Pediatric Pulmonology 48:5258 (2013)

Antibiotic Treatment of Children With Community-Acquired Pneumonia: Comparison of Penicillin or Ampicillin Versus Cefuroxime
Yael Dinur-Schejter, MD, Malena Cohen-Cymberknoh, MD, Ariel Tenenbaum, MD, Rebecca Brooks, MD, Diana Averbuch, MD, Sigmund Kharasch, MD, and Eitan Kerem, MD*
Summary. Objective: Adherence to current guidelines for treatment of non-complicated community-acquired pneumonia (CAP) in children, recommending penicillin or ampicillin as rstline treatment, has been poor. Our objective was to examine whether cefuroxime confers an advantage over penicillin or ampicillin for the treatment of children hospitalized with noncomplicated CAP . Patients and Methods: All children aged 3 months to 2 years with non-complicated CAP treated with penicillin or ampicillin or cefuroxime, admitted during 20032008, in the Departments of Pediatrics, Hadassah University Medical Center were included. Presenting signs, symptoms, laboratory ndings at presentation, clinical parameters including number of days with IV antibiotics, oxygen treatment, length of hospital stay, change of antibiotics, and clinical course 72 hr and 1 week after admission, were compared. Results: Of the 319 children admitted for non-complicated CAP , 66 were treated with IV penicillin or ampicillin, 253 with IV cefuroxime. Number of days of IV treatment, days of oxygen requirement, and days of hospitalization were similar (2.36 1.6 days vs. 2.59 1.6 days, 0.31 1.2 days vs. 0.64 1.3 days, and 2.67 1.4 days vs. 2.96 1.7 days, respectively). Treatment failure was not signicantly different (7.6% vs. 4.7%). The number of patients who were febrile or required oxygen 72 hr after admission was similar (13.0% vs. 16.5% and 8.7% vs. 20.9%, respectively). One week after admission no difference between the two groups was seen. Conclusions: In previously healthy children, parenteral penicillin or ampicillin for treatment of non-complicated CAP in-hospital is as effective as cefuroxime, and should remain the recommended rst-line therapy. Pediatr Pulmonol. 2013; 48:5258. 2012 Wiley Periodicals, Inc. Key words: community-acquired pneumonia; resistance; penicillin; ampicillin; children; pediatrics. treatment; cefuroxime;

Funding source: none reported.

INTRODUCTION

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality, especially in children <5 years of age.111 The annual incidence of pneumonia among North American and European children <5 years of age is approximately 36 per 1,000.1,6 National guidelines for the assessment of severity of CAP and its management were adopted in many countries. Streptococcus pneumoniae is the leading bacterial cause of CAP in all age groups after the introduction of the HIB vaccine.3,5,8,1017 It was found to be the causative agent in approximately 3973% of patients with CAP for which the pathogen could be identied.5,8,15 All the guidelines recommend penicillin or ampicillin as the rst-line treatment for non-complicated CAP in children. However, studies have shown that adherence to guidelines has been poor, resulting in inappropriate management which may affect both morbidity and mortality.18,19 Misuse or over-use of antibiotics can result
2012 Wiley Periodicals, Inc.

in antibiotic-associated diarrhea or colonization with antibiotic-resistant organisms, increased hospital stay, and increased costs.2022 In the past three decades, S. pneumoniae has developed in vitro resistance to b-lactams, with unclear clini-

Departments of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Conict of interest: None. *Correspondence to: Eitan Kerem, MD, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel. E-mail: kerem@hadassah.org.il Received 17 July 2011; Accepted 24 January 2012. DOI 10.1002/ppul.22534 Published online 19 March 2012 in Wiley Online Library (wileyonlinelibrary.com).

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cal signicance. A number of studies demonstrated good clinical response to therapy despite in vitro resistance, and showed no adverse outcomes in patients infected with non-susceptible isolates.1,2,4,5,7 9,12,1417,24,25,27,28 Despite these reports many physicians continue to treat children with CAP with second and third generation cephalosporins. A study of adults in the UK showed that over half of patients with CAP received third generation cephalosporins, which are only recommended by the British Thoracic Society guidelines for use in severe cases.29 Furthermore, while implementing the guidelines, a continued preference for broad-spectrum antibiotic use for less severe patients was noted, attributed to a just in case approach to antibiotic choice.30,31 Studies from Israel have documented a high pneumococcal resistance ratio.10,17 From 1986 to 1997, in 111 children with culture-conrmed CAP in Jerusalem, 16% S. pneumoniae isolates were found to be resistant to penicillin, half of which were fully resistant and half of intermediate resistance.17 In another study, performed in Jerusalem during the years 19871992, a 23% resistance rate was observed in 366 children and adults with proven S. pneumoniae infections, 19.5% of which were of intermediate resistance and 3.4% were fully resistant.10 In the same study, 4.2% of the isolates had intermediate resistance to cefuroxime and cefotaxime, but no high level resistance was recorded. The two hospitals of the Hadassah Medical Center have used different approaches to the treatment of CAP: at the Ein Kerem hospital the protocol is to treat hospitalized children between 3 months and 2 years of age with IV cefuroxime (100 mg/kg/24 hr tid), and children older than 2 years with IV penicillin (400,000 IU/kg/24 hr qid). At the Mount Scopus hospital, the policy is to treat all children above 3 months of age with IV penicillin (400,000 IU/kg/24 hr qid) or ampicillin (100200 mg/kg/24 hr tid-qid). To the best of our knowledge, there are no other differences in treatment between the two departments. Using different protocols in the same Medical Center provided the unique opportunity to compare the outcome of the two treatments.

5,7,1013,15,16,2326

We retrospectively reviewed the clinical course and outcome of children hospitalized with CAP between the years 2003 and 2008 in the pediatric departments of both hospitals, and compared the efcacy of intravenous penicillin or ampicillin with cefuroxime.
MATERIALS AND METHODS

The medical records of all children between the ages of 3 months and 2 years who were admitted with the rst episode of CAP to the pediatric departments of the Hadassah Medical Center (Ein Kerem and Mount Scopus) in Jerusalem, between the years 2003 and 2008 were retrospectively reviewed by one researcher. For the purpose of this study, the denition of pneumonia was based on the diagnosis of the physicians in the Emergency Department and the Pediatric Ward as specied in the discharge letter. Exclusion criteria were chronic disease such as recurrent infections, immunodeciency, lung or heart diseases, cancer, or post cancer chemotherapy, patients receiving chronic medication treatment, patients with chronic pulmonary conditions including asthma and patients with a previous diagnosis of pneumonia. Other exclusion criteria included children receiving antibiotic treatment immediately prior to admission, and children with complicated pneumonia at any point during their hospital stay (dened as the presence of pleural effusion, and/or necrotizing pneumonia with pneumatocele on chest X-ray, and those who needed intubation). Data from in-patient hospitalization, symptoms on presentation, physical examination at presentation, laboratory and microbiologic indices, and treatment were reviewed. Outcome variables included duration of fever, number of days of oxygen treatment (given by protocol when oxygen saturation fell below 91% in room air), duration of total IV antibiotic therapy, treatment failure (dened as change of antibiotic therapy), and duration of hospital stay. Data were collected on all patients in the study group, including those who failed treatment. A febrile day was dened as a 24-hr period during which a temperature of 38.08C and above was measured at least once. In cases of antibiotic changes in the rst 12 hr of treatment, patients were considered according to the second antibiotic they received. The study was approved by the Hadassah Medical Center Institutional Review Board.
Statistical Analysis

ABBREVIATIONS: CAP IV HIB CXR CRP MIC ARI WHO PCR community-acquired pneumonia intravenous hemophilus inuenza B chest X ray C reactive protein minimal inhibitory concentration Acute respiratory infections World Health Organization polymerase chain reaction

Results are presented as mean and standard deviation for continuous variables, and percentage for nominal variables. Differences between the penicillin or ampicillin and cefuroxime treatment groups were calculated using a two-tailed t-test or chi-square test for interval/ ratio or non-parametric variables, as appropriate. The statistical analysis was performed using Open Source
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Epidemiologic Statistics for Public Health software, version 2.3. We also used an analysis of covariance to assess the inuence of confounders (age, weight percentile, duration of fever and cough before admission, respiratory rate, saturation in room air, and percentage of patients who had fever on admission) upon the main outcomes: duration of intravenous treatment and hospital stay.
RESULTS Clinical Characteristics of the Patients

A total of 319 children aged 3 months to 2 years, admitted for non-complicated CAP and meeting the inclusion criteria, were analyzed for the study: 66 were treated with penicillin (n 50) or ampicillin (n 16) and 253 were treated with cefuroxime (Table 1). The mean age of all patients was 12.2 months (range 3 23 months; median, 12 months). Clinical characteristics and presenting signs and symptoms, as well as initial blood tests are listed in Table 1. Treatment outcome were similar between the penicillin or ampicillin group and the cefuroxime group

(Table 2) including the number of days requiring IV treatment (2.36 1.6 days vs. 2.59 1.6 days, respectively), days of oxygen requirement (0.31 1.2 days vs. 0.64 1.3 days, respectively) and the number of hospitalization days (2.67 1.4 days vs. 2.96 1.7 days, respectively). The number of patients with treatment failure (dened as requiring a change of rst-line treatment) was also similar between the two groups (7.6% vs. 4.7%, Table 2). There was no signicant difference in the number of patients hospitalized for more than 72 hr; 23 patients in the penicillin or ampicillin group (34.8%) and 91 patients in the cefuroxime group (36.0%). The numbers of patients still febrile and requiring oxygen 72 hr after admission was also similar between both groups (13.0% vs. 16.5% and 8.7% vs. 20.9%, respectively, P > 0.05, Table 2). Two patients in the penicillin or ampicillin group and seven patients in the cefuroxime group were still hospitalized 1 week after admission, none required oxygen and only one patient of the cefuroxime group was still febrile at that time (Table 2). In analysis of covariance, the length of hospital stay had a signicant but low-level correlation with

TABLE 1 Clinical Characteristics of Patients Aged 3 Months to 2 Years Penicillin (n 50) or ampicillin (n 16) Means age, months Mean weight percentile for age Mean duration of cough before admission, days Mean duration of fever before admission, days Mean respiratory rate Mean SaO2 on room air (%) % of patients with fever above 388C Mean WBC, 109/L % of PMN Mean CRP, mg/dl Standard deviation. Number of patients tested. P < 0.01 for comparison between penicillin\ampicillin to cefuroxime.
b a

Cefuroxime (n 253)
11.7 (5.5)a 27.7 (26.6)a 4.1 (4.7)a 2.9 (2.6)a 46.6 (13.6)a [242]b 94.1 (5.3)a [253]b 39.0 [251]b 20.9 (9.7)a [250]b 59.0 (17.3)a [240]b 14.0 (12.6)a [131]b

14.2 (4.4)a 23.5 (24.8)a 3.7 (4.9)a 3.5 (2.9)a 48.7 (12.9)a [58]b 95.1 (3.3)a [58]b 36.0 [65]b 25.0 (10.2)a [63]b 63.4 (15.7)a [62]b 16.3 (14.0)a [35]b

TABLE 2 Treatment Outcomes of Patients Aged 3 Months to 2 Years Penicillin (n 50) or ampicillin (n 16) Mean duration of IV treatment, days Mean duration of hospitalization, days Mean duration of oxygen requirement, days Decision to change antibiotic treatment, n Patients hospitalized over 72 hr, n Patients with fever above 388C at 72 hr, n Patients with oxygen requirement at 72 hr, n Patients hospitalized over 1 week, n Patients with fever above 388C after 1 week, n Patients with oxygen requirement after 1 week, n
a

Cefuroxime (n 253) 2.59 (1.6)a 2.96 (1.7)a 0.64 (1.3)a 12 (4.7%) 91 (36.0%) 15 (16.5%) 19 (20.9%) 7 (2.8%) 1 (14.3%) 0 (0%)

2.36 (1.2) 2.67 (1.4)a 0.31 (1.2)a 5 (7.6%) 23 (34.8%) 3 (13.0%) 2 (8.7%) 2 (3.0%) 0 (0%) 0 (0%)

Standard deviation.

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saturation in room air and white blood count on admission (Pearson correlation 0.246 and 0.195, respectively). Saturation in room air also had a low-level correlation with length of IV treatment (Pearson correlation score 0.182). Since some of the treatment guidelines relate to children under 6 years of age we further analyzed the data to include all the patients aged 3 months to 6 years of age. There were a total of 530 patients meeting the inclusion criteria: 204 patients were treated with either intravenous penicillin (n 178) or ampicillin (n 26), and 326 patients were treated with intravenous cefuroxime. Clinical characteristics and presenting signs and symptoms for these patients, as well as initial blood tests are listed in Table 3. There was no change in the patients outcomes between both treatment groups (Table 4). In analysis of covariance in this group, length of hospital stay again had low-level correlation with saturation in room air and white blood count on admission (Pearsons correlation 0.209 and 0.226, respec-

tively). Total days of IV treatment had low-level correlation with age (Pearsons correlation 0.09), saturation in room air (Pearsons correlation 0.152), and WBC (Pearsons correlation 0.17) on admission. For patients between 3 months to 6 years, blood cultures were positive in 24/502 patients (4.7%): 20 cultures (83.3%) were positive for S. pneumoniae, and another four cultures were positive for Streptococci other than S. pneumoniae (in two patients), Morraxela catarrhalis, and Haemophilus parainuenzae (one patient each). No signicant difference was seen in the rate of positive cultures for S. pneumoniae between the two groups, namely 11 (5.4%) cultures in the penicillin or ampicillin treatment group and 9 (2.8%) cultures in the cefuroxime-treatment group (P > 0.05). All 11 S. pneumoniae isolates in the penicillin or ampicillin-treatment group were susceptible to penicillin (MIC < 0.1 mg/L). Of the nine S. pneumoniae isolates in the cefuroxime-treatment group, four isolates were susceptible to penicillin and ve isolates showed

TABLE 3 Clinical Characteristics of Patients Aged 3 Months to 6 Years at Presentation Penicillin (n 178) or Ampicillin (n 26) Mean age, months Mean weight percentile for age Mean duration of cough before admission, days Mean duration of fever before admission, days Mean SaO2 on room air Patients with fever >388C Mean WBC, 109/L Mean % of PMN CRP, mg/dl Standard deviation. Number of patients tested. P < 0.01 for comparison between penicillin\ampicillin to cefuroxime.
b a

Cefuroxime (n 326) 29.4 (27.1) 4.2 (4.5)a 3.0 (2.9)a 94.3% (5.1)a [326]b 54.9% [324]b 20.6 (9.7)a [320]b 61.4 (17.6)a [308]b 14.7 (13.0)a [173]b
17.6 (13.7)a a

39.4 (31.0) 3.8 (5.4)a 2.8 (3.1)a 95.7% (2.6)a [203]b 61.3% [199]b 24.1 (11.1)a [199]b 74.3 (15.9)a [193]b 18.2 (14.6)a [106]b

37.8 (20.1)a a

TABLE 4 Treatment Outcomes of Patients Aged 3 Months to 6 Years Penicillin (n 178) or Ampicillin (n 26) Total IV treatment, days Duration of hospitalization, days Duration of oxygen treatment, days Number of patients with changed antibiotic treatment Patients hospitalized over 72 hr, n Patients with fever above 388C at 72 hr, n Patients with oxygen requirement at 72 hr, n Patients hospitalized over 1 week, n Patients with fever above 388C after 1 week, n Patients with oxygen requirement after 1 week, n
a

Cefuroxime (n 326) 2.6 (1.5)a 2.9 (1.7)a 0.5 (1.2)a 19 (5.8%) 118 (36.2%) 16 (13.6%) 19 (16.1%) 9 (2.8%) 1 (11.1%) 0 (0%)

2.7 (1.8)a 2.9 (1.9)a 0.2 (0.9)a 14 (6.9%) 69 (33.8%) 8 (11.6%) 3 (4.3%) 8 (3.9%) 2 (0.25%) 0 (0%)

Standard deviation. P < 0.01 for comparison between penicillin\ampicillin to cefuroxim.

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intermediate resistance (MIC 0.121.0 mg/L). None of the isolates were fully resistant to penicillin (MIC > 2 mg/L).
DISCUSSION

Acute respiratory infections (ARI) are among the ve leading causes of death in children <5 years old in developing countries, causing more than 2 million deaths per year.32,33 S. pneumoniae is the bacterium that causes the most ARI (especially pneumonia) in this age group.34,35 The World Health Organization (WHO) has developed a strategy to reduce the burden of ARI among children, based on standard case management with appropriate empirical antibiotic treatment.36 This approach, when optimally used, effectively reduced childhood pneumonia-related mortality by 50% and overall child mortality by 25%.37 However, the emergence of penicillin-resistant pneumococcal strains rendered the choice of empirical antibiotic therapy more difcult. Penicillin resistance resulted in poor clinical outcomes for bacterial meningitis and changed the recommendation for the empirical treatment of this disease.38 However, the guidelines worldwide continue to recommend penicillin as the drug of choice for noncomplicated CAP. This policy is based on studies that demonstrate good clinical response to therapy despite in vitro resistance of S. pneumoniae, and show no adverse outcomes in patients infected with non-susceptible isolates.1,2,4,5,79,12,1417,24,25,27,28 Despite these guidelines many physicians changed their practice and treated children with CAP with second and third generation cephalosporins.29 Furthermore, while implementing the guidelines, a continued increasing preference for broad-spectrum antibiotic use for less severe patients was noted, that was attributed to a just in case approach to antibiotic choice.30,31 A recent study of pediatric antibiotic prescribing practices in the ambulatory setting highlighted the issue of broad-spectrum antibiotic use in the United States.39 Data analyzed from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 2006 and 2008 revealed that broad-spectrum antibiotics accounted for 50% of antibiotic prescriptions. Respiratory conditions accounted for most (72.3%) of the visits in this study. In this retrospective analysis of infants <2 years of age, treated with two different protocols for uncomplicated CAP, we showed that the clinical outcomes of treatment with penicillin or ampicillin were similar to treatment with cefuroxime. No differences were observed in length of hospitalization, duration of fever, duration of IV treatment, complications, and treatment failure. This is in spite of the results from previous studies at the Hadassah Medical Center which showed
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that 23% isolates of S. pneumoniae were resistant to penicillin.10 The current study also shows that regardless of departmental guidelines children were still treated with cefuroxime, most likely because the treating physician considered this therapy to be better than penicillin. Penicillin-resistance of S. pneumoniae is due to altered b-lactam target sites (penicillin-binding proteins) and hence cannot be overcome by addition of a blactamase inhibitor.9 However, the mechanism suggests that resistance can be overcome by achieving adequate local drug levels using higher doses.1,2,4,5,8,12,16,24 Therefore, the recommended therapy for pneumonia caused by penicillin-resistant S. pneumoniae is with high dose penicillin. All studies that evaluated the clinical outcome of this treatment showed recovery rates similar to that of all other antibiotics assessed, especially cephalosporins.7,8,11,17,21,25 In a prospective observational study of 844 hospitalized adult patients with positive blood cultures for S. pneumoniae a 24.6% of pneumococcal non-susceptibility to penicillin was described.23 In the rst 48 hr after blood for cultures was drawn, 6.9% of the patients were treated with an antibiotic for which S. pneumoniae isolated from blood showed in vitro resistance. Treating the patients with penicillin-resistant strains with penicillin was not associated with worse outcome including time to defervescence or rate of suppurative complications. Interestingly, discordant therapy with cefuroxime was related to increased mortality. In a prospective observational study of 240 children aged 359 months hospitalized for severe CAP8 in 12 hospitals in South America, all patients received penicillin or ampicillin after collection of blood for culture. Fifty-two percent of S. pneumoniae isolates were susceptible to penicillin, 26% showed intermediate resistance and 22% were fully resistant. Treatment failure, dened as a lack of clinical improvement or deterioration under antimicrobial treatment, was found in 21% of patients. No association between in vitro resistance of S. pneumoniae to penicillin and treatment failure was observed. Another randomized prospective study in children with presumed acute invasive bacterial infection including pneumonia, compared the clinical recovery among children treated with penicillin or cefuroxime and no differences were found.24 In the current study, the diagnosis of pneumonia was determined by clinical judgment, which in turn was based on the clinical symptoms (fever, cough) and signs (dyspnea, tachypnea) localizing signs (dullness on percussion, crackles, decreased air entry, bronchial breathing), and laboratory ndings (increased leukocyte counts with left shift and CRP levels or inltrate on chest X-ray). Only 4.5% of blood cultures grew bacteria, similar to data of other studies.1,3,8,9 Nevertheless,

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the high leukocyte count and CRP levels are suggestive of a bacterial infection in the majority of patients. While it is possible that some patients in our study had viral pneumonia, nasopharyngeal aspirate for RSV and other respiratory viruses are not routinely performed for patients with diagnosis of bacterial pneumonia at our institution. Previous work has documented that coinfection, most commonly with S. pneumonia in association with other respiratory viruses may occur in as many as 3040% of cases of childhood CAP 1,4,13 and therefore would not inuence therapeutic decision making. Furthermore, with current diagnostic methods, bacteriological conrmation of CAP is not possible in most cases. It is important to note that using various techniques such as cultures, serology, PCR tests, or immunouorescence, a microbiological diagnosis was possible in only 2744% children with CAP.1 It is important to notice that the pneumococcal conjugated vaccination has become a part of the vaccination routine in Israel since May 2009, it is implied that the majority of our patients were not immunized to S. pneumonia. Our results should be further validated in the settings of the current practice to vaccinate all children with a conjugated pneumococcal vaccination. Our treatment groups differed from each other in several baseline parameters, mainly age and WBC at admission. Although these differences were statistically signicant; their clinical signicance is in doubt. Only 66 patients under 2 years of age were treated with either penicillin or cefuroxime, presumably because of the treating physicians decision. This is in contrast to 253 patients treated with cefuroxime in this age group. The small number of patients weakens the strength of the conclusions somewhat, and requires further research. An analysis of covariance demonstrated a low level correlation between several characteristics, such as saturation in room air and WBC, and main treatment outcomes (total days of IV treatment and hospital stay). This correlation contributes little, if any, to the comparison between treatment groups and outcomes. In conclusion, the current study shows that high dose penicillin or ampicillin is as effective as cefuroxime in the treatment of previously healthy infants and young children with non-complicated CAP. This highlights the necessity to adhere to the current guidelines of treatment of CAP in children with high dose penicillin or ampicillin as the rst-line therapy.
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20.

29.

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