Pediatric Pulmonology 48:52–58 (2013)

Antibiotic Treatment of Children WithCommunity-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 com-

munity-acquired pneumonia (CAP) in children, recommending penicillin or ampicillin as first-

line 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 non-

complicated CAP. Patients and Methods: All children aged 3 months to 2 years with non-com-

plicated CAP treated with penicillin or ampicillin or cefuroxime, admitted during 2003–2008, in

the Departments of Pediatrics, Hadassah University Medical Center were included. Presenting

signs, symptoms, laboratory findings 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 hospital-

ization 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

significantly 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-complicat-

ed CAP in-hospital is as effective as cefuroxime, and should remain the recommended first-line

therapy. Pediatr Pulmonol. 2013; 48:52–58. � 2012 Wiley Periodicals, Inc.

Key words: community-acquired pneumonia; resistance; treatment; cefuroxime;

penicillin; ampicillin; children; pediatrics.

Funding source: none reported.

INTRODUCTION

Community-acquired pneumonia (CAP) is a leadingcause of morbidity and mortality, especially in children<5 years of age.1–11 The annual incidence of pneumo-nia among North American and European children <5years of age is approximately 36 per 1,000.1,6 Nationalguidelines for the assessment of severity of CAP and itsmanagement were adopted in many countries. Strepto-coccus pneumoniae is the leading bacterial cause ofCAP in all age groups after the introduction of the HIBvaccine.3,5,8,10–17 It was found to be the causative agentin approximately 39–73% of patients with CAP forwhich the pathogen could be identified.5,8,15 All theguidelines recommend penicillin or ampicillin as thefirst-line treatment for non-complicated CAP in chil-dren. However, studies have shown that adherence toguidelines has been poor, resulting in inappropriatemanagement which may affect both morbidity and mor-tality.18,19 Misuse or over-use of antibiotics can result

in antibiotic-associated diarrhea or colonization withantibiotic-resistant organisms, increased hospital stay,and increased costs.20–22

In the past three decades, S. pneumoniae has devel-oped in vitro resistance to b-lactams, with unclear clini-

Departments of Pediatrics, Hadassah Hebrew University Medical Center,

Jerusalem, Israel.

Conflict 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).

� 2012 Wiley Periodicals, Inc.

cal significance.5,7,10–13,15,16,23–26 A number of studiesdemonstrated good clinical response to therapy despitein vitro resistance, and showed no adverse outcomes inpatients infected with non-susceptible isolates.1,2,4,5,7–9,12,14–17,24,25,27,28 Despite these reports many physi-cians continue to treat children with CAP with secondand third generation cephalosporins. A study of adultsin the UK showed that over half of patients with CAPreceived third generation cephalosporins, which areonly recommended by the British Thoracic Societyguidelines for use in severe cases.29 Furthermore, whileimplementing the guidelines, a continued preference forbroad-spectrum antibiotic use for less severe patientswas noted, attributed to a ‘‘just in case’’ approach toantibiotic choice.30,31

Studies from Israel have documented a high pneumo-coccal resistance ratio.10,17 From 1986 to 1997, in 111children with culture-confirmed CAP in Jerusalem, 16%S. pneumoniae isolates were found to be resistant topenicillin, half of which were fully resistant and half ofintermediate resistance.17 In another study, performedin Jerusalem during the years 1987–1992, a 23% resis-tance rate was observed in 366 children and adults withproven S. pneumoniae infections, 19.5% of which wereof intermediate resistance and 3.4% were fully resis-tant.10 In the same study, 4.2% of the isolates had inter-mediate resistance to cefuroxime and cefotaxime, butno high level resistance was recorded.

The two hospitals of the Hadassah Medical Centerhave used different approaches to the treatment ofCAP: at the Ein Kerem hospital the protocol is to treathospitalized children between 3 months and 2 years ofage with IV cefuroxime (100 mg/kg/24 hr tid), andchildren older than 2 years with IV penicillin(400,000 IU/kg/24 hr qid). At the Mount Scopus hospi-tal, the policy is to treat all children above 3 months ofage with IV penicillin (400,000 IU/kg/24 hr qid) or am-picillin (100–200 mg/kg/24 hr tid-qid). To the best ofour knowledge, there are no other differences in treat-ment between the two departments. Using different pro-tocols in the same Medical Center provided the uniqueopportunity to compare the outcome of the twotreatments.

We retrospectively reviewed the clinical course andoutcome of children hospitalized with CAP between theyears 2003 and 2008 in the pediatric departments ofboth hospitals, and compared the efficacy of intravenouspenicillin or ampicillin with cefuroxime.

MATERIALS AND METHODS

The medical records of all children between the agesof 3 months and 2 years who were admitted with thefirst episode of CAP to the pediatric departments ofthe Hadassah Medical Center (Ein Kerem and MountScopus) in Jerusalem, between the years 2003 and 2008were retrospectively reviewed by one researcher. Forthe purpose of this study, the definition of pneumoniawas based on the diagnosis of the physicians in theEmergency Department and the Pediatric Ward as spec-ified in the discharge letter. Exclusion criteria werechronic disease such as recurrent infections, immunode-ficiency, lung or heart diseases, cancer, or post cancerchemotherapy, patients receiving chronic medicationtreatment, patients with chronic pulmonary conditionsincluding asthma and patients with a previous diagnosisof pneumonia. Other exclusion criteria included chil-dren receiving antibiotic treatment immediately prior toadmission, and children with complicated pneumonia atany point during their hospital stay (defined as the pres-ence of pleural effusion, and/or necrotizing pneumoniawith pneumatocele on chest X-ray, and those who need-ed intubation). Data from in-patient hospitalization,symptoms on presentation, physical examination at pre-sentation, laboratory and microbiologic indices, andtreatment were reviewed. Outcome variables includedduration of fever, number of days of oxygen treatment(given by protocol when oxygen saturation fell below91% in room air), duration of total IV antibiotic thera-py, treatment failure (defined as change of antibiotictherapy), and duration of hospital stay. Data were col-lected on all patients in the study group, including thosewho failed treatment. A febrile day was defined as a24-hr period during which a temperature of 38.08C andabove was measured at least once. In cases of antibioticchanges in the first 12 hr of treatment, patients wereconsidered according to the second antibiotic they re-ceived. The study was approved by the Hadassah Medi-cal Center Institutional Review Board.

Statistical Analysis

Results are presented as mean and standard deviationfor continuous variables, and percentage for nominalvariables. Differences between the penicillin or ampicil-lin and cefuroxime treatment groups were calculatedusing a two-tailed t-test or chi-square test for interval/ratio or non-parametric variables, as appropriate. Thestatistical analysis was performed using Open Source

ABBREVIATIONS:

CAP community-acquired pneumonia

IV intravenous

HIB hemophilus influenza B

CXR chest X ray

CRP C reactive protein

MIC minimal inhibitory concentration

ARI Acute respiratory infections

WHO World Health Organization

PCR polymerase chain reaction

Management of Childhood Community-Acquired Pneumonia 53

Pediatric Pulmonology

Epidemiologic Statistics for Public Health software,version 2.3.

We also used an analysis of covariance to assess theinfluence of confounders (age, weight percentile, dura-tion of fever and cough before admission, respiratoryrate, saturation in room air, and percentage of patientswho 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 in-clusion criteria, were analyzed for the study: 66 weretreated with penicillin (n ¼ 50) or ampicillin (n ¼ 16)and 253 were treated with cefuroxime (Table 1). Themean age of all patients was 12.2 months (range 3–23 months; median, 12 months). Clinical characteristicsand presenting signs and symptoms, as well as initialblood tests are listed in Table 1.

Treatment outcome were similar between the penicil-lin or ampicillin group and the cefuroxime group

(Table 2) including the number of days requiring IVtreatment (2.36 � 1.6 days vs. 2.59 � 1.6 days, respec-tively), days of oxygen requirement (0.31 � 1.2 daysvs. 0.64 � 1.3 days, respectively) and the number ofhospitalization days (2.67 � 1.4 days vs. 2.96 � 1.7days, respectively). The number of patients with treat-ment failure (defined as requiring a change of first-linetreatment) was also similar between the two groups(7.6% vs. 4.7%, Table 2).There was no significant difference in the number of

patients hospitalized for more than 72 hr; 23 patientsin the penicillin or ampicillin group (34.8%) and91 patients in the cefuroxime group (36.0%). The num-bers of patients still febrile and requiring oxygen 72 hrafter 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 orampicillin group and seven patients in the cefuroximegroup were still hospitalized 1 week after admission,none required oxygen and only one patient of the cefur-oxime group was still febrile at that time (Table 2).In analysis of covariance, the length of hospital

stay had a significant but low-level correlation with

TABLE 1—Clinical Characteristics of Patients Aged 3 Months to 2 Years

Penicillin (n ¼ 50) or ampicillin (n ¼ 16) Cefuroxime (n ¼ 253)

Means age, months �14.2 (4.4)a �11.7 (5.5)a

Mean weight percentile for age 23.5 (24.8)a 27.7 (26.6)a

Mean duration of cough before admission, days 3.7 (4.9)a 4.1 (4.7)a

Mean duration of fever before admission, days 3.5 (2.9)a 2.9 (2.6)a

Mean respiratory rate 48.7 (12.9)a [58]b 46.6 (13.6)a [242]b

Mean SaO2 on room air (%) 95.1 (3.3)a [58]b 94.1 (5.3)a [253]b

% of patients with fever above 388C 36.0 [65]b 39.0 [251]b

Mean WBC, 109/L �25.0 (10.2)a [63]b �20.9 (9.7)a [250]b

% of PMN 63.4 (15.7)a [62]b 59.0 (17.3)a [240]b

Mean CRP, mg/dl 16.3 (14.0)a [35]b 14.0 (12.6)a [131]b

aStandard deviation.bNumber of patients tested.�P < 0.01 for comparison between penicillin\ampicillin to cefuroxime.

TABLE 2—Treatment Outcomes of Patients Aged 3 Months to 2 Years

Penicillin (n ¼ 50) or ampicillin (n ¼ 16) Cefuroxime (n ¼ 253)

Mean duration of IV treatment, days 2.36 (1.2)a 2.59 (1.6)a

Mean duration of hospitalization, days 2.67 (1.4)a 2.96 (1.7)a

Mean duration of oxygen requirement, days 0.31 (1.2)a 0.64 (1.3)a

Decision to change antibiotic treatment, n 5 (7.6%) 12 (4.7%)

Patients hospitalized over 72 hr, n 23 (34.8%) 91 (36.0%)

Patients with fever above 388C at 72 hr, n 3 (13.0%) 15 (16.5%)

Patients with oxygen requirement at 72 hr, n 2 (8.7%) 19 (20.9%)

Patients hospitalized over 1 week, n 2 (3.0%) 7 (2.8%)

Patients with fever above 388C after 1 week, n 0 (0%) 1 (14.3%)

Patients with oxygen requirement after 1 week, n 0 (0%) 0 (0%)

aStandard deviation.

54 Dinur-Schejter et al.

Pediatric Pulmonology

saturation in room air and white blood count on admis-sion (Pearson correlation ¼ �0.246 and �0.195, re-spectively). Saturation in room air also had a low-levelcorrelation with length of IV treatment (Pearson corre-lation score ¼ �0.182).

Since some of the treatment guidelines relate to chil-dren under 6 years of age we further analyzed the datato include all the patients aged 3 months to 6 years ofage. There were a total of 530 patients meeting the in-clusion criteria: 204 patients were treated with eitherintravenous penicillin (n ¼ 178) or ampicillin (n ¼ 26),and 326 patients were treated with intravenous cefurox-ime. Clinical characteristics and presenting signs andsymptoms for these patients, as well as initial bloodtests are listed in Table 3. There was no change in thepatients’ outcomes between both treatment groups(Table 4).

In analysis of covariance in this group, length of hos-pital stay again had low-level correlation with satura-tion in room air and white blood count on admission(Pearson’s correlation ¼ �0.209 and �0.226, respec-

tively). Total days of IV treatment had low-levelcorrelation with age (Pearson’s correlation ¼ 0.09),saturation in room air (Pearson’s correlation ¼�0.152), and WBC (Pearson’s correlation ¼ �0.17) onadmission.For patients between 3 months to 6 years, blood cul-

tures were positive in 24/502 patients (4.7%): 20 cul-tures (83.3%) were positive for S. pneumoniae, andanother four cultures were positive for Streptococci oth-er than S. pneumoniae (in two patients), Morraxelacatarrhalis, and Haemophilus parainfluenzae (one pa-tient each). No significant difference was seen in therate of positive cultures for S. pneumoniae betweenthe two groups, namely 11 (5.4%) cultures in the peni-cillin or ampicillin treatment group and 9 (2.8%) cul-tures in the cefuroxime-treatment group (P > 0.05). All11 S. pneumoniae isolates in the penicillin or ampicil-lin-treatment group were susceptible to penicillin(MIC < 0.1 mg/L). Of the nine S. pneumoniae isolatesin the cefuroxime-treatment group, four isolates weresusceptible to penicillin and five isolates showed

TABLE 3—Clinical Characteristics of Patients Aged 3 Months to 6 Years at Presentation

Penicillin (n ¼ 178) or Ampicillin (n ¼ 26) Cefuroxime (n ¼ 326)

Mean age, months �37.8 (20.1)a �17.6 (13.7)a

Mean weight percentile for age �39.4 (31.0)a �29.4 (27.1)a

Mean duration of cough before admission, days 3.8 (5.4)a 4.2 (4.5)a

Mean duration of fever before admission, days 2.8 (3.1)a 3.0 (2.9)a

Mean SaO2 on room air �95.7% (2.6)a [203]b �94.3% (5.1)a [326]b

Patients with fever >388C 61.3% [199]b 54.9% [324]b

Mean WBC, 109/L �24.1 (11.1)a [199]b �20.6 (9.7)a [320]b

Mean % of PMN �74.3 (15.9)a [193]b �61.4 (17.6)a [308]b

CRP, mg/dl �18.2 (14.6)a [106]b �14.7 (13.0)a [173]b

aStandard deviation.bNumber of patients tested.�P < 0.01 for comparison between penicillin\ampicillin to cefuroxime.

TABLE 4—Treatment Outcomes of Patients Aged 3 Months to 6 Years

Penicillin (n ¼ 178) or Ampicillin (n ¼ 26) Cefuroxime (n ¼ 326)

Total IV treatment, days 2.7 (1.8)a 2.6 (1.5)a

Duration of hospitalization, days 2.9 (1.9)a 2.9 (1.7)a

Duration of oxygen treatment, days �0.2 (0.9)a �0.5 (1.2)a

Number of patients with changed antibiotic treatment 14 (6.9%) 19 (5.8%)

Patients hospitalized over 72 hr, n 69 (33.8%) 118 (36.2%)

Patients with fever above 388C at 72 hr, n 8 (11.6%) 16 (13.6%)

Patients with oxygen requirement at 72 hr, n �3 (4.3%) �19 (16.1%)

Patients hospitalized over 1 week, n 8 (3.9%) 9 (2.8%)

Patients with fever above 388C after 1 week, n 2 (0.25%) 1 (11.1%)

Patients with oxygen requirement after 1 week, n 0 (0%) 0 (0%)

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

Management of Childhood Community-Acquired Pneumonia 55

Pediatric Pulmonology

intermediate resistance (MIC 0.12–1.0 mg/L). Noneof the isolates were fully resistant to penicillin(MIC > 2 mg/L).

DISCUSSION

Acute respiratory infections (ARI) are among the fiveleading causes of death in children <5 years old in de-veloping countries, causing more than 2 million deathsper year.32,33 S. pneumoniae is the bacterium thatcauses the most ARI (especially pneumonia) in this agegroup.34,35 The World Health Organization (WHO) hasdeveloped a strategy to reduce the burden of ARIamong children, based on standard case managementwith appropriate empirical antibiotic treatment.36 Thisapproach, when optimally used, effectively reducedchildhood pneumonia-related mortality by 50% andoverall child mortality by 25%.37 However, the emer-gence of penicillin-resistant pneumococcal strains ren-dered the choice of empirical antibiotic therapy moredifficult. Penicillin resistance resulted in poor clinicaloutcomes for bacterial meningitis and changed the rec-ommendation for the empirical treatment of this dis-ease.38 However, the guidelines worldwide continue torecommend penicillin as the drug of choice for non-complicated CAP. This policy is based on studies thatdemonstrate good clinical response to therapy despitein vitro resistance of S. pneumoniae, and show no ad-verse outcomes in patients infected with non-suscepti-ble isolates.1,2,4,5,7–9,12,14–17,24,25,27,28 Despite theseguidelines many physicians changed their practice andtreated children with CAP with second and third gener-ation cephalosporins.29 Furthermore, while implement-ing the guidelines, a continued increasing preferencefor broad-spectrum antibiotic use for less severepatients was noted, that was attributed to a ‘‘just incase’’ approach to antibiotic choice.30,31 A recent studyof pediatric antibiotic prescribing practices in the ambu-latory setting highlighted the issue of broad-spectrumantibiotic use in the United States.39 Data analyzedfrom the National Ambulatory Medical Care Survey(NAMCS) and the National Hospital Ambulatory Medi-cal Care Survey (NHAMCS) between 2006 and 2008revealed that broad-spectrum antibiotics accounted for50% of antibiotic prescriptions. Respiratory conditionsaccounted for most (72.3%) of the visits in this study.

In this retrospective analysis of infants <2 years ofage, treated with two different protocols for uncompli-cated CAP, we showed that the clinical outcomes oftreatment with penicillin or ampicillin were similar totreatment with cefuroxime. No differences were ob-served in length of hospitalization, duration of fever,duration of IV treatment, complications, and treatmentfailure. This is in spite of the results from previousstudies at the Hadassah Medical Center which showed

that 23% isolates of S. pneumoniae were resistant topenicillin.10 The current study also shows that regard-less of departmental guidelines children were stilltreated with cefuroxime, most likely because the treat-ing physician considered this therapy to be better thanpenicillin.Penicillin-resistance of S. pneumoniae is due to al-

tered b-lactam target sites (penicillin-binding proteins)and hence cannot be overcome by addition of a b-lactamase inhibitor.9 However, the mechanism suggeststhat resistance can be overcome by achieving adequatelocal drug levels using higher doses.1,2,4,5,8,12,16,24

Therefore, the recommended therapy for pneumoniacaused by penicillin-resistant S. pneumoniae is withhigh dose penicillin. All studies that evaluated the clini-cal outcome of this treatment showed recovery ratessimilar to that of all other antibiotics assessed, especial-ly cephalosporins.7,8,11,17,21,25 In a prospective observa-tional study of 844 hospitalized adult patients withpositive blood cultures for S. pneumoniae a 24.6% ofpneumococcal non-susceptibility to penicillin was de-scribed.23 In the first 48 hr after blood for cultureswas drawn, 6.9% of the patients were treated withan antibiotic for which S. pneumoniae isolated fromblood showed in vitro resistance. Treating the patientswith penicillin-resistant strains with penicillin wasnot associated with worse outcome including time todefervescence or rate of suppurative complications. In-terestingly, discordant therapy with cefuroxime wasrelated to increased mortality. In a prospective observa-tional study of 240 children aged 3–59 months hospital-ized for severe CAP8 in 12 hospitals in South America,all patients received penicillin or ampicillin after collec-tion of blood for culture. Fifty-two percent ofS. pneumoniae isolates were susceptible to penicillin,26% showed intermediate resistance and 22% were ful-ly resistant. Treatment failure, defined as a lack of clini-cal improvement or deterioration under antimicrobialtreatment, was found in 21% of patients. No associationbetween in vitro resistance of S. pneumoniae to penicil-lin and treatment failure was observed. Another ran-domized prospective study in children with presumedacute invasive bacterial infection including pneumonia,compared the clinical recovery among children treatedwith penicillin or cefuroxime and no differences werefound.24

In the current study, the diagnosis of pneumonia wasdetermined by clinical judgment, which in turn wasbased on the clinical symptoms (fever, cough) and signs(dyspnea, tachypnea) localizing signs (dullness on per-cussion, crackles, decreased air entry, bronchial breath-ing), and laboratory findings (increased leukocytecounts with left shift and CRP levels or infiltrate onchest X-ray). Only 4.5% of blood cultures grew bacte-ria, similar to data of other studies.1,3,8,9 Nevertheless,

56 Dinur-Schejter et al.

Pediatric Pulmonology

the high leukocyte count and CRP levels are suggestiveof a bacterial infection in the majority of patients.While it is possible that some patients in our study hadviral pneumonia, nasopharyngeal aspirate for RSV andother respiratory viruses are not routinely performed forpatients with diagnosis of bacterial pneumonia at ourinstitution. Previous work has documented that coinfec-tion, most commonly with S. pneumonia in associationwith other respiratory viruses may occur in as many as30–40% of cases of childhood CAP 1,4,13 and thereforewould not influence therapeutic decision making. Fur-thermore, with current diagnostic methods, bacteriologi-cal confirmation of CAP is not possible in most cases.It is important to note that using various techniquessuch as cultures, serology, PCR tests, or immunofluo-rescence, a microbiological diagnosis was possible inonly 27–44% children with CAP.1 It is important to no-tice that the pneumococcal conjugated vaccination hasbecome a part of the vaccination routine in Israel sinceMay 2009, it is implied that the majority of our patientswere not immunized to S. pneumonia. Our resultsshould be further validated in the settings of the currentpractice to vaccinate all children with a conjugatedpneumococcal vaccination.

Our treatment groups differed from each other in sev-eral baseline parameters, mainly age and WBC at ad-mission. Although these differences were statisticallysignificant; their clinical significance is in doubt. Only66 patients under 2 years of age were treated with ei-ther penicillin or cefuroxime, presumably because ofthe treating physician’s decision. This is in contrast to253 patients treated with cefuroxime in this age group.The small number of patients weakens the strength ofthe conclusions somewhat, and requires further re-search. An analysis of covariance demonstrated a lowlevel correlation between several characteristics, suchas saturation in room air and WBC, and main treatmentoutcomes (total days of IV treatment and hospital stay).This correlation contributes little, if any, to the compar-ison between treatment groups and outcomes.

In conclusion, the current study shows that high dosepenicillin or ampicillin is as effective as cefuroxime inthe treatment of previously healthy infants and youngchildren with non-complicated CAP. This highlights thenecessity to adhere to the current guidelines of treat-ment of CAP in children with high dose penicillin orampicillin as the first-line therapy.

REFERENCES

1. Hale KA, Isaacs D. Antibiotics in childhood pneumonia. Pae-

diatr Respir Rev 2006;7:145–151.

2. Stralin K. Usefulness of aetiological tests for guiding antibiotic

therapy in community-acquired pneumonia. Int J Antimicrobial

Agents 2008;31:3–11.

3. Kabra SK, Lodha R, Pandey RM. Antibiotics for community

acquired pneumonia in children. Cochrane Database Syst Rev

2006;3:1–98.

4. Zar HJ, Jeena P, Argent A, Gie R, Madhi SA, Members of

the Working Groups of the Paediatric Assembly of the South

African Thoracic Society. Diagnosis and Management of

Community-Acquired Pneumonia in Childhood—South African

Thoracic Society Guidelines. S Afr Med J 2005;95:977–989.

5. Sinaniotis CA, Sinaniotis AC. Community-acquired pneumonia

in children. Curr Opin Pulm Med 11:218–225.

6. McIntosh K. Community acquired pneumonia in children. N

Engl J Med 2002;346:429–437.

7. Mufson MA, Chan G, Stanek RJ. Penicillin resistance not a fac-

tor in outcome from invasive Streptococcus pneumoniae com-

munity-acquired pneumonia in adults when appropriate empiric

therapy is started. Am J Med Sci 2007;333:161–167.

8. Cardoso MRA, Nascimento-Carvalho CM, Ferrero F, Berezin

EN, Ruvinsky R, Camargos PAM, Sant’Anna CC, Brandileone

MCC, March MFP, Feris-Iglesias J, et al. Penicillin resistant

pneumococcus and risk of treatment failure in pneumonia. Arch

Dis Child 2007. DOI: 10.11136/adc.2006.111625.

9. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH,

Canadian Community-Acquired Pneumonia Working Group.

Canadian Guidelines for the Initial Management of Community-

Acquired Pneumonia: An evidence-based update by the Canadi-

an Infectious Diseases Society and the Canadian Thoracic Soci-

ety. Clin Infect Dis 2000;31:383–421.

10. Rahav G, Toledano Y, Engelhard D, Simhon A, Moses AE,

Sacks T, Shapiro M. Invasive pneumococcal infections: A com-

parison between adults and children. Rev Mol Med 1997;76:

295–303.

11. Feikin DR, Schuchat A, Kolczak M, Barrett NL, Harrison LH,

Lefkowitz L, McGeer A, Farley MM, Vugia DJ, Lexau C, et al.

Mortality from invasive pneumococcal pneumonia in the era of

antibiotic resistance, 1995–1997. Am J Public Health 2000;90:

223–229.

12. Tan TQ, Mason EO, Jr, Barson WJ, Wald ER, Schutze GE,

Bradley JS, Arditi M, Givner LB, Yogev R, Kim KS, et al. Clin-

ical characteristics and outcome of children with pneumonia at-

tributable to penicillin-susceptible and penicillin-nonsusceptible

Streptococcus pneumoniae. Pediatrics 1998;102:1369–1375.

13. Juven T, Mertsola J, Waris M, Leinonen M, Ruuskanen O. Clin-

ical response to antibiotic therapy for community-acquired

pneumonia. Eur J Pediatr 2004;163:140–144.

14. Tan TQ, Mason EO, Jr, Wald ER, Barson WJ, Schutze GE,

Bradley JS, Givner LB, Yogev R, Kim KS, Kaplan SL. Clinical

characteristics of children with complicated pneumonia caused

by Streptococcus pneumoniae. Pediatrics 2002;110:1–6.

15. Peterson LR. Penicillins for treatment of pneumococcal pneu-

monia: Does in vitro resistance really matter? Clin Infect Dis

2006;42:224–233.

16. Falagas ME, Siempos II, Bliziotis IA, Panos GZ. Impact of ini-

tial discordant treatment with beta-lactam antibiotics on clinical

outcomes in adults with pneumococcal pneumonia: A systemat-

ic review. Mayo Clin Proc 2006;81:1567–1574.

17. Wexler IS, Knoll S, Picard E, Villa Y, Shoseyov D, Engelhard

D, Kerem E. Clinical characteristics and outcome of complicat-

ed pneumococcal pneumonia in a pediatric population. Pediatr

Pulmonol 2006;41:726–734.

18. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH,

Abboud PA, Rubin HR. Why don’t physicians follow clinical

practice guidelines? A framework for improvement. JAMA

1999;282:1458–1465.

19. Nathwani D, Williams F, Winter J, Winter J, Ogston S,

Davey P. Use of indicators to evaluate the quality of

Management of Childhood Community-Acquired Pneumonia 57

Pediatric Pulmonology

community-acquired pneumonia management. Clin Infect Dis

2002;34:318–323.

20. Shek FW, Stacey BS, Rendell J, Hellier MD, Hanson PSV. The

rise of Clostridium difficile: The effect of length of stay, patient

age and antibiotic use. J Hosp Infect 2000;45:235–237.

21. Spencer RC. Clinical impact and associated costs of Clostridium

difficile associated disease. J Anti microb Chemother 1998;41:

5–12.

22. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-

acquired Clostridium difficile-associated diarrhoea: A systematic

review. J Antimicrob Chemother 2003;51:1339–1350.

23. Yu VL, Chiou CCC, Feldman C, Ortqvist A, Rello J, Morris AJ,

Baddour LM, Luna CM, Snydman DR, Ip M, et al. An Interna-

tional Prospective Study of Pneumococcal Bacteremia: Correla-

tion with in vitro resistance, antibiotics administered, and

clinical outcome. Clin Infect Dis 2003;37:230–237.

24. Vuori-Holopainen E, Peltola H, Kallio MJ. Narrow-versus

broad-spectrum parenteral antimicrobials against common infec-

tions of childhood: A prospective and randomised comparison

between penicillin and cefuroxime. Eur J Pediatr 2000;159:

878–884.

25. Aspa J, Rajas O, Rodriguez de Castro F, Blanquer J, Zalacain

R, Fenoll A, de Celis R, Vargas A, Salvanes FR, Espana PP, et

al. Drug-resistant pneumococcal pneumonia: Clinical relevance

and related factors. Clin Infect Dis 2004;38:787–798.

26. Heffelfinger JD, Dowell SF, Jorgensen JH, Klugman KP, Mabry

LR, Mushe DM, Plouffe JF, Rakowsky A, Schuchat A, Whitney

CG, Drug-Resistant Streptococcus pneumoniae Therapeutic

Working Group. Management of community-acquired pneumo-

nia in the era of pneumococcal resistance: A report from the

Drug-Resistant Streptococcus pneumoniae Therapeutic Working

Group. Arch Intern Med 2000;160:1399–1408.

27. Kaplan SL, Mason EO, Jr, Barson WJ, Tan TQ, Schutze GE,

Bradley JS, Givner LB, Kim KS, Yogev R, Wald ER. Outcome

of invasive infections outside the central nervous system caused

by Streptococcus pneumoniae isolates nonsusceptible to ceftri-

axone in children treated with beta-lactam antibiotics. Pediatr

Infect Dis J 2001;20:392–396.

28. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell

GD, Dean NC, Dowell SF, File TM, Jr, Musher DM, Niederman

MS, et al. Infectious Diseases Society of America/American

Thoracic Society Consensus Guidelines on the Management of

Community-Acquired Pneumonia in Adults. Clin Infect Dis

2007;44:S27–S72.

29. British Thoracic Society. Guidelines for the management of

community acquired pneumonia in adults 2004 update. http://

wwwbrit-thoracicorguk/c2/uploads/MACAPrevisedApr04pdf,

2004.

30. Barlow G, Nathwani D, Davey P. The effect of implementing

the British Thoracic Society community-acquired pneumonia

guidelines on antibiotic prescribing and costs in a UK teaching

hospital. Clin Microbiol Infect 2006;12:498–500.

31. Collini P, Beadsworth M, Anson J, Neal T, Burnham P, Deegan

P, Beeching N, Miller A. Community-acquired pneumonia:

Doctors do not follow national guidelines. Postgrad Med J

2007;83:552–555.

32. Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye C. Esti-

mates of worldwide distribution of child deaths from acute

respiratory infections. Lancet Infect Dis 2002;2:25–32.

33. World Health Organization. The World Health Report 2005.

Make every mother and child count. Geneva: World Health

Organization; 2005. http://www.who.int/whr2005_en.pdf

34. World Health Organization (WHO). Technical bases for the

WHO recommendations on management of pneumonia in chil-

dren at first level health facilities. Geneva: WHO; 1991, WHO/

ARI/91.20.

35. Michelow IC, Olsen K, Lozano J, et al. Epidemiology and char-

acteristics of community-acquired pneumonia in hospitalized

children. Pediatrics 2004;113:701–707.

36. World Health Organization (WHO). ARI in children: Case man-

agement in small hospitals in developing countries. A manual

for doctors other senior health workers. Programme for the Con-

trol of ARI. Geneva: WHO; 1990.

37. Sazawal S, Black RE. Effect of pneumonia case management

on mortality in neonates, infants, and preschool children: A

meta-analysis of community-based trials. Lancet Infect Dis

2003;3:547–556.

38. Kwang SK. Acute bacterial meningitis in infants and children.

Lancet Infect Dis 2010;10:32–42.

39. Hersh AL, Shapiro DJ, Pavia AT, et al. Antibiotic prescribing

in ambulatory pediatrics in the United States. Pediatrics 2011;

128:1053–1061.

58 Dinur-Schejter et al.

Pediatric Pulmonology