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Eur J Pediatr

DOI 10.1007/s00431-011-1592-5

REVIEW

Social-economic factors and irrational antibiotic use as reasons


for antibiotic resistance of bacteria causing common childhood
infections in primary healthcare
Katarina Ili & Emil Jakovljevi &
Vesna kodri-Trifunovi

Received: 13 June 2011 / Accepted: 21 September 2011


# Springer-Verlag 2011

Abstract The most prevalent childhood bacterial infections


in primary healthcare are respiratory, gastrointestinal and
urogenital infections. The main aim of this paper was to
consider factors (socio-economic factors and irrational
antibiotic use) that contribute to the development of
bacterial resistance, as well as measures that resulted in a
reduction of this problem. Computerized search through the
Medline of published articles on antibiotic resistance from
1996 to 2011 in English or Serbian was completed in
August 2011. Combinations of used terms were antimicrobial/
antibacterial/antibiotic and resistance/susceptibility in pediatric/
children, and Streptococcus pneumoniae/Streptococci/
Haemophilus influenzae/Salmonellae/Escherichia coli/
Shigella/Staphylococcus aureus as well as antibiotics/
antimicrobials/antibacterials and consumption/utilization/
use. In many developing countries, antibiotic dispensing
and its use in medicine, cattle breeding and agriculture are
inadequately regulated, or existing laws are not being
appropriately implemented. In addition, human travel
contributes to antimicrobial drug resistance around the
world. All of these factors have led to a very high level of
bacterial resistance. On the contrary, in countries with a
clearly defined and implemented legal framework
concerning antibiotic prescribing, dispensing and utilization,
the use of antibiotics is under constant surveillance. That
K. Ili (*) : E. Jakovljevi
Department of Pharmacology, School of Pharmacy,
University of Belgrade,
PO BOX 146, Vojvode Stepe 450,
11221 Belgrade, Republic of Serbia
e-mail: katarina.v.ilic@gmail.com
V. kodri-Trifunovi
Clinic for Pulmonology, Clinical Centre of Serbia,
Koste Todorovia 26,
11129 Belgrade, Republic of Serbia

resulted in a significantly lower antibacterial resistance. In


conclusion, bacterial resistance could be reduced by the
implementation of systemic and long-term measures at a
country level as well as at all levels of healthcare. In order to
reduce bacterial resistance, antibiotic use needs to be
precisely regulated, and regulations should be coherent with
practice. The international community must have a more
active role in solving this global problem.
Keywords Bacterial infections . Children . Antibacterial
resistance . Antibiotic use

Introduction
Resistance to antibiotics is a global problem that is
especially pronounced in developing countries. Bacterial
resistance significantly prolongs the time of treatment and
contributes to the occurrence of side effects which elevates
the cost of treatment [8, 12, 42]. In addition, once the genes
that determine bacterial resistance to antibiotics are acquired,
these genes cannot be easily lost since they become a
relatively stable part of the bacterial genome. Bacteria, after
contact with a number of antibiotics, become multiresistant,
which then reduces the number of treatment options [48].
Infections caused by resistant bacterial strains were
previously acquired mainly in hospital settings. However,
nowadays, they are increasingly present in the extrahospital environment [35]. Children, especially infants, are
particularly sensitive to these infections which contribute to
high mortality in countries with inadequate health care. For
example, in Asia, one infant dies every 2 min due to
infections caused by resistant bacteria [15].
The most common bacterial infections in children are the
acute infections of the respiratory, gastrointestinal and

Eur J Pediatr

genitourinary systems. The main factors influencing the


increasing resistance of pathogens causing these infections
are poor hygiene, lack of education in general population
(especially parents) and uncontrolled use of antibiotics in
animal husbandry and agriculture as well as the irrational
use of antibiotics in medicine [46, 49, 83]. This paper
considers the impact of socio-economic factors, as well as
irrational antibiotic use, on the development of bacterial
resistance in children and the experiences that have
contributed to the reduction of bacterial resistance.

Methods
Computerized search through the Medline of published
articles on antibiotic resistance from 1996 to 2011 in English
or Serbian was completed in August 2011. Combinations of used terms were antimicrobial/antibacterial/
antibiotic and resistance/susceptibility in pediatric/children,
and Streptococcus pneumoniae/Streptococci/Haemophilus
influenzae/Salmonellae/Escherichia coli/Shigella/
Staphylococcus aureus and antibiotics/antimicrobials/
antibacterials consumption/utilization/use. Reviews, editorials
and case reports were excluded. Collected pieces of information included author, year of study and publication,
country where the study was conducted, age and size of
the studied population, level of antibiotic resistance and
antibiotic utilization (in defined daily doses (DDD) per
1,000 inhabitants per day).

Acute bacterial respiratory tract infections


In children, acute respiratory tract infections are one of the
most common reasons for visit to a doctor's office. In
minors, rhinitis, pharyngitis, tonsillitis, bronchitis and
community acquired pneumonia are often caused by
viruses. In these patients, the use of antibiotics is often
not justified, except in cases of bacterial super-infection
[13, 57]. The most common causes of acute bacterial
infections of the upper respiratory tract in children are
Streptococcus pneumoniae, -haemolytic Streptococci and
H. influenzae [36, 52].
Streptococcus pneumoniae
Streptococcus pneumoniae can cause serious infectious
diseases (pneumonia, meningitis, febrile bacteremia, etc.).
According to the World Health Organization (WHO), 0.7 to
1 million children under 5 years of age die of pneumococcal
infections every year around the world, mostly in underdeveloped and developing countries [34, 36, 52, 74]. The most
usually prescribed antibiotics for the upper respiratory tract

infections were penicillins, macrolides, co-trimoxazole and,


in less extent, new-generation antibiotics [5, 16, 27, 34, 36,
68, 77]. The first data on resistance of Streptococcus
pneumoniae to penicillin and tetracycline came from
Australia in 1967 [4]. In the USA, prescribing of antibiotics
(especially penicillin) to pediatric population increased by
48% from 1980 to 1992, while in 44% of cases, antibiotics
were prescribed to children for common cold [56]. This led
to a significant increase in resistance of Streptococcus
pneumoniae to penicillin (from 1% to 40%) [66], whereas
in no US states, resistance exceeded 50% until 1994
(Table 1).
After 1994, the resistance shown by Streptococcus
pneumoniae in 13 European countries was correlated with
the use of antibiotics, and its further growth was recorded.
The highest resistance levels were registered in Spain
(72%), where the highest antibiotic consumption (about
1,400 prescriptions/1,000 inhabitants) was observed in
1994 and 1997. In the same period, in The Netherlands
and Germany where antibiotic consumption was significantly lower (less than 400 prescriptions/1,000 inhabitants
and less than 600 prescriptions/1,000 inhabitants, respectively), resistance levels were still below 50% [5, 59]. In
France, in the period from 1998 to 1999, antibiotic
utilization was approximately three times higher compared
to Germany (36.5 to 13.6 defined daily doses (DDD) per
1,000 inhabitants per day) [14], as well as the resistance
shown by Streptococcus pneumoniae to penicillin and
erythromycin (Table 1). The high resistance of Streptococcus
pneumoniae in Switzerland despite the relatively modest
consumption of antibiotics (about 9.6 DDD/1,000 inhabitants
per day) was ascribed to the treatment of residents at the
border parts of Switzerland with France, where antibiotics
are more frequently used and more easily purchased [36].
The highest rates of antimicrobial resistance shown by
Streptococcus pneumoniae strains were recorded in the
countries of the Far East for which there are no reliable data
on the extent of antibiotic utilization. In Vietnam, the
observed resistance to tetracyclines and co-trimoxazole
during March and April 1999 was 88% and 32%,
respectively. Antibiotics were purchased over the counter
in pharmacies and given to children without appropriate
medical supervision [42]. In Singapore, during the period
from 1988 to 1995, antibiotics were prescribed empirically
in about 60% of cases. Approximately 51.3% of children
received penicillin, 21.9% macrolides, 7.6% cephalosporin
and 11% two or more antibiotics at the same time. No
penicillin resistance was detected among Streptococcus
pneumoniae isolates in 1988. However, by 1995, penicillin
resistance was found in 17%. Thirty per cent of isolates were
also resistant to erythromycin, and 23% to co-trimoxazole.
A few years later, the resistance to erythromycin and
co-trimoxazole increased to 80% and 72%, respectively [16].

Eur J Pediatr
Table 1 Antibiotic resistance shown by Streptococcus pneumoniae in children from 1984 to 2006
Country

Year and region

Study author and year of


the study

Antibiotic resistance (%)


Penicillin

Erythromycin

Tetracycline

Co-trimoxazole

Sweden

1997

Arri et al. 2006 [5]

4.7

The Netherlands

1998

Arri et al. 2006 [5]

France

1984

Soh et al. 2000 [78]

13

1990

Soh et al. 2000 [78]

48

19951996

Syrogiannopoulos et al. 2000 [82]

5768

1997, 1998

Arri et al. 2006 [5]; Harbarth et al. 2002 [29]

46.253

47

1993

Zbinden 2006 [90]

5.5

1998

Harbarth et al. 2002 [29]

2002

Arri et al. 2006 [5]; Zbinden 2006 [90]

3.5

12.2

1989

Jaecklin et al. 2006 [36]

2004

Jaecklin et al. 2006 [36]

42

47

Italy

19961997

Syrogiannopoulos et al. 2000 [82]

4260

Spain

19921996

Syrogiannopoulos et al. 2000 [82]

2336

1998

Arri et al. 2006 [5]

72

Portugal

20002001

Zbinden 2006 [90]

Turkey

19931996

Sener 1998 [71]

Germany

Switzerland

SaudiArabia
Singapore

43.9

20.7

3.539.9

9.8

28

1999

Al-Tawfiq 2006 [3]

14

33

2004

Al-Tawfiq 2006 [3]

3.4

42

34.6

44

1988

Chiang et al. 2007 [16]

1995

Chiang et al. 2007 [16]

17

30

19971999

Soh et al. 2000 [78]

67.8

87.7

n.d.

Chiang et al. 2007 [16]

80

72
32

0
23

Vietnam

1999

Larsson et al 2000 [42]

88

China

19982000 (Hong Kong)

Chiang et al. 2007 [16]

80

20002002

Yao et al. 2007 [88]

6.4

7090

7090

7090

20002005 (Beijing)

Yu et al. 2008 [89]

25.9

90

94

87b

20052006

Liu et al. 2008 [52]

64.389.6

1997

Lauderdale et al. 2006 [43]

399a

70

2003

Lauderdale et al. 2006 [43]

399a

97

19992004

Lin et al. 2006 [50]

25.550

93

82.2

79.4

19982000

Chiang et al. 2007 [16]

71

20022003

Sunakawa and Farell 2007 [81]

75.2

70

87.6

14.9

Taiwan

Japan
South Korea

19992000

Arri et al. 2006 [5]

Australia

19971999 (Canberra)

Nasrin et al. 2002 [62]

USA

1995

Halstead and Yao 2001 [27]

67

19981999 (South)

Zbinden 2006 [90]

32.5

38.6

19981999 (South-East)

Zbinden 2006 [90]

36.4

40.2

19981999 (North-West)

Zbinden 2006 [90]

17.3

23.3

19992000 (Texas)

Doern et al. 2001 [20]

38.2

49.1

27.3

50.9

19992000 (Washington)

Doern et al. 2001 [20]

35

45

20

40

19992000 (Wisconsin)

Doern et al. 2001 [20]

32.1

34

16.7

41.5

2000 (Jacksonville)

Halstead and Yao 2001 [27]

52

64

n.d. no data
a

Antibiotic resistance depends on the serotype of bacteria

This study also assessed the antibiotic utilization. There was a high correlation between antibiotic use and occurrence of resistant strains of
Streptococcus pneumoniae. The rationalization of antibiotic utilization decreased antibiotic resistance levels

Multiresistant strains of Streptococcus pneumoniae (resistant


to at least three antibiotic classes) were first isolated after 1990.
The treatment of infections caused by multiresistant strains is

longer, more complex and more expensive [12, 34, 36, 43, 74].
Thus, during the 14-month study period in Greece (from 1997
to 1998) in children under 2 years of age, the existence of

Eur J Pediatr

multiresistant strains (23 F, 19 F, 6A and 14) was detected in


31% of isolates. These strains were similar to the ones isolated
in Singapore during the same period [78, 82], suggesting that
in the era of intense migration and exchange of goods, the
bacterial infection spread despite a considerable geographic
distance.
Results indicate that Streptococcus pneumoniae resistance
depends on the age of patients, the sites of isolation and the
conditions (hospital or outpatient). Penicillin-resistant strains
were statistically significantly more often isolated in children
under the age of 5 compared to children 517 years of age
(32.2%:21.0%, p<0.001) [86]. The resistance of Streptococcus pneumoniae to penicillin in children (patients under the
age of 18 years) in outpatient conditions in France was 1.3
times higher than in adults (patients aged over 18 years)
(52.7%:39.8%) [19]. In a pediatric hospital in Saudi Arabia,
the rate of intermediately penicillin-susceptible isolates in
children under 2 years of age was almost two times higher as
compared to children 2 to 17 years of age (41.9%:22.7%, p=
0.02). However, the resistance to tetracyclines was 1.7 times
higher (42.4%:25%, p=0.03), co-trimoxazole 1.6 times higher
(54%:33.8%, p=0.02) and clindamycin almost two times
higher (33%:17%, p=0.04). All isolates were susceptible to
ceftriaxone and vancomycin [3]. According to the results of a
study conducted in children in France, Streptococcus pneumoniae isolated from middle ear was 1.5 times more resistant to
penicillin than blood culture isolates (63.6%:41.8%) [19].
Beta-haemolytic Streptococci
-haemolytic Streptococci often cause an acute bacterial
infection of the upper respiratory tract (usually pharyngitis),
especially in primary care. Penicillin has long been a drug of
choice, while erythromycin was used in cases of hypersensitivity to penicillin. In addition to penicillin and macrolides,
cephalosporins and clindamycin were used to a significant
extent [26, 51]. According to Shulman and Gerber (2004),
there is no justification for the replacement of penicillin-G
with cephalosporins as their efficacy is not higher, but they are
significantly more expensive [75]. Interestingly, within the
past five decades, the sensitivity of beta-haemolytic Streptococci was changed to a lesser extent to penicillin than to
erythromycin [54, 75]. Approximately two decades ago, an
increase of strains resistant to macrolides has been reported in
the USA (in Pittsburgh up to 38%), Finland, Italy, Spain,
Japan and Korea [54]. In Finland, the increasing resistance
of beta-haemolytic Streptococci to erythromycin (from
5% in 1989 to 13% in 1990) was associated with almost
three-fold increase of the extent of its consumption during
the 1980s. In response, the change in policies regarding
outpatient antibiotic therapy was introduced, requiring
reductions in the use of macrolide antibiotics. Decreased

erythromycin use resulted in the reduced beta-haemolytic


Streptococci resistance from 13% in 1990 to 8.6% in 1996
[66, 72]. These data suggest that the control over antibiotic
prescribing patterns could regain the sensitivity of bacteria to
certain antibiotics.
H. influenzae
Besides Streptococcus pneumoniae and -haemolytic
Streptococci, H. influenzae is a common cause of respiratory
bacterial infections in children. Strains producing betalactamase (resistant to amoxicillin and ampicillin) represent
a special problem. These were the most prevalent strains in
the period from 1989 to 2004 in Spain, Greece and France
(2040%); then much less common in Switzerland, Belgium
and UK (1020%) and the least in Sweden, Germany,
Hungary and Russia (010%) [36]. Furthermore, according
to the results of the SENTRY program (The SENTRY
Antimicrobial Surveillance Program), significant regional
differences in H. influenzae susceptibility were found in the
period from 1997 to 1999 [32]. The highest rate of
amoxicillin-resistant strains was observed in the USA
(31.5%) and Canada (27.0%), while a significantly lower
rate was found in Asia (16.2%), Latin America (12.5%) and
Europe (11.8%). In the USA, the resistance of H. influenzae
to co-trimoxazole showed a two-fold increase during a
4-year period (from 9.0% in 1995 to 18.2% in 1999). In
Latin America, for the same period, the resistance to
co-trimoxazole was 30.8%. A very good sensitivity of H.
influenzae was noted to ciprofloxacin and levofloxacin in all
regions included in this study (USA, Canada, Europe, Latin
America and Asia-Pacific) [32].

Intestinal bacterial infections


Diarrhea has a significant place among the causes of
mortality in children as every year worldwide over
600,000 children die from diarrhea or its complications.
Children in Africa and Asia under the age of 5 years are the
most affected. The main reasons for the high incidence of
diarrhea are poor hygiene and living conditions, lack of
sewerage network, dense population, lack of clean running
water, bacteriologically unsafe food and lack of necessary
health care. The most common causes of diarrhea are
strains of Salmonella, Shigella and E. coli [73].
Salmonellae
Salmonellae represent a group of highly adaptable bacteria
that has developed effective survival mechanisms and is
well known for the ability of persistence in the host

Eur J Pediatr

organism. Salmonella enterica, with over 2,500 serovars, is


the most significant Salmonella species. More than 2,000
serovars of Salmonella enterica are zoonotics. They usually
cause diarrheic diseases in animals, while in high-risk
patients (newborns, immunosuppressed individuals
AIDS, etc.), bacteriemia can develop. Salmonella Typhi
and Salmonella Paratyphi are the only serovars for which
humans are the main reservoir [25, 55]. They produce
systemic diseases in humans and may cause serious
complications with fatal outcomes. Salmonella Typhi and
Salmonella Paratyphi infections are most common in Asia,
Africa, India and Latin America (where Salmonellae strains
are endemic). They spread through contaminated food and
water and sometimes through direct contact (faecaloral
route) with infected animals or people [11, 55]. Salmonella
Typhi and Salmonella Paratyphi most commonly cause
gastroenteritis, enteric fever and bacteremia. Infections
manifest with diarrhea, fever and abdominal cramps and
usually resolve within 47 days without the use of
antibiotics [11, 55].
The most sensitive to infection are children in the first
years of life because of the reduced acidity of gastric fluid
and the possibility of infection via contaminated milk. In
diseased young children in developing countries (due to
their poor general physical condition), Salmonellae can
cause septicemia and other serious complications. Individual
susceptibility to infections caused by Salmonella Typhi and
Salmonella Paratyphi increases in patients with the history of
antibiotic use and malnutrition [11]. A study conducted in
Nepal by Maskey et al. during the period JanuaryAugust
2004 included 609 patients of any age suspected to have
enteric fever. Salmonella Typhi and Salmonella Paratyphi
were isolated from blood of 409 and 200 patients,
respectively. There was no difference in clinical manifestations and complication rates between infections caused by
Salmonella Paratyphi and Salmonella Typhi. The authors
emphasize that Salmonella Paratyphi can cause as equally
severe diarrheic disease as Salmonella Typhi, and therefore,
it may become a major world health problem [55].
The most frequently used antibiotics for the treatment
of infections caused by Salmonella enterica serovars
were ampicillin, chloramphenicol and trimethoprim
sulfamethoxazole. Due to irrational use of these antibiotics
over the course of time, they became inefficient. They are
therefore frequently replaced by fluoroquinolones. As a
result, in Tajikistan in 1997, the emergence of Salmonellae
strains resistant to nalidixic acid was noted, and for the
first time, Salmonella Typhi strains resistant to ciprofloxacin
were isolated [60]. In Japan, antibiotic resistance of
Salmonella Typhi to nalidixic acid increased from 10% in
1997 to 31.8% in 1999, while Salmonella Paratyphi showed
an increase from 0% in 1997 to 8.3% in 1999. The strains

with decreased ciprofloxacin susceptibility were uniformly


resistant to nalidixic acid [31].
Salmonella Typhi and Salmonella Paratyphi are nowadays
endemic in several countries in the Indian subcontinent
(South Asia). Thus, in Kathmandu in 2005, resistance to
ciprofloxacin and ofloxacin was reported in 14% of
Salmonella Typhi isolates. Also, an increase of Salmonella
Typhi and Salmonella Paratyphi susceptibility to ampicillin,
chloramphenicol, co-trimoxazole and gentamicin was noted.
This phenomenon was explained by the very low extent of
use of the older antibiotics in the decade preceding the
study [73]. In the study conducted in Nepal in 2004,
Salmonella Typhi and Salmonella Paratyphi were highly
resistant to nalidixic acid (50.5% and 75.3%, respectively).
Antibiotic resistance of Salmonella Paratyphi to ofloxacin
and ciprofloxacin was higher in comparison to Salmonella
Typhi (3.6%:0.5% and 0.5%:0.25%, respectively), but the
general susceptibility to these two antibiotics was still
preserved [55].
Overuse of chloramphenicol, ampicillin and co-trimoxazole
for the treatment of enteric fever contributed to a high number
of multidrug-resistant (MDR) isolates of Salmonella Typhi and
Salmonella Paratyphi in the late 1980s and early 1990s,
particularly in Asia. In recent years, however, there have been
reports of declining resistance levels to these antibiotics. At a
major hospital in Mumbai, India, the share of MDR
Salmonella Typhi and Salmonella Paratyphi isolates declined
from 46% in 2000 to 17% in 2002 [65].
Shigella
Diarrhea caused by Shigella genus is recognized by the
World Health Organization as a major global public health
problem. Infections usually occur during warm summer
months in underdeveloped countries with poor sanitary
conditions, nonfunctional sewerage networks and unsafe
food/drinking water. Shigella is an endemic genus and
frequently causes epidemics in tropical underdeveloped parts
of the world. Shigella bacteria are highly contagious; only 10
to 100 organisms are sufficient to transmit the disease. It is
spread easily from person to person by the feces of infected
people, particularly among those in close contact. The
incubation period is 24 days. Symptoms and signs include
fever, dehydration, high diarrhea frequency (more than 10
times within 24 h) and, in a small percentage of cases,
hemorrhagic stools. The most vulnerable are children 2 to
5 years of age, especially if they are malnourished.
According to available publications, Shigella in children of
up to 5 years of age causes acute diarrhea in 412% of cases
and hemorrhagic diarrhea in 2230% of cases [24].
There are four species of Shigella: Shigella boydii,
Shigella dysenteriae, Shigella flexneri and Shigella sonnei.

Eur J Pediatr

These species are present in several serotypes. The species


with the highest number of identified serotypes is Shigella
flexneri, while for Shigella sonnei only one serotype is
known [40]. The most toxic serotype is Shigella dysenteriae
type 1, which produces Shiga toxin (Stx) that can cause
haemolytic uremic syndrome, one of the most serious
complications of systemic shigellosis [33, 44, 69].
Ashkenazi et al. (2003) emphasize differences in
representation of the individual Shigella species in the
world. Shigella sonnei and Shigella flexneri are the most
frequently isolated species, while Shigella dysenteriae and
Shigella boydii are rarely isolated. Shigella sonnei is most
common in the USA, Europe, Canada and other developed
countries, while Shigella flexneri is dominant in poor and
underdeveloped parts of the world [6, 21, 30, 63, 70, 76,
85]. However, in Bangladesh, large-scale epidemics
with Shigella dysenteriae were observed in approximately
10-year intervals (in 1973, 1984, 1993 and 2002) [61].
Antibiotic treatment shortens the duration of shigellosis
symptoms and prevents further spread of the infection.
Ampicillin, co-trimoxazole, chloramphenicol and tetracycline
were used in the past due to low prices. As a consequence,
Shigella became resistant to these antibiotics. In the period
19941995 in Vietnam, 90% of Shigella spp. was resistant to
co-trimoxazole and 7085% to ampicillin, while 78.6% of
Shigella isolates were MDR [63]. In Chile, during the period
19972001, 51% of Shigella strains were MDR, while the
resistance to new-generation antibiotics (ciprofloxacin,
nalidixic acid and amoxicillin/clavulanic acid) was below
10% [24]. The study conducted in Jakarta (Indonesia) from
February 2005 to September 2007 showed that Shigella
species isolated from 612 children 012 years of age were
highly resistant to ampicillin, co-trimoxazole, tetracycline
and chloramphenicol, while there was no difference in
resistance to nalidixic acid, norfloxacin, ciprofloxacin and
ceftriaxone [30]. Also, a study conducted in the USA from
19992003 showed that Shigella isolates remained susceptible
to ciprofloxacin and ceftriaxone [76]. In Bangladesh, where
periodic epidemic outbreaks occur regularly, the share of
Shigella dysenteriae is as high as 20%, especially in children
living in rural areas. Resistance of Shigella dysenteriae type 1,
the most pathogenic serotype, to nalidixic acid, cotrimoxazole and ampicillin was 100%. On the contrary, all
Shigella species and serotypes showed high sensitivity levels
(0% resistance) to mecillinam and ciprofloxacin [40].
Results of a study conducted in Belgium from 1990 to
2007 showed an increased resistance of Shigella spp. to lowcost and widely used antibiotics (tetracycline, streptomycin,
trimethoprim, sulfonamides and co-trimoxazole), while
susceptibility to ciprofloxacin and gentamicin was fully
preserved. A very important aspect of this study was the
monitoring of MDR isolates, which had increased from
50% in 1990 to 82% in 2007 [85]. Based on the

available data, ampicillin, amoxicillin, chloramphenicol


and gentamicin are not recommended for infections
caused by Shigella species.
E. coli
Strains of E. coli normally colonize gastrointestinal tract in
humans and animals (faecal bacteria). They have a
significant role in digestion and synthesis of certain
vitamins (e.g. vitamin K). However, pathogenic strains that
can cause intestinal (enteritis) and extra-intestinal infections
(mainly urinary tract infections but also eye, ear, wound
infections, etc.) could also be present. Acute and chronic
diarrhea caused by mutiresistant pathogenic strains of E.
coli are a significant problem, especially in developing
countries where E. coli strains are mostly resistant to
WHO's essential antibiotics (ampicillin, co-trimoxazole,
chloramphenicol and tetracycline) [87]. The most common
cause of acute enteritis is enterotoxigenic (ETEC),
enterohemorrhagic (EHEC), enteropathogenic (EPEC) and
enteroaggregative E. coli (EAggEC). In Tanzania, during
the study period (from April to June 1998) in children of up
to 5 years of age, EAggEC, ETEC and EPEC strains showed
resistance to chloramphenicol and other essential antibiotics
(ampicillin, tetracycline and co-trimoxazole) in the ranges
25.057.0% and 68.290.8%, respectively [84]. In countries
where no strict control over medication dispensing is in place,
patients often purchase antibiotics over the counter, even
when antibiotics are not indicated for diarrhea (food poisoning
or viral infection) [14]. In addition, in countries without a
proper medical supervision and without antibiogram results,
new-generation antibiotics (imipenem, fluoroquinolones and
quinolones) are used and often misused. Thus, in Vietnam,
where drugs (including antibiotics) are commercially available
(over the counter) since 1986, pathogenic E. coli strains were
MDR in 89.5% of isolates, while EHEC strain showed
resistance to ampicillin, co-trimoxazole, tetracycline and
chloramphenicol in 100% of cases [63]. In Saudi Arabia,
in children under the age of 3 years during the period from
2001 to 2002, strains of all the four categories of E. coli
showed high-level resistance to ampicillin, trimethoprim
sulphamethoxazole and tetracycline, whereas chloramphenicol
and amoxicillinclavulanic acid showed moderate activity, and
ciprofloxacin, amikacin and gentamicin had excellent activity.
Thus, ampicillin and trimethoprimsulphametoxazolethe
commonly used antibiotics for treatment of diarrhea in
childrenare not suitable as empirical therapy [2].
In order to postpone the emergence of bacterial
resistance to new-generation antibiotics, especially in
developing countries, their rational use is recommended,
as well as continuous surveillance of bacterial sensitivity
and antibiotic utilization (optimal dose and dose interval as
well as a sufficient length of treatment regimen) [63, 73].

Eur J Pediatr

Bacterial urinary tract infections


Bacterial urinary tract infections (UTI) in children are very
common. In the USA, the incidence of UTI for children
younger than 6 years is 37% for girls and 12% for boys
of the same age [18]. In pediatric population, pathogenic
strains of E. coli are among the most common cause of UTI
in hospital and outpatient settings. If UTI is quickly
diagnosed and treated by appropriate antibiotics, it is thought
that vesicoureteral reflux (VUR) (which usually occurs in
3040% of children with UTI) and severe complications of
UTI (kidney damage) can be prevented [18].
The study of Conway et al. (2007) which included 666
children under 6 years of age, with a confirmed first UTI,
hospitalized at least twice during the period from July 1,
2001 to May 31, 2006 in one of the three US states
(Delaware, New Jersey and Pennsylvania) showed that the
risk of developing resistant strains of E. coli was 7.5 times
higher in children who received antibiotic prophylaxis
(95% confidence interval, 1.6035.17), while the risk of
recurrent UTI was not significantly reduced [18].
Infants and young children with UTI and fever are at
highest risk of incurring renal damage. The American
Academy of Pediatrics Guidelines from 2011 recommend
that in febrile infants and children 224 months of age, who
had been diagnosed with a UTI, antibiotics should be
administered 7 to 14 days. However, prophylactic use of
antibiotics for prevention of UTI recurrences is not
recommended. UTI is diagnosed if a urinalysis and a urine
culture are positive, while only positive urine culture may
indicate asymptomatic bacteriuria. Recent literature and
meta-analyses on the effectiveness of antimicrobial prophylaxis in the prevention of recurrent UTI revealed no
significant reduction in symptomatic UTI, regardless of
whether VUR was present [22, 80].
The results of the study of antibiotic resistance of E. coli
urinary tract isolates in pediatric patients hospitalized at the
Institute for Child and Youth Health Care of Vojvodina in
Novi Sad, Serbia, showed that E. coli was more frequently
isolated from female urine samples (FUS) compared to
male urine samples (MUS) (78.9%:60.7%). However,
strains isolated from MUS were significantly more resistant
(p<0.001) to parenteral cephalosporins (66.7%:20.3%)
(n = 80), oral cephalosporins (73.2%:32.8%) (n = 250),
aminoglycosides (55.0%:13.9%) (n=162) and folate pathway
inhibitors (82.6%:37.5%) (n=87). Moreover, E. coli strains
isolated from MUS showed significantly higher level of
MDR compared to strains isolated from FUS (82.6%:40.3%)
[37, 38].
The surveillance of resistance and MDR patterns of
E. coli is especially important for the empirical utilization
of antibiotics. Thus, effectiveness of ampicillin and
co-trimoxazole in Switzerland during two decades was

considerably reduced, while effectiveness of the second- and


third-generation cephalosporins remained at a satisfactory
level [23]. A study conducted in the USA in 2008 by Lutter
and associates showed that in children, the empirical
antibiotic treatment of urinary tract infections (UTI) caused
by resistant bacterial strains was risky due to the development
of complications. The sensitivity of E. coli to third generation
of cephalosporins (which are often administered empirically)
was low, while the sensitivity to nitrofurantoin (which is used
less often) was over 90%. Sensitivity to aminoglycosides was
over 99% in children who did not receive antibiotics for the
prophylaxis of UTI, while it was slightly lower (to the same
class of antibiotics) in children who received antibiotic
prophylaxis (95%) [53].
Based on the previously presented data, antibiotic resistance
depends on the tested antibiotic, isolate type, geographic
region, patient age, previous antibiotic treatment, etc. In
general, all bacterial species had shown a wide range of
resistance levels, which have a potential to increase over time.

Factors contributing to bacterial resistance


and measures for its containment
One of the biggest problems that health care is facing,
especially in underdeveloped and developing countries, is
the rapid increase of resistant and multiresistant bacterial
strains. The factors contributing to the development of
bacterial resistance are poor sanitary conditions, global travels
of inhabitants and irrational use of antibiotics. Even in
countries with high bacterial resistance, antibiotic prescribing
and dispensing are (usually) regulated by appropriate
legal means. However, antibiotic utilization in health
care, agriculture and farming is usually not appropriately
controlled, epidemiological studies are not conducted, and
there is no continual education of primary care physicians,
pharmacists and veterinarians as well as parents and patients
[17, 79].
The presence of antibiotics in food contributes to an
increase in bacterial resistance. Fertilization of fields with
farm waste from animals treated with antibiotics is a major
environmental problem as the antibiotic residues remain on
plants and can be re-absorbed by humans or animals. In
China, the use of antibiotics in poultry farming contributed
to the development of resistance to tetracycline and cotrimoxazole in patients. As these antibiotics have not been
used for almost 10 years in hospital settings, the emergence
of resistance is associated with the consumption of poultry
from chickens treated with antibiotics [1, 9, 47, 89].
In Europe, the lowest levels of antibiotic resistance are
registered in Scandinavian countries, Germany, Great
Britain and The Netherlands, where a very strict law on
antibiotic prescribing and utilization is enforced in medicine

Eur J Pediatr

and agriculture. In these countries, data on the extent of use


and type of prescribed antibiotics, as well as the information
on bacterial resistance levels, are continuously collected and
analyzed. The data are also published in journals (professional
and research) and presented to doctors in primary health care
[8, 36, 41]. In Sweden, for example, a strategic program for
the rational use of antibiotics reduced antibiotic utilization
from 15.7 DDD/1,000 inhabitants per day in 1995 to 12.6
DDD/1,000 inhabitants per day in 2004. Furthermore,
antibiotic utilization was decreased in children from 5 to 14
and from 0 to 4 years of age by 52% and 37%, respectively.
However, despite of this significant reduction in antibiotic
consumption, it takes a long period of time to reduce
resistance of bacteria (Streptococcus pneumoniae, Staphylococcus aureus, H. influenzae, E. coli, etc.) [58].
The monitoring of the resistance of Streptococcus
pneumoniae strains that colonize nasopharynx in young
children showed to be very useful due to the existence of
regional differences in bacterial susceptibility. In Romania,
in children of up to 2 years of age, resistant strains of
Streptococcus pneumoniae were isolated from nasal and
throat swabs in 59% of cases, while in Sweden, this was the
case in only 6% of preschool children [45, 58]. Resistance

levels shown by colonized bacteria were higher in children


who received an antibiotic (usually, this was one of the
beta-lactams) in the preceding 3 months. According to the
model developed by Nasrin and his associates for the
probability assessment of occurrence of bacterial resistance
in children, the likelihood for isolation of penicillinresistant pneumococci increases by 4% for each day of
therapy with beta-lactam antibiotics during the preceding
6 months [62].
A very good experience in prevention and reduction of
nose and throat colonization with Streptococcus pneumoniae
has been achieved in children by the use of vaccines
(a four-dose seven-valent pneumococcal conjugate vaccine
containing commonly isolated invasive strains) [88]. The
vaccine is particularly effective in children under the age of
2 years. Vaccination of children decreased for 80% the
occurrence of invasive disease caused by serotypes contained
in the vaccine and contributed significantly to reduction of
antibiotic resistance. However, in vaccinated children, a 33%
increase in nasopharyngeal colonization with serotypes of
Streptococcus pneumoniae not contained in the vaccine was
observed [39]. Table 2 lists the factors contributing to the
development of resistance and gives an overview of previous

Table 2 Factors contributing to the development of antibiotic resistance and strategies to control its advancement
Factors contributing to AB resistance

Strategies to control AB resistance

Administration of ABa when not indicated (e.g. in viral infections)


Inaccurate diagnosis, lack of knowledge regarding diseases and
antibiotics (pharmacodynamics, pharmacokinetics, interactions
and side effects). Insufficient monitoring of the patient
Dispensing over the counter especially in developing countries
Empirical administration of AB

Prescribe AB only in bacterial infections [7, 56, 64]


Administration of AB in the optimal dose and dosing interval,
over a sufficiently long period of time [67]

Prophylactic administration of AB

Use of most effective AB, a drug of first choice

Prolonged hospitalization of patients in inpatient settings.


Collective accommodation
Application of AB in farming, agriculture and food industry
Health workers' insufficient knowledge. Ignorance of the problem
of bacterial resistance
Inadequate attention to the problem of antibiotic resistance by
federal and professional associations
Administration of combined antibiotic therapy, as well as broad
spectrum AB, when not indicated. Inappropriate utilization of
microbiological data
Wide use of available AB
a

Antibiotic

Ban a sale of AB without prescription [39, 42]


Empirical administration of AB in emergency cases of severe
bacterial infections. AB prescribing based on biograms and
antibiograms (whenever possible) [41, 66]
Basic hygiene measures (washing hands, fruits and vegetables
and boiling of well or spring water). Vaccination [8, 12, 23,
36, 45, 73, 74]
Use of reserve AB (ureidopenicillins, the latest generation of
cephalosporins, amikacin, vancomycin, etc.) only in severe
bacterial infections [87]
Shortening of hospitalization duration. Avoiding hospitalization
in large groups. Keeping sick children at home. Sick individuals
should not go to work [12, 45]
Control and surveillance of AB utilization in agriculture,
veterinary practice and food industry [8, 47]
Continual education of health workers and patients. Publishing
of results in scientific and professional magazines [10, 28]
Regional surveillance of resistance to AB and reporting of
resistance development to international associations [6, 12, 32]
Combined AB therapy for treatment of infections caused by
bacterial species highly prone to resistance development
(e.g. Mycobacterium tuberculosis) [67]
Development of new AB [15]

Eur J Pediatr

experiences that have proved to be effective in tackling


this problem.

Conclusion
The most important socio-economic factors leading to the
development of antibiotic resistance are irrational and
uncontrolled use of antibiotics in medicine, veterinary
medicine and agriculture; poor sanitary conditions in certain
parts of the world and global migration of people and goods.
Antibiotic resistance needs to be addressed by each country,
depending on its specific issues and requirements. It is
mandatory to have clearly defined regulations on prescribing,
dispensing and using antibiotics in human and veterinary
medicine as well as in agriculture. In addition, it is necessary to
have a control over the implementation of regulations and to
sanction the violations. Education of physicians, pharmacists
and the general community is also an important component.
Patients need to understand that their adherence to therapeutic
regimen is of crucial importance not only to the effectiveness of
therapy but also to reducing bacterial resistance. Developed
countries already managed to reduce problem of antibiotic
resistance with antibiotic surveillance and by implementation
of a strict control over antibiotic utilization. However, as
antibiotic resistance is a global problem, in order to be solved, it
requires a joint effort of the whole international community.
Acknowledgements Katarina Ilis and Vesna kodri-Trifunovis
work is supported by the Ministry of Education and Science, Republic
of Serbia, Project No. 175064 and 175046, respectively, 2011-2014.
Conflicts of interest None.

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