Curr Infect Dis Rep (2016) 18:3

DOI 10.1007/s11908-015-0509-2

RESPIRATORY INFECTIONS (F ARNOLD, SECTION EDITOR)

The Impact of Prior Antibiotic Therapy on Outcomes in Children

Hospitalized for Community-Acquired Pneumonia
Eran Lavi 1 & Oded Breuer 1,2

# Springer Science+Business Media New York 2015

Abstract Here, we review current available literature regard- Introduction

ing the effect of prior antibiotic treatment on outcomes of
children hospitalized for community-acquired pneumonia Community-acquired pneumonia (CAP) is a major cause of
(CAP). To date, no prospective trial has reported information morbidity and the leading cause of mortality in pediatric pa-
regarding morbidity or mortality in this group of patients. tients worldwide. This high disease burden primarily affects
Retrospective studies have provided evidence for the advan- low- and middle-income countries, mainly in Africa and South
tage of treatment with broad-spectrum antibiotics in children East Asia, nonetheless even in developed countries, CAP ac-
who failed prior antibiotic therapy. We discuss the changing counts for a significant number of hospitalizations annually
epidemiology of CAP in the post PCV13 and Hib vaccines era [1•, 2, 3••]. Studies have identified Streptococcus pneumoniae
and its relevance to the outcome of pediatric patients hospital- as the leading typical bacterial cause of pediatric CAP in all age
ized for CAP. Current studies still report Streptococcus groups [4–8]. Other typical bacteria less frequently identified
pneumoniae as the most common typical bacterial causative are non-typeable Haemophilus influenza, considered to be the
agent in pediatric CAP. However, in children who fail to re- second most common typical bacterial causative agent,
spond to guideline directed antibiotic therapy, a non-pneumo- Moraxella catarrhalis and Staphylococcus aureus [4, 8–11].
coccal, possibly one of several β-lactam resistant causative Nevertheless, in standard practice, an infectious cause for CAP
bacterial agents should be considered thus clarifying the ad- is infrequently identified [7, 12••]. Furthermore, even in studies
vantage for broad-spectrum empirical antibiotic treatment in involving extensive microbiological diagnostic work-ups, in
this group of patients. 20–60 % of cases, no bacterial pathogen is identified [3••,
13••]. Therefore, the treatment of pediatric CAP is often em-
piric, based on data from local epidemiological studies. Cur-
Keywords Community-acquired pneumonia . rent guidelines from the Pediatric Infectious Diseases Society
Non-responsive . Antibiotics . Pediatrics . S. pneumonia . and the Infectious Diseases Society of America (PIDS/IDSA)
PCV13 and guidelines from the British Thoracic Society (BTS) and
Cochrane Systemic Review recommend initial empiric therapy
of ampicillin or penicillin G for hospitalized children and
amoxicillin for outpatient children with CAP; targeting S.
This article is part of the Topical Collection on Respiratory Infections pneumoniae as the major bacterial causative agent [12••,
13••, 14••]. These guidelines were created to reduce unwarrant-
* Oded Breuer ed empiric therapy with broad-spectrum antibiotics, which has
odedbr@hadassah.org.il
been shown to induce bacterial resistance [15]. Several aspects
in the management of pediatric CAP have not been adequately
1
Department of Pediatrics, Hadassah-Hebrew University Medical addressed in current guidelines due to lack of sufficient litera-
Center, Jerusalem, Israel ture at the time of their publication. First, existing guidelines
2
Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical regarding the treatment choice in children not responding to
Center, 91120 Jerusalem, Israel outpatient oral antibiotic therapy for CAP have been based on
3 Page 2 of 7 Curr Infect Dis Rep (2016) 18:3

informal expert opinion due to lack of research addressing this children was observed. Specifically, Kyaw et al. reported that
common situation. Second, the 13-valent pneumococcal con- the rates of disease caused by penicillin-non-susceptible
jugated vaccine (PCV13) was approved by the U.S. Food and strains decreased from 70.3 to 13.1 cases per 100,000 (a de-
Drug Administration on February 24, 2010 [16], and its effect cline of 81 %) [29] among children under 2 years of age. In the
on the epidemiology and etiology of pediatric CAP at the time post PCV13 era, an additional decline of invasive pneumo-
of guideline publication was yet unestablished. In this review, coccal disease was noticed in all ages, owing to the reduction
we report recent literature evaluating the outcome of CAP in in the proportion of disease caused by serotype 19A [25, 30].
pediatric patients not responding to guideline directed oral an- Furthermore, after the introduction of the PCV13 vaccine, a
tibiotic therapy, in the era of the PCV13 vaccine. total reduction of 78–96 % in invasive pneumococcal disease;
penicillin-non-susceptible, erythromycin-non-susceptible,
and multiple non-susceptible among children younger than
Background 5 years was reported [31].

Epidemiology of CAP After the Introduction Current Treatment Guidelines for Pediatric CAP
of the Pneumococcal Conjugate Vaccine
Treatment of suspected bacterial pneumonia is based on the
The 7-valent pneumococcal conjugated vaccine (PCV7) was presumptive bacterial cause, the patients’ age and the clinical
licensed for use in young children in the USA in the year 2000 situation. S. pneumoniae is the most common bacterial path-
and replaced by the 13-valent vaccine (PCV13) in 2010. ogen in children in the post HIB vaccine era [12••, 32]. The
PCV7 provokes protective antibody response to seven of latest guideline update by the PIDS/IDSA, recommend the use
more than 92 serotypes of S. pneumoniae (4, 6B, 9V, 14, of ampicillin or penicillin-G as first line therapy for immu-
18C, 19F, and 23F), whereas PCV13 covers the additional 1, nized hospitalized children older than 3 months with CAP
3, 5, 6A, 7F, and 19A serotypes [17, 18]. given local epidemiological data, which shows limited propor-
After the introduction of PCV7, a substantial reduction in tion of high level penicillin resistance of S. pneumoniae [14••].
admissions for invasive pneumococcal disease, lobar pneumo- Therapy with a parenteral 3rd-generation cephalosporin is re-
nia caused by vaccine serotypes and pneumonia of all causes served for patients who are not fully vaccinated, have a life
was documented [19–22]. Nevertheless, a rise in the non- threatening infection (including empyema) or when local ep-
vaccine serotypes (NVTs) was noticed among asymptomatic idemiologic data indicates a high prevalence of penicillin re-
carriers, called Bserotype replacement^ [23, 24]. Concern re- sistance. Similarly, guideline update of the British Thoracic
garding serotype replacement led to the development of PCV13 Society for the management of CAP in children published in
in 2010. Studies investigating the impact of the PCV13 vaccine 2011 recommends the use of amoxicillin as first line therapy
of the incidence of invasive pneumococcal disease rates have with co-amoxiclav, cefuroxime, and cefotaxime or ceftriaxone
shown a further decline in children. This decline was accom- as second and third choices [13••].
panied by a substantial population-level decline in This approach is supported by the previously mentioned
pneumococcal-related mortality of nearly 30 % among non- reduction in antibiotic-resistant pneumococcal infections in
vaccinated persons [25]. Moreover, lower rates of hospitaliza- children after the introduction of the conjugate vaccine [29]
tions and ambulatory visits for pneumonia among children of as well as the recognition that high doses of penicillin were
all ages and a lower infant mortality rate were observed [26]. In found to be effective in the treatment of CAP in resistant pneu-
a time series analysis conducted in the USA, the PCV13 vac- mococci (minimum inhibitory concentration ≤2.0 mcg/mL)
cine significantly reduced residual invasive and non-invasive [33–36].
pneumococcal hospital admissions in children younger than Several randomized control studies have shown similar ef-
5 years, as well as in some adult age groups [27]. ficacy for a macrolide or a β-lactam (penicillin, amoxicillin,
Importantly, early data shows an increase in the rate of amoxicillin/clavulanate, cefixime, cefpodoxime, cefuroxime,
invasive pneumococcal disease due to non-PCV13 serotypes, or ceftriaxone) for the treatment of CAP further advocating the
particularly in children younger than 5 years in 2014. These use of narrow-spectrum antibiotics for treatment of pediatric
findings suggest that the maximal benefit of the PCV13 vac- CAP [37–40]. Thus, by implementing current guidelines, a
cine in children has already been achieved [28]. reduction in antimicrobial resistance and a decrease in medical
care costs are achieved.
Pneumococcal ß-Lactam Antibiotic Resistance Unfortunately, despite the overwhelming evidence and na-
in Pediatric CAP tional guidelines to support the use of narrow-spectrum anti-
biotics in the treatment of CAP, several studies have shown
After the introduction of the PCV7, an overall decrease in the poor adherence and a significant variation between different
rate of antibiotic-resistant invasive pneumococcal disease in institutions regarding the choice of antibiotic treatment
Curr Infect Dis Rep (2016) 18:3 Page 3 of 7 3

[41–43]. The use of broad-spectrum antibiotics in treatment of preceding antibiotic treatment, H. influenza was the most
CAP is caused by a concern regarding the possible bacterial common isolated bacterial agent, found in 44 % of cases,
etiology. This is due to the fact that in standard practice, an while S. pneumoniae was found only in 31 % of cases. Where-
infectious cause for CAP is rarely identified. This concern is as, in children with no prior antibiotic treatment, S.
increased when a patient does not rapidly respond to the pneumoniae and H. influenza were found in 62 and 14 %,
guideline directed narrow-spectrum antibiotic treatment. respectively [5].
Thus, a pediatric patient not responding to antibiotic therapy The increase in prevalence of H. influenza infection
for CAP is usually administered broader spectrum antibiotics. in CAP after prior antibiotic treatment has also been
In the next sections, we will review available literature regard- demonstrated in a study of non-responding and recurrent
ing the approach to patients not responding to prior antibiotic pneumonia in children. This retrospective study by De
treatment. Schutter et al. analyzed microbiological data in two
groups of pediatric patients with CAP who underwent
flexible bronchoscopy with bronchoalveolar lavage
The Consequence of Prior Antibiotic Treatment (BAL): children with acute non-responsive CAP (persis-
on Pediatric CAP tent symptoms despite at least 48 h of antibiotic treat-
ment) and children with recurrent CAP (a history of at
Current Guidelines Regarding Prior Antibiotic Treatment least two other treated CAP episodes). In this study of
children with recent exposure to antibiotics, a typical
Information regarding outcome of CAP in children after prior bacterial infectious agent was detected in 51.2 % of
oral antibiotic therapy is scarce [12••]. It may be speculated infections, of which 75.0, 28.9, and 13.3 % were
that recent antibiotic use may increase incidence of resistant H. influenzae, M. catarrhalis, and S. pneumoniae, re-
bacteria, and thus necessitates treatment with broad-spectrum spectively. Most (97.9 %) of the H. influenzae strains
antibiotics. Indeed, a review by Chenoweth et al. suggested were non-typeable (NTHi) [45].
that prior exposure to antibiotic treatment increases, the
chance of infection with resistant S. pneumoniae and thus
adversely affects the outcome of CAP [44]. But this has never Prevalence of H. influenzae in Pediatric Respiratory
been prospectively evaluated in pediatric patients. Current Infections
guidelines for treatment of pediatric CAP recommend the
use of broad-spectrum antibiotics in children who failed initial The shift in prevalence of NTHi as a pathogen in infections of
antibiotic treatment, but these recommendations are based on the upper and lower respiratory tract and in invasive disease
expert opinion and not on established data [13••, 14••]. Inad- has been recently reviewed [46]. After the introduction of the
equate dosing, non-compliance, a complication or an under- H. influenzae type b (Hib) conjugate vaccine in the 1990s and
lying chronic disease may also account for failure of outpa- the rapid and sustained reduction in Hib disease across all age
tient oral antibiotic treatment and does not necessarily neces- groups, it was speculated that other H. influenzae strains might
sitate broadened antibiotic coverage. Thus, even though every replace Hib in causing invasive disease. Indeed, data from an
pediatrician frequently encounters such pediatric patients, pro- international European collaboration on invasive
spective controlled trials specifically addressing this common H. influenzae infections identified a 3.5 % annual increase in
clinical situation are lacking. invasive non-type b H. influenzae disease, mainly caused by
NTHi [47•]. However, other countries have reported no
Effect of Prior Antibiotic Treatment on the Bacterial change in the rate of invasive NTHi after the introduction of
Etiology routine Hib vaccination [48, 49].
A study by Pírez et al. evaluated changes in hospitaliza-
Exposure to antibiotics in the recent past may have an impact tions for pediatric CAP after universal vaccination with PCV7
on the etiological cause of CAP. Two studies were found to or 13 and Hib conjugate vaccines [50]. As mentioned previ-
report information regarding the bacterial etiology of CAP in ously, the implementation of PCV7 and 13 have markedly
patients with recent antibiotic use. A study by Lahti et al. reduced the incidence of pneumonia in children [27, 51]. This
investigated the usefulness of induced sputum in searching study has additionally shown that alongside the decreased
for causative agents of pneumonia in children. The final study incidence of pneumococcal CAP, hospitalization following
population consisted of 76 children, aged 6 months to 15 years, PCV 7 and 13, H. influenzae pneumonia hospitalization rates
and found a possible causative agent in 90 % of cases, mainly among children remained unchanged [50]. Thus, although a
S. pneumoniae (46 %) and rhinovirus (29 %). A significant reduction in overall CAP had been demonstrated, the propor-
difference in the bacterial etiology was found between chil- tion of CAP caused by bacteria other than pneumococci and
dren with and without prior antibiotic therapy. In children with especially H. influenzae has increased.
3 Page 4 of 7 Curr Infect Dis Rep (2016) 18:3

Prior Antibiotics and the Resistance to β-Lactam amoxicillin or to receive only home-based treatment with
Antibiotics amoxicillin. This study did provide a subgroup analysis on
patients with prior antibiotic use. However, Hazir et al. report-
Resistance to β-lactam antibiotics is a major concern in treat- ed that antibiotic use in the 7 days before randomization was
ment of CAP. As mentioned earlier, after the introduction of associated with increased treatment failure rates on univariate
the PCV7, a decrease in the degree of penicillin resistant pneu- but not multivariate analysis [63]. It is important to note that in
mococci was documented [29]. Furthermore, several studies this study, all patients received narrow-spectrum antibiotics,
have provided evidence for the effectiveness of high doses of irrespective of prior antibiotic treatment.
penicillin for the treatment of CAP in resistant pneumococci We have recently published results of a retrospective study
(minimum inhibitory concentration ≥2.0 mcg/mL) [33–36, comparing the outcome of treatment with narrow-vs. broad-
52]. Therefore, as previously mentioned, current guidelines spectrum antibiotics in children hospitalized with CAP who
advocate treatment of CAP with narrow-spectrum antibiotics. received oral antibiotic treatment prior to their hospitalization
Β-lactamase production is the dominant resistance mecha- [64••]. Children treated with broad-spectrum antibiotics dur-
nism of H. influenzae and NTHi against β-lactam antibiotics. ing hospitalization had significantly better outcomes in terms
Most studies report occurrence of β-lactamase-positive NTHi of number of febrile days, number of days treated with IV
in 10 to 25 % of isolated strains [53, 54]. However, strains antibiotics, and hospital length of stay. A subgroup analysis,
with β-lactamase independent resistance to β-lactams have according to the type of antibiotic treatment prior to hospital-
emerged, are spreading, and have been documented in up to ization, showed that in patients who were treated with broad-
50 % of isolated strains in some areas of the world [55–59]. A spectrum antibiotics in the community, there was no signifi-
current review regarding the impact of resistant H. influenzae cant difference between broad- and narrow-spectrum treat-
strains concluded that a further spread of these resistant strains ments during hospitalization [64••]. Unfortunately, due to
could make it necessary to change the current treatment guide- the retrospective nature of the study, extensive microbiologi-
lines for community-acquired infections of the upper and low- cal studies were not performed and a bacterial etiological
er respiratory tracts [46]. agent was only identified in 2 % of patients. Therefore, this
Therefore, in view of the increased incidence of non- study fails to provide a microbiological explanation for its
pneumococcal CAP in children with prior antibiotic treatment findings. However, given the above mentioned data of in-
and the reports on the emergence of β-lactam resistant strains creased incidence of CAP due to bacteria other than
of H. Influenza, it is reasonable to speculate that broad- S. pneumoniae in patients with recent antibiotic treatment, it
spectrum antibiotics might be beneficial for pediatric patients was speculated that such a cohort of patients existed with CAP
with CAP who do respond to oral outpatient narrow-spectrum due to penicillin-resistant bacteria, such as H. influenzae,
antibiotic treatment. M. catarrhalis, and S. aureus. Furthermore, the fact that
broad-spectrum antibiotics during admission did not improve
Pediatric CAP Outcome After Exposure to Prior outcome in patients who received prior broad-spectrum oral
Antibiotic Treatment antibiotic treatment supports the assumption of increased fre-
quency of penicillin-resistant bacteria in this cohort of patients.
A number of observational and prospective studies have in- Currently, no study has evaluated the disease course
cluded information on past antibiotic use in their patients [60, of pediatric CAP in patients who are not responding to
61]. However, subgroup analysis for the patients who received prior antibiotic treatment. Retrospective studies reporting
recent antibiotic treatment was generally not available. this cohort of patients have excluded subjects with a
A limited number of studies have discussed the implication severe or complicated disease course [64••]. Only pro-
of prior antibiotic use on outcomes. A case control study by spective studies can effectively evaluate morbidity and
Emery et al. evaluated primary care factors associated with complications in these patients.
emergency department (ED) presentation and hospital admis-
sion of children with CAP. This study found that the prescrip-
tion of prior antibiotics was a significant risk factor for hospi- Conclusion
tal admissions in children presenting to the ED with CAP.
Unfortunately, this study did not report clinical findings or Guidelines for the treatment of pediatric CAP advocate the use
the disease course of the included patients, and thus, no infor- of narrow-spectrum antibiotics targeting S. pneumoniae as the
mation regarding the effect of prior antibiotics on disease pro- major causative agent in all age groups. Following the intro-
gression and outcome can be determined [62]. duction of PCV7 and 13 and Hib conjugate vaccine, there has
An open-label equivalence trial by Hazir et al. randomized been a significant decrease in the incidence of CAP, hospital-
2100 children from seven study sites in Pakistan to receive izations for CAP, pneumococcal pneumonia, and the isolation
either parenteral ampicillin for 48 h followed by oral of penicillin-resistant pneumococci causing CAP. Some
Curr Infect Dis Rep (2016) 18:3 Page 5 of 7 3

studies have reported that the incidence of non-pneumococcal 2. Lee GE, Lorch SA, Sheffler-Collins S, Kronman MP, Shah SS.
National hospitalization trends for pediatric pneumonia and associ-
pneumonia has not significantly changed following the imple-
ated complications. Pediatrics. 2010;126(2):204–13.
mentation of routine vaccination programs. Thus, the propor- 3.•• Jain S, Williams DJ, Arnold SR, Ampofo K, Bramley AM, Reed C,
tion of CAP caused by bacteria other than S. pneumoniae et al. Community-acquired pneumonia requiring hospitalization
might have potentially increased. Of these bacteria, NTHi among U.S. children. N Engl J Med. 2015;372(9):835–45.
Updated data on pediatric community aquired pneumonia hos-
has been shown to be the most common typical agent causing
pitalization in the U.S..
pediatric CAP. In addition, an increased incidence of β-lactam 4. Michelow IC, Olsen K, Lozano J, Rollins NK, Duffy LB, Ziegler T,
resistance in NTHi has been shown to occur in some part of et al. Epidemiology and clinical characteristics of community-
the world and might increase concern regarding appropriate acquired pneumonia in hospitalized children. Pediatrics.
2004;113(4):701–7.
antibiotic treatment for CAP. Thus, although S. pneumoniae
5. Lahti E, Peltola V, Waris M, Virkki R, Rantakokko-Jalava K, Jalava
remains by far the most common typical bacterial causative J, et al. Induced sputum in the diagnosis of childhood community-
agent in pediatric CAP, in children who fail to respond to acquired pneumonia. Thorax. 2009;64(3):252–7.
antibiotic therapy, a non-pneumococcal, possibly β-lactam 6. Blaschke AJ, Heyrend C, Byington CL, Obando I, Vazquez-Barba
I, Doby EH, et al. Molecular analysis improves pathogen identifi-
resistant causative bacterial agent, should be considered. Un-
cation and epidemiologic study of pediatric parapneumonic empy-
fortunately, controlled trials regarding appropriate therapy for ema. Pediatr Infect Dis J. 2011;30(4):289–94.
CAP in patients who failed prior oral antibiotic treatment are 7. Juven T, Mertsola J, Toikka P, Virkki R, Leinonen M, Ruuskanen
lacking. Retrospective and observational data supports the use O. Clinical profile of serologically diagnosed pneumococcal pneu-
of broad-spectrum antibiotics for CAP in children with prior monia. Pediatr Infect Dis J. 2001;20(11):1028–33.
8. Juven T, Mertsola J, Waris M, Leinonen M, Meurman O, Roivainen
antibiotic treatment, speculating an increased frequency of M, et al. Etiology of community-acquired pneumonia in 254 hos-
penicillin-resistant bacteria in such patients. However, pitalized children. Pediatr Infect Dis J. 2000;19(4):293–8.
broad-spectrum antibiotics should always be used cautiously 9. Claesson BA, Lagergard T, Trollfors B. Antibody response to outer
to minimize the development of bacterial resistance. There- membrane of noncapsulated Haemophilus influenzae isolated from
the nasopharynx of children with pneumonia. Pediatr Infect Dis J.
fore, we conclude that current data is insufficient to provide 1991;10(2):104–8.
appropriate evidence regarding the antibiotic choice in pa- 10. Isaacs D. Problems in determining the etiology of community-
tients presenting with CAP after prior antibiotic exposure. A acquired childhood pneumonia. Pediatr Infect Dis J. 1989;8(3):
prospective study comparing the treatment outcomes of pa- 143–8.
11. Gendrel D, Raymond J, Moulin F, Iniguez JL, Ravilly S, Habib F, et
tients hospitalized with CAP after prior antibiotic treatment is al. Etiology and response to antibiotic therapy of community-
warranted in order to accurately assess the bacterial etiology in acquired pneumonia in French children. Eur J Clin Microbiol
such patients, to assess the complications arising from possi- Infect Dis: Off Publ Eur Soc Clin Microbiol. 1997;16(5):388–91.
ble inappropriate antibiotic therapy, and to provide treatment 12.•• Lodha R, Kabra SK, Pandey RM. Antibiotics for community-
acquired pneumonia in children. Cochrane Database Syst Rev.
guidelines for this subset of patients. 2013;6, CD004874. Treatment guidelines for pediatric commu-
nity aquired pneumonia.
13.•• Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et
Compliance with Ethical Standards al. British Thoracic Society guidelines for the management of com-
munity acquired pneumonia in children: update 2011. Thorax.
Conflict of Interest The authors declare no competing interests. 2011;66 Suppl 2:ii1–23. Treatment guidelines for pediatric com-
munity aquired pneumonia.
Human and Animal Rights and Informed Consent This article does 14.•• Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER,
not contain any studies with human or animal subjects performed by the Harrison C, et al. The management of community-acquired pneu-
author. monia in infants and children older than 3 months of age: clinical
practice guidelines by the Pediatric Infectious Diseases Society and
the Infectious Diseases Society of America. Clin Infect Dis: Off
Publ Infect Dis Soc Am. 2011;53(7):e25–76. Treatment guide-
lines for pediatric community aquired pneumonia.
15. Dellit TH, Owens RC, McGowan Jr JE, Gerding DN, Weinstein
References RA, Burke JP, et al. Infectious Diseases Society of America and the
Society for Healthcare Epidemiology of America guidelines for
developing an institutional program to enhance antimicrobial stew-
Papers of particular interest, published recently, have been ardship. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2007;44(2):
highlighted as: 159–77.
16. FDA. FDA approves pneumococcal disease vaccine with broader
• Of importance protection 2010 [updated 04/24/2013 cited 2015 14 June].
•• Of major importance Available from: http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm201758.htm.
1.• Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et 17. Advisory Committee on Immunization P. Preventing pneumococcal
al. Global burden of childhood pneumonia and diarrhoea. Lancet. disease among infants and young children. Recommendations of
2013;381(9875):1405–16. Global epidemilogical data regarding the Advisory Committee on Immunization Practices (ACIP).
childhood pneumonia. MMWR Recommendations and reports : Morbidity and mortality
3 Page 6 of 7 Curr Infect Dis Rep (2016) 18:3

weekly report Recommendations and reports / Centers for Disease coping with antimicrobial susceptibility in an era of resistance. Clin
Control. 2000 Oct 6;49(RR-9):1–35. PubMed. Infect Dis: Off Publ Infect Dis Soc Am. 2009;48(11):1596–600.
18. Nuorti JP, Whitney CG, Centers for Disease C, Prevention. 34. Bradley JS, Garonzik SM, Forrest A, Bhavnani SM.
Prevention of pneumococcal disease among infants and chil- Pharmacokinetics, pharmacodynamics, and Monte Carlo simula-
dren—use of 13-valent pneumococcal conjugate vaccine and 23- tion: selecting the best antimicrobial dose to treat an infection.
valent pneumococcal polysaccharide vaccine—recommendations Pediatr Infect Dis J. 2010;29(11):1043–6.
of the Advisory Committee on Immunization Practices (ACIP). 35. Dagan R, Hoberman A, Johnson C, Leibovitz EL, Arguedas A,
MMWR Recommendations and reports: Morbidity and mortality Rose FV, et al. Bacteriologic and clinical efficacy of high dose
weekly report Recommendations and reports / Centers for Disease amoxicillin/clavulanate in children with acute otitis media. Pediatr
Control. 2010 Dec 10;59(RR-11):1–18. PubMed Infect Dis J. 2001;20(9):829–37.
19. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, 36. Friedland IR. Comparison of the response to antimicrobial therapy
Lynfield R, et al. Decline in invasive pneumococcal disease after of penicillin-resistant and penicillin-susceptible pneumococcal dis-
the introduction of protein-polysaccharide conjugate vaccine. N ease. Pediatr Infect Dis J. 1995;14(10):885–90.
Engl J Med. 2003;348(18):1737–46. 37. Aurangzeb B, Hameed A. Comparative efficacy of amoxicillin,
20. Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett cefuroxime and clarithromycin in the treatment of community-
NM, et al. Sustained reductions in invasive pneumococcal disease acquired pneumonia in children. J Coll Physicians Surg Pak:
in the era of conjugate vaccine. J Infect Dis. 2010;201(1):32–41. JCPSP. 2003;13(12):704–7.
21. Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, 38. Vuori-Holopainen E, Peltola H, Kallio MJ, Group S-TS. Narrow-
Griffin MR. Decline in pneumonia admissions after routine child- versus broad-spectrum parenteral anatimicrobials against common
hood immunisation with pneumococcal conjugate vaccine in the infections of childhood: a prospective and randomised comparison
USA: a time-series analysis. Lancet. 2007;369(9568):1179–86. between penicillin and cefuroxime. Eur J Pediatr. 2000;159(12):
22. Simonsen L, Taylor RJ, Young-Xu Y, Haber M, May L, Klugman 878–84.
KP. Impact of pneumococcal conjugate vaccination of infants on 39. Klein M. Multicenter trial of cefpodoxime proxetil vs. amoxicillin-
pneumonia and influenza hospitalization and mortality in all age clavulanate in acute lower respiratory tract infections in childhood.
groups in the United States. MBio. 2011;2(1):e00309–10. International Study Group. Pediatr Infect Dis J. 1995;14(4 Suppl):
23. Spratt BG, Greenwood BM. Prevention of pneumococcal disease S19–22.
by vaccination: does serotype replacement matter? Lancet. 40. Amir J, Harel L, Eidlitz-Markus T, Varsano I. Comparative evalu-
2000;356(9237):1210–1. ation of cefixime versus amoxicillin-clavulanate following ceftriax-
24. Lipsitch M. Vaccination against colonizing bacteria with multiple one therapy of pneumonia. Clin Pediatr. 1996;35(12):629–33.
serotypes. Proc Natl Acad Sci U S A. 1997;94(12):6571–6. 41. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud
25. Harboe ZB, Dalby T, Weinberger DM, Benfield T, Molbak K, PA, et al. Why don’t physicians follow clinical practice guidelines?
Slotved HC, et al. Impact of 13-valent pneumococcal conjugate A framework for improvement. JAMA. 1999;282(15):1458–65.
vaccination in invasive pneumococcal disease incidence and mor- 42. Nathwani D, Williams F, Winter J, Winter J, Ogston S, Davey P.
tality. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2014;59(8): Use of indicators to evaluate the quality of community-acquired
1066–73. pneumonia management. Clin Infect Dis: Off Publ Infect Dis Soc
26. Becker-Dreps S, Amaya E, Liu L, Moreno G, Rocha J, Briceno R, Am. 2002;34(3):318–23.
et al. Changes in childhood pneumonia and infant mortality rates 43. Levy G, Perez M, Rodriguez B, Hernandez Voth A, Perez J, Gnoni
following introduction of the 13-valent pneumococcal conjugate M, et al. Adherence with national guidelines in hospitalized patients
vaccine in Nicaragua. Pediatr Infect Dis J. 2014;33(6):637–42. with community-acquired pneumonia: results from the CAPO
27. Simonsen L, Taylor RJ, Schuck-Paim C, Lustig R, Haber M, study in Venezuela. Arch Bronconeumol. 2015;51(4):163–8.
Klugman KP. Effect of 13-valent pneumococcal conjugate vaccine 44. Chenoweth CE, Saint S, Martinez F, Lynch 3rd JP, Fendrick AM.
on admissions to hospital 2 years after its introduction in the USA: a Antimicrobial resistance in Streptococcus pneumoniae: implica-
time series analysis. Lancet Respir Med. 2014;2(5):387–94. tions for patients with community-acquired pneumonia. Mayo
28. Waight PA, Andrews NJ, Ladhani NJ, Sheppard CL, Slack MP, Clin Proc. 2000;75(11):1161–8.
Miller E. Effect of the 13-valent pneumococcal conjugate vaccine 45. De Schutter I, De Wachter E, Crokaert F, Verhaegen J, Soetens O,
on invasive pneumococcal disease in England and Wales 4 years Pierard D, et al. Microbiology of bronchoalveolar lavage fluid in
after its introduction: an observational cohort study. Lancet Infect children with acute nonresponding or recurrent community-
Dis. 2015;15(6):629. acquired pneumonia: identification of nontypeable Haemophilus
29. Kyaw MH, Lynfield R, Schaffner W, Craig AS, Hadler J, Reingold influenzae as a major pathogen. Clin Infect Dis: Off Publ Infect
A, et al. Effect of introduction of the pneumococcal conjugate vac- Dis Soc Am. 2011;52(12):1437–44.
cine on drug-resistant Streptococcus pneumoniae. N Engl J Med. 46. Van Eldere J, Slack MP, Ladhani S, Cripps AW. Non-typeable
2006;354(14):1455–63. Haemophilus influenzae, an under-recognised pathogen. Lancet
30. Moore CE, Paul J, Foster D, Mahar SA, Griffiths D, Knox K, et al. Infect Dis. 2014;14(12):1281–92.
Reduction of invasive pneumococcal disease 3 years after the in- 47.• Ladhani S, Slack MP, Heath PT, von Gottberg A, Chandra M,
troduction of the 13-valent conjugate vaccine in the Oxfordshire Ramsay ME, et al. Invasive Haemophilus influenzae disease,
region of England. Journal Infect Dis. 2014;210(7):1001–11. Europe, 1996–2006. Emerg Infect Dis. 2010;16(3):455–63.
31. Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C, Review regarding invasive haemophilus influenza disease in
Bennett NM, et al. Effect of use of 13-valent pneumococcal conju- europe.
gate vaccine in children on invasive pneumococcal disease in chil- 48. Giufre M, Cardines R, Caporali MG, Accogli M, D’Ancona F,
dren and adults in the USA: analysis of multisite, population-based Cerquetti M. Ten years of Hib vaccination in Italy: prevalence of
surveillance. Lancet Infect Dis. 2015;15(3):301–9. non-encapsulated Haemophilus influenzae among invasive isolates
32. Sinaniotis CA, Sinaniotis AC. Community-acquired pneumonia in and the possible impact on antibiotic resistance. Vaccine.
children. Curr Opin Pulm Med. 2005;11(3):218–25. 2011;29(22):3857–62.
33. Weinstein MP, Klugman KP, Jones RN. Rationale for revised pen- 49. MacNeil JR, Cohn AC, Farley M, Mair R, Baumbach J, Bennett N,
icillin susceptibility breakpoints versus Streptococcus pneumoniae: et al. Current epidemiology and trends in invasive Haemophilus
Curr Infect Dis Rep (2016) 18:3 Page 7 of 7 3

influenzae disease—United States, 1989–2008. Clin Infect Dis: Off Haemophilus influenzae in Sweden, 1997 to 2010. Antimicrob
Publ Infect Dis Soc Am. 2011;53(12):1230–6. Agents Chemother. 2012;56(8):4408–15.
50. Pirez MC, Algorta G, Chamorro F, Romero C, Varela A, Cedres A, 57. Sill ML, Tsang RS. Antibiotic susceptibility of invasive
et al. Changes in hospitalizations for pneumonia after universal Haemophilus influenzae strains in Canada. Antimicrob Agents
vaccination with pneumococcal conjugate vaccines 7/13 valent Chemother. 2008;52(4):1551–2.
and haemophilus influenzae type b conjugate vaccine in a 58. Hotomi M, Fujihara K, Billal DS, Suzuki K, Nishimura T, Baba S,
Pediatric Referral Hospital in Uruguay. Pediatr Infect Dis J. et al. Genetic characteristics and clonal dissemination of beta-
2014;33(7):753–9. lactamase-negative ampicillin-resistant Haemophilus influenzae
51. Angoulvant F, Levy C, Grimprel E, Varon E, Lorrot M, Biscardi S, strains isolated from the upper respiratory tract of patients in
et al. Early impact of 13-valent pneumococcal conjugate vaccine on Japan. Antimicrob Agents Chemother. 2007;51(11):3969–76.
community-acquired pneumonia in children. Clin Infect Dis: Off 59. Garcia-Cobos S, Campos J, Lazaro E, Roman F, Cercenado E,
Publ Infect Dis Soc Am. 2014;58(7):918–24. Garcia-Rey C, et al. Ampicillin-resistant non-beta-lactamase-
52. Deeks SL, Palacio R, Ruvinsky R, Kertesz DA, Hortal M, Rossi A, producing Haemophilus influenzae in Spain: recent emergence of
et al. Risk factors and course of illness among children with inva- clonal isolates with increased resistance to cefotaxime and
sive penicillin-resistant Streptococcus pneumoniae. The cefixime. Antimicrob Agents Chemother. 2007;51(7):2564–73.
Streptococcus pneumoniae Working Group. Pediatrics. 60. Queen MA, Myers AL, Hall M, Shah SS, Williams DJ, Auger KA,
1999;103(2):409–13. et al. Comparative effectiveness of empiric antibiotics for
53. Alpuche C, Garau J, Lim V. Global and local variations in antimi- community-acquired pneumonia. Pediatrics. 2014;133(1):e23–9.
crobial susceptibilities and resistance development in the major 61. Williams DJ, Hall M, Shah SS, Parikh K, Tyler A, Neuman
respiratory pathogens. Int J Antimicrob Agents. 2007;30 Suppl 2: MI, et al. Narrow vs broad-spectrum antimicrobial therapy
S135–8. for children hospitalized with pneumonia. Pediatrics.
2013;132(5):e1141–8.
54. Beekmann SE, Heilmann KP, Richter SS, Garcia-de-Lomas J,
62. Emery DP, Milne T, Gilchrist CA, Gibbons MJ, Robinson E, Coster
Doern GV, Group GS. Antimicrobial resistance in Streptococcus
GD, et al. The impact of primary care on emergency department
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and
presentation and hospital admission with pneumonia: a case-control
group A beta-haemolytic streptococci in 2002–2003. Results of
study of preschool-aged children. NPJ Primary Care Respir Med.
the multinational GRASP surveillance program. Int J Antimicrob
2015;25:14113.
Agents. 2005;25(2):148–56.
63. Hazir T, Fox LM, Nisar YB, Fox MP, Ashraf YP, MacLeod WB, et
55. Cohen R, Bingen E, Levy C, Benani M, Thollot F, Klink Z, et al. al. Ambulatory short-course high-dose oral amoxicillin for treat-
Antibiotic resistance of pneumococci and H. influenzae isolated ment of severe pneumonia in children: a randomised equivalency
from the nasopharyngeal flora of children with acute otitis media trial. Lancet. 2008;371(9606):49–56.
between 2006 and 2010. Arch Pediatrie: Organe Off Soc Fr 64.•• Breuer O, Blich O, Cohen-Cymberknoh M, Averbuch D,
Pediatrie. 2011;18(8):926–31. PubMed Resistance aux Kharasch S, Shoseyov D, et al. Antibiotic treatment for chil-
antibiotiques des pneumocoques et H. influenzae isoles de la flore dren hospitalized with community-acquired pneumonia after
rhinopharyngee d’enfants presentant une otite moyenne aigue entre oral therapy. Pediatr Pulmonol. 2015;50(5):495–502. The
2006 et 2010. only current research evaluating the outcome of commu-
56. Resman F, Ristovski M, Forsgren A, Kaijser B, Kronvall G, nity aquired pneumonia in children with prior antibiotic
Medstrand P, et al. Increase of beta-lactam-resistant invasive therapy.