CURB65 was also dichotomized between 0---1 and 2 or more points. Given that it is part of the CURB65 scale, patient age was not considered independently in the statistical analysis. Categorical variables were compared using the 2 test or Fisher’s exact test, and the continuous variables were compared using the nonparametric Mann---Whitney U test. The living patient group was compared to the dead patient group at hospital discharge or on day 28 from the admission to the emergency department or the ICU, if the patients were admitted directly from the community. We decided a priori to (a) not consider admission to the ICU to be an outcome or episode for analysis, given that the admission criteria to the ICU in Uruguay are heterogeneous depending on the care center and, (b) given that the influence of bacteremia on the prognosis of CAP is unknown18 and that two different strategies were used in this study for acquiring patients, we considered bacteremia in the entire population for solely descriptive and not prognostic ends. In addition, we decided to perform a specific analysis of the variables associated with mortality in the subgroup of bacteremic patients. For each comparison, we performed a univariate analysis that included the first available clinical and laboratory variables; those variables with a p ≤ 0.1 were included in an estimated logistics regression model. We considered the threshold for the two-tailed p value to be less than 0.05. The association between variables and the study episode was estimated using the odds ratio (OR) and 95% confidence interval (CI).

Results We analyzed 192 patients with CAP due to S. pneumoniae, and no patients were excluded. The CASMU-IAMPP was the medical center that provided the study with the most patients (98, 51%), followed by the Military Hospital (35, 18%), the Clinical Hospital (31, 16%), the Spanish Hospital (21, 11%) and the Police Hospital (7, 4%). The mean age of the entire population was 54.6 ± 19.2 years. One hundred and six (55%) were males. The comorbidities and severity at admission assessed according to the CURB65 scale are shown in Tables 1 and 2, respectively. In the first 72 h after hospital admission, 52 (13%) patients presented septic shock and 80 (42%) required invasive mechanical respiratory assistance.

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P. Cardinal-Fernández et al.

Table 1 Pathological history of the general population and univariate analysis according to outcome at discharge or at day 28 from hospital admission. General population (n = 192)

Alcoholism, n (%) Chronic liver disease n (%) Immunosuppression, n (%) Cancer, n (%) Ischemic heart disease, n (%) Chronic renal failure, n (%) COPD, n (%) Diabetes mellitus, n (%)

At hospital discharge or day 28

35 (18.2) 3 (1.6) 25 (13.0) 8 (4.2) 5 (4.2) 3 (1.6) 42 (21.9) 16 (8.3)

Died (n = 37)

Survived (n = 155)

7 (18.9) 0 (0.0) 4 (10.8) 2 (5.4) 3 (8.1) 3 (8.1) 12 (32.4) 4 (10.8)

28 (18.1) 3 (1.9) 21 (13.5) 6 (3.9) 5 (3.2) 0 (0.0) 30 (19.4) 12 (7.7)

p value

0.90 0.39 0.66 0.68 0.18 <0.01 0.08 0.54

COPD, chronic obstructive pulmonary disease.

Microbiology and treatment At least one blood culture was performed, allowing for the isolation of 147 (76.6%) strains of S. pneumoniae. Blood cultures were taken for 141 patients, along with capsular antigen detection in urine. Of these patients, 45 presented negative blood culture but positive antigen, 75 presented positive blood culture and positive antigen and 21 presented positive blood culture and negative antigen. Eighteen strains could not be sent for serotyping and another was defined as belonging to pool i. The most common serotypes among the remaining 128 were 7F, 1 and 3

Table 2

(Table 3). All strains presented a MIC for penicillin ≤2 ␮g/ml (sensitive); however, 8 (5%) cases presented a MIC for erythromycin >0.25 ␮g/ml (resistant). The percentage of strains that corresponded to the serotypes included in the 23-valent pneumococcal vaccine was 93% (119/128). The serotypes not included in the vaccine were 6A, 13, 16F, 18F, 22, 23B, 24F and 34. The number of patients who received the influenza vaccine in the year they presented CAP (which led to their inclusion in this study) or who received the pneumococcal vaccine in the 5-year period prior to the acquisition of the infection was 19 (10%) and 7 (4%), respectively. In

Baseline characteristics and univariate analysis for deaths at hospital discharge or at day 28 from hospital admission. General population (n = 192)

At hospital discharge or day 28 Died (n = 37)

Male gender, n (%) Length of stay in days Admission to the intensive care unit, n (%) At hospital admission Bacteremia, n (%) Bilateral radiological involvement, n (%) Pleural effusion, n (%) Hemoglobin (g/dl) Leukocytosis (mm3 ) Platelets (×103 /mm) Excess base Combined antibiotic therapy, n (%) Delay ≥6 h in the start of antibiotic therapy, n (%)a CURB65 −0, n (%) CURB65 −1, n (%) CURB65 −2, n (%) CURB65 −3, n (%) CURB65 −4, n (%) CURB65 ≥2, n (%) During the first 72 h of hospitalization Mechanical ventilation Septic shock a

106 (55.2) 13.5 ± 10.6 124 (64.6) 145 (75.5) 59 (30.7) 31 (16.1) 12.7 ± 2.0 17,712 ± 19,486 220 ± 101 −3.6 ± 5.6 123 (64.1) 96 (51.6) 34 (17.7) 66 (34.4) 51(26.6) 27 (14.1) 14 (7.3) 92 (47.9) 88 (45.8) 52 (27.1)

21 (56.8) 7.0 ± 7.8 34 (91.1) 29 (76.1) 17 (45.9) 6 (16.2) 12.2 ± 2.7 15,109 ± 12,419 220 ± 121 −6.6 ± 8.9 20 (54.1) 22 (64.7) 3 (8.1) 8 (21.6) 10 (27.0) 8 (21.6) 8 (21.6) 26 (70.3) 30 (81.1) 24 (64.9)

The number of patients for whom this data was provided was 186, 34 of whom died.

p value

Survived (n = 155) 85 (54.8) 16.9 ± 12.0 90 (58.1)

0.83 <0.01 <0.01

118 (78.4) 42 (27.1) 25 (16.1) 12.8 ± 1.8 14,726 ± 8133 214 ± 91 −3.1 ± 4.4 103 (66.5) 74 (48.7) 31 (20.0) 58 (37.4) 41 (26.5) 19 (12.3) 6 (3.9) 66 (43.6)

0.77 0.03 0.99 0.19 0.60 0.91 0.11 0.16 0.09 <0.01

58 (37.4) 28 (18.1)

<0.01 <0.01

<0.01

Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae Table 3

93

Absolute and percentage frequency of each identified serotype.

Serotype

Absolute frequency

Percentage of the total

Serotype

Absolute frequency

Percentage of the total

7F 1 3 14 8 12F 23F 4 9V 19A 5 6A 13 19F

23 20 13 11 10 9 6 4 4 4 3 2 2 2

18 16 10 9 8 7 5 3 3 3 2 2 2 2

23B 17F 9N 11A 16F 18 6B 22 22F 24F 34 18C 15B Pool i

2 2 1 1 1 1 1 1 1 1 1 1 1 1

2 2 1 1 1 1 1 1 1 1 1 1 1 1

During the follow-up period, 37 patients died (19%). The age range for presenting pneumonia was very wide; however, death associated with pneumonia was exceptional before the age of 40 (Fig. 1). Death occurred in the first 72 h in 17 patients due to MODS in 12, refractory hypoxemia in 1, arrhythmia in 1, limitation of the therapeutic effort in 1 and was undetermined in 2. The remaining deaths occurred after the previously mentioned period and were due to MODS in 9 cases, refractory hypoxemia in 2, undetermined causes in 7 and limitation of the therapeutic effort in 2 patients.

Survived

Died

100

100

80

80

60

60

40

40

20

20

0

0

Age

Mortality

The univariate analysis for death is presented in Tables 1 and 2. Septic shock that occurred in the first 72 h was more common in patients who died than in those who did not (24/37 compared with 28/155 patients, p ≤ 0.01). Similarly, the number of patients who required invasive mechanical ventilation in the above-mentioned time period was greater in the group that died when compared with the group that survived (27/37 compared with 53/155, p ≤ 0.01). The maximum likelihood multivariate logistical model included the following variables: bilateral radiological involvement, delay in the administration of the first antibiotic dose ≥6 h, CURB65 score ≥2, shock in the first 72 h after hospital admission, chronic renal failure and COPD. The variables independently associated with mortality were the presence of shock in the first 72 h after hospital admission (OR: 7.51; 95% CI: 2.94---19.17; p ≤ 0.01) and a delay in the start of antibiotics equal to or greater than 6 h (OR: 2.47; 95% CI: 1.00---6.17; p = 0.05).

Age

4 patients who were vaccinated with the pneumococcal vaccine, the following serotypes were identified: 7F (62year-old male and 55-year-old female; both survived), 8 (73-year-old female, survived) and 23F (82-year-old female, died). All were sensitive to macrolides. The mean time between hospital admission and the administration of the first dose of antibiotics was recorded for 186 patients and was 7.1 ± 7.0 h. Using the ROC curve, we identified a value of 6 h in the delay to the start of antibiotic therapy as that with the greatest sensitivity and specificity for discriminating the outcome of death at hospital discharge or day 28 of hospitalization. In approximately 6 of every 10 patients who died, antibiotic therapy was initiated after the above-mentioned period (Table 2). Antibiotic treatment included a single antibiotic in 69 (36%) patients and 2 or more antibiotics in 123 (64%) participants. The single antibiotic therapy group was administered ampicillin/sulbactam in 41 (59%) patients, ceftriaxone in 26 (38%) patients, ampicillin in 1 (1%) patient and ciprofloxacin in 1 (1%) patient. In the combined antibiotic therapy group, all patients received at least a beta-lactam antibiotic, which was combined with a macrolide in 115 patients (clarithromycin in 112), with an aminoglycoside (amikacin) in 2, with a quinolone (ciprofloxacin) in 2, with a lincosamide (clindamycin) in 3 and with a second beta-lactam antibiotic (ceftriaxone) in 1 patient.

20

15

10

5

0

5

10

15

20

Number of cases distributed by age and final outcome

Figure 1 Number of patient cases distributed by age and outcome at day 28 or at hospital discharge.

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Mortality in the bacteremic patient subgroup We recorded 29 (20%) deaths during the follow-up period in the subgroup of patients with bacteremia. The time between hospital admission and the administration of the first dose of antibiotics was recorded for 143 patients. The presence of bilateral radiological involvement, combined antibiotic therapy, CURB65 score ≥2, shock in the first 72 h after hospital admission and chronic renal failure had a p < 0.1 in the univariate analysis (data not shown), and were therefore incorporated into the maximum likelihood multivariate logistical model. The variables independently associated with mortality in this subgroup of patients with bacteremia were the presence of shock in the first 72 h after hospital admission (OR: 16.72; 95% CI: 4.33---64.60; p ≤ 0.01) and combined antibiotic therapy (OR: 0.15; 95% CI: 0.04---0.58; p ≤ 0.15).

Discussion The main findings of the present study are (a) the mortality of pneumococcal CAP in Montevideo-Uruguay is close to 20%, and the 2 variables associated with the disease are the presence of shock during the first 72 h after hospital admission and a delay greater than or equal to 6 h before starting antibiotic therapy; (b) the main issues in optimizing treatment consist of reducing the time elapsed between hospital admission and the first antibiotic dose and the promotion of the combined use of antimicrobial drugs; (c) the main serotypes of S. pneumoniae were 7F, 1 and 3; and (d) the potential coverage of the 23-valent pneumococcal vaccine is 93%. Mortality in the present series was high and exceeded the figures published by other groups,7,19,20 which may be explained at least partially by the greater severity in our population (the presence of septic shock in 13%, a need for mechanical ventilation in 41.7% and CURB65 score ≥2 in 47.9%). Regardless, the most important correctable factor that was identified in the present study, which could also at least partially explain the increased mortality, is the delay in the start of antibiotic therapy. Promptness with antimicrobial therapy and compliance with guidelines are 2 easily implementable, low-cost actions that have shown to be capable of improving the prognosis of CAP.21,22 The fact that more than 50% of patients receive the first dose of antibiotic after more than 6 h is essentially unacceptable and undoubtedly constitutes one of the most important aspects to improve. A second issue to consider is the benefit of administering combined antibiotic therapy, especially in the subgroup of patients with bacteremia, for whom combined therapy represents an independent protective factor for mortality. The benefits of combined antimicrobial therapy (beta-lactam antibiotics and macrolides or fluoroquinolones) was initially proposed due to the results of a number of retrospective studies.23,24 Recently, two observational studies found that the combination of macrolides with beta-lactam antibiotics reduced mortality when compared with the isolated administration of beta-lactam antibiotics in CAP that required hospitalization25 or with the combination of beta-lactam antibiotics and quinolones in severe CAP, which requires endotracheal intubation.26 The exact

P. Cardinal-Fernández et al. reason macrolides might improve the prognosis is unknown; however, it is speculated that the improvement may be linked to the high concentration of macrolides in phagocytes and/or to the macrolides’ immunomodulatory effects.27---32 In this study, we found that virtually all patients received a beta-lactam antibiotic; however, less than 60% received macrolides, which may constitute another factor to be corrected. In reference to the causes of death in CAP, García-Vidal et al.33 analyzed the deaths of 181 patients with pneumonia and found that 70% of those who died in the first 48 h were older than the others and had a more severe initial clinical presentation. The deceased had a greater number of late comorbidities, especially heart failure and chronic renal failure. The main causes of death, as with our series, were MODS and respiratory dysfunction; however, the relative percentages of each etiology were different, which may be explained by the different definitions used in each study. S. pneumoniae is a Gram-positive, facultative, anaerobic microorganism with a polysaccharide capsule whose antigens allow us to subclassify it into 46 serogroups and into more than 90 distinct serotypes.34 An international group studying S. pneumoniae analyzed 796 strains in adults from 10 different countries (South Africa, US, Sweden, Spain, New Zealand, Taiwan, Argentina, Brazil, Hong Kong and France).18 They reported that the main serotypes were 1, 14, 4 and 3; the overall mortality in the study was 17%, which was not associated with any particular serotype. In Spain, Viciana et al.19 reported 31 different strains in cultures from a heterogeneous group of pneumococcal diseases (93 pneumonias, 60 uncompensated respiratory infections, 6 meningitis, 5 bacteremia without apparent focus and 6 to other less common causes). The most common serotypes were 19, 3 and 6B. In Uruguay, Hortal et al.35 found that the main circulating serotypes in children over 5 years of age and in adults were 5, 1, 7/7F and 14. The above study by Viciana et al.19 found that 43.4% of the S. pneumoniae strains were resistant to penicillin. In Spain, the first strain of penicillin-resistant pneumococcus was isolated from an adult patient from a hospital in Barcelona in 1979. Subsequently, Spain experienced a marked increase, reaching approximately 40% during the 1990s. Currently, this proportion has decreased to 22.3%.36 The absence of identification of penicillin-resistant strains in our community is a relevant issue that provides a considerable advantage given that it reduces the risk of inadequate antibiotic therapy, restricts the required antibiotic arsenal, decreases costs and facilitates the national implementation of protocols. The resistance to macrolides in our study approached 5%. Its influence on the prognosis of pneumonia is also controversial; however, the search for resistance may be important in individuals who are sick enough to require hospitalization. Currently, the only method proven to be capable of reducing the risk of pneumococcal infection is vaccination. The results of the implementation of a universal campaign of pneumococcal immunoprophylaxis in children from Uruguay have been recently submitted by Dr. Hortal’s group.37 The administration of PCV7 and subsequently PCV13 determined a reduction of close to 50% in the number of hospitalizations for pneumonia in those under 2 years of age, while simultaneously affecting the circulating serotypes, mainly with an

Clinical and microbiological aspects of acute community-acquired pneumonia due to Streptococcus pneumoniae extreme reduction in serotype 14 and disruption of serotype 1 as the most common. In adults, the 23-valent pneumococcal vaccine is recommended, which is composed of 25 g of capsular polysaccharide antigens from 23 distinct serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F; the cross-protective reactions against strains not included in the vaccine [such as 6B, 6A, 15B and 15A] have also been demonstrated). Given that it contains no proteins, the vaccine is capable of inducing the response of B lymphocytes independently of the T lymphocytes.38 It is estimated that 75---85% of individuals will present a humoral response to the vaccination. In this study, we found that approximately 90% of the patients presented serotypes included in the 23-valent vaccine, which suggests that a considerable proportion of the analyzed cases could have been avoided if they had been vaccinated, especially since the majority of the analyzed population suffered an invasive disease for which the benefits are greatest.39 All serotypes identified in patients who had received the 23valent vaccine in the previous 5 years are included in the vaccine’s potential coverage and could reflect the known loss of efficacy in the elderly population, the presence of some undiagnosed immunocompromised state or the lack of response to a number of specific antigens. The present study has a number of strengths, including the following: (a) it was conducted prospectively and multicentrically with the participation of the main healthcare centers of Uruguay; (b) the diagnosis of CAP was performed by specialist physicians and supported by microbiological findings; and (c) we comprehensively considered clinical and microbiological factors using variables typically available in clinical practice. The primary weakness of the present study consists of the use of two different strategies for identifying patients, which resulted in not including patients who were admitted to the ward with an etiological diagnosis of pneumococcal pneumonia by urinary antigen. In summary, the present study found that CAP is a severe disease with a high mortality, despite not having identified beta-lactam-resistant S. pneumoniae strains. Two therapeutic factors were identified (reduction in the time to administration of the first antibiotics and the combined use of antibiotics), which are relatively easy to correct and whose impact in the prognosis of the disease may be significant.

Funding The clinical and genetic research project on CAP was partially funded by a donation from the ROEMMERS-Uruguay laboratory exclusively directed toward the purchase of laboratory consumables. The money was managed through the Manuel Pérez Foundation of the School of Medicine, University of the Republic, Uruguay. None of the authors received compensation or any other type of benefit for participating in this study.

Conflicts of interest The authors have no conflicts of interest to declare.

95

Acknowledgements First, we would like to express our appreciation to the patients and family members who, under difficult conditions, agreed to participate in this research study. Additionally, we would like to thank the nursing graduates and assistants, the clinical and microbiology laboratory technicians, the physicians, chemists and biologists who participated in the study. Given that the standards of publication of the Revista Clínica Espa˜ nola limit the number of authors to a maximum of 6, we would like to recognize the following colleagues for their enthusiasm and outstanding participation in this research study: Dr. Gabriela Bello, Police hospital ‘‘Inspector General Uruguay-Genta’’; Dr. Claudia Bentancourd, Chair of Pulmonology, School of Medicine, University of the Republic; Dr. Teresa Camou, Department of Laboratories of the MSP; Ex Prof. Dr. Cristina Bazet, Chair of Microbiology, School of Medicine, University of the Republic; Dr. Walter Pedreira, Head of microbiology, Hospital Maciel; Dr. N. Zefferino, Ex Head of the Intensive Care Unit, Armed Forces Central Hospital; Dr. Jorge Gerez, Head of the Intensive Care Unit, Police Hospital ‘‘Inspector General Uruguay Genta’’, and Dr. Alberto Deicas, Head of the Intensive Care Unit, CASMU-IAMPP.

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