Journal of Antimicrobial Chemotherapy (1999) 44, 709-715 © 1999 The British Society for Antimicrobial
Chemotherapy
Antimicrobial practice
Sequential antimicrobial therapy: treatment of severe
lower respiratory tract infections in children
Fahad A. Al-Eidana, James C. McElnaya,*, M. G. Scottb, M. P. Kearneyc, K. E. U.
Troughtond and J. Jenkinsd
a
Pharmacy Practice Research Group, School of Pharmacy, The Queen's University of
Belfast, 97 Lisburn Road, Belfast BT9 7BL; b Antrim Hospital Academic Pharmacy
Practice Unit, Antrim Area Hospital, Bush Road, Antrim BT41 2RL; c Department of
Microbiology, United Hospital Group Trust, Bush Road, Antrim BT41 2RL d Paediatric
Department, United Hospital Group Trust, Bush Road, Antrim BT41 2RL, N. Ireland
Abstract
Although there have been a number of studies in adults, to date there has been little
research into sequential antimicrobial therapy (SAT) in paediatric populations. The
present study evaluates the impact of a SAT protocol for the treatment of severe lower
respiratory tract infection in paediatric patients. The study involved 89 paediatric patients
(44 control and 45 SAT). The SAT patients had a shorter length of hospital stay (4.0
versus 8.3 days), shorter duration of inpatient antimicrobial therapy (4.0 versus 7.9 days)
with the period of iv therapy being reduced from a mean of 5.6 to 1.7 days. The total
healthcare costs were reduced by 52%. The resolution of severe lower respiratory tract
infection with a short course of iv antimicrobials, followed by conversion to oral therapy
yielded clinical outcomes comparable to those achieved using longer term iv therapy.
SAT proved to be an important cost-minimizing tool for realizing substantial healthcare
costs savings.
Introduction
Severe lower respiratory tract infections, such as community-acquired pneumonia, are a
common reason for hospitalization of children. Intravenous administration of
antimicrobials is usually used to help ensure that high serum and tissue antimicrobial
concentrations are achieved rapidly. It is the route of choice in acutely ill children with
lower respiratory tract infection and is essential for children unable to tolerate oral
medication. In today's era of cost-containment, it has become common practice to
streamline the empirical regimen to a more cost-effective one, when the patient's clinical
condition has been identified. Sequential (i.e. iv followed by oral administration)
antimicrobial therapy (SAT) is a cost-minimization strategy in reducing healthcare costs
while maintaining patient care.
1
The concept that a full course of iv antimicrobial therapy is needed to treat hospitalized
patients with infectious diseases is no longer valid. It has been suggested that iv
antimicrobials can often be discontinued when patients show clinical improvement with
initial therapy.1 An important factor in determining the length of hospital stay in patients
with lower respiratory tract infection is the duration of iv therapy. Unnecessarily
prolonged iv administration of antimicrobials leads to increased costs associated with iv
drug acquisition costs, labour, iv fluids and with the associated expenses of
administration apparatus. In addition, iv therapy can lead to increased morbidity,
particularly thrombophlebitis and exposure to nosocomial pathogens, 2,3,4 both of which
can also prolong the length of hospital stay.
Although some clinicians are hesitant to initiate an early transition to oral antimicrobial
therapy, even in patients who are demonstrating signs of improvement, there is increasing
evidence to support the early use of oral agents in the treatment of several infections.
Several studies have assessed the efficacy of oral antimicrobial therapy in various
infections including respiratory tract, skin and soft tissue, and bone and joint infections.
These have provided considerable evidence to suggest that the use of oral agents is both
safe and cost-effective. Louie5 has reviewed a number of clinical trials comparing iv with
oral therapy. With the exception of patients with infections in areas into which
antimicrobial penetration is poor (e.g. meningitis and infective endocarditis), the majority
of hospitalized patients do not require prolonged courses of iv therapy.
The aim of the study was to examine the impact of the introduction of a SAT prescribing
protocol on the clinical and economic outcomes of hospitalized children with severe
lower respiratory tract infection.
Materials and methods
Study site
The study was carried out in the paediatric wards of Antrim Area Hospital, a 378-bed
teaching hospital.
Baseline data collection
Data were collected on a standard custom-designed form to record the patient history,
physical examination, treatment and laboratory data. Data collection was divided into two
phases, baseline data and intervention data (SAT). Baseline data were collected
retrospectively before the implementation of the SAT protocol to assess current practice
and for comparative purposes, covering the period from December 1994 to February
1995.
Introduction of SAT
A major aim of the introduction of SAT was to minimize the duration of hospital stay for
acute illness in children. It was agreed by the paediatric wards' team that any paediatric
2
patient with a severe lower respiratory tract infection, diagnosed on clinical grounds, with
or without radiological changes, should be included in the study. The team also agreed
the following as part of the SAT programme:
(a) Empirical antimicrobial treatment
(i)
Intravenous cefotaxime or co-amoxiclav.
(ii)
Oral cefixime or co-amoxiclav to be prescribed following the empirical iv
treatment as soon as the patient is clinically stable.
(iii)
Azithromycin should also be used when atypical infection is considered
likely.
(b) SAT criteria
As soon as the following criteria are met, the patient should be switched from iv to oral
therapy:
Cough, sputum and respiratory distress are improving
Patient is a febrile
WBC count and/or C-reactive protein is/are decreasing Patient tolerating oral
preparation
(c) Protocol implementation
Before the implementation of the protocol, three techniques were employed to promote its
use:
(i)
Presentation to the medical staff: this brief dialogue described the aims of
the protocol and highlighted the potential cost saving.
(ii)
Distribution of the SAT protocol to the medical staff.
(iii)
Preparation of an algorithm (Figure) and display of this on each paediatric
ward.
3
Figure. Algorithm for SAT protocol.
View larger version (31K):
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Prospective data collection was initiated concurrently with implementation of the SAT
protocol, covering the period from December 1995 to February 1996.
Patient inclusion criteria
All patients admitted to the paediatric wards of the Antrim Area Hospital, during the
period from December 1994 to February 1995 (control group) and the period from
December 1995 to February 1996 (SAT group) and diagnosed with severe lower
respiratory tract infection were included in the study. A lower respiratory tract infection
was defined as an acute infection of the lower respiratory tract (or bronchial tree)
resulting in acute bronchitis or pneumonia. All patients were adjudged to have severe
illness by the clinician responsible on the basis of clinical and chest X-ray features.
The following definitions were used in assessing therapeutic outcome:
(i)
Treatment success—major improvement or complete resolution of all signs and
symptoms.
(ii)
Treatment failure—persistence or progression of signs and symptoms;
development of new clinical findings consistent with active infection or death
from primary diagnosis; presence of adverse reaction to the prescribed medication
leading to its discontinuation.
Pharmacoeconomic analysis
The economic analysis was limited to three main healthcare costs i.e. total antimicrobial
costs (antimicrobial acquisition costs and hidden costs, including cost of consumable
materials, staff time and waste disposal); diagnostic test costs and hospital bed costs.
4
Patient follow-up
All parents of SAT-treated patients were given a letter regarding their child's clinical
progress after discharge. Within 4–6 weeks after the discharge, patients' parents were
contacted by telephone and asked whether there had been a return of symptoms of the
infection.
Statistical analysis
Data were entered on to a desktop computer using Paradox (version 3.5; Corel
Corporation Ltd., Dublin, Republic of Ireland) software and analysed using SPSS
(version 7) software. Differences in variables between patient groups, i.e. baseline and
protocol groups, were analysed using the chi-squared test and Fisher's exact test for
categorical variables as appropriate. Student's t-test was used for continuous variables. A
logarithmic transformation to base 10 was performed to normalize some outcome
measures' data (length of hospital stay, duration of iv administration, duration of oral
treatment, duration of treatment in hospital and elements of healthcare cost) and to
calculate confidence intervals for the mean data.6 Results were reported as statistically
significant at P< 0.05.
Results
Patient characteristics
From December 1995 through to February 1996, 45 patients were recruited for the SAT
group while 44 patients admitted from December 1994 to February 1995 formed the
control group.
No patient was excluded because of non-functioning of their gastrointestinal tract or
inability to tolerate oral therapy. Also no patient was found to be hypersensitive to
penicillin or cephalosporin at the time of entry into the study. Characteristics of patients
entering the SAT and control groups were as follows: the mean age ± S.D.) of the SAT
group was 3.3 years ± 1.4), ranging from 1 to 6.5 years compared with 3.2 ± 1.9), ranging
from 10 months to 7.5 years in the control group (P = 0.809). Twenty-two (48.0%)
patients were male in the SAT group compared with 21 (47.7%) patients in the control
group (P = 0.920). The mean duration of symptoms ± S.D.) before hospital treatment
commencement was 4.7 days ± 1.3) for the SAT group compared with 4.8 >± 1.1) for the
control group (P= 0.674).
There were also no statistically significant differences between the two groups at baseline
in the following variables: mean temperature at the time of hospital admission (P=
0.119); the number of patients with fever (P= 1.00); blood urea (P= 0.452); serum
creatinine (P= 0.198); WBC (P= 0.979). By the second day of iv therapy in both groups,
95% or more of patients had normal body temperatures. The mean ± S.D.) time to
resolution of fever was 1.7 days ± 0.8) ranging from 1 to 3 days in the SAT group
compared with 1.6 days ± 0.9) ranging from 1 to 4 days in the control group (P= 0.79).
5
Clinical outcome measures
The rates of therapeutic response were identical in both study groups, with no patient
failing to respond to therapy. All SAT-treated patients were assessed 4–6 weeks after
discharge and no return of the signs and symptoms of the infection or re-admission had
occurred. No adverse effects, severe enough to lead to discontinuation of antimicrobial
therapy including rash, nausea, vomiting or diarrhoea, occurred in either arm of the study.
Summary outcome measures are presented in the Table. There were statistical differences
as follows: decreased length of hospital stay, decreased duration of iv antimicrobial
therapy, decreased duration of total antimicrobial therapy and decreased total healthcare
costs for the SAT group. The mean decrease in hospital stay amounted to 4.3 days.
View this table: Table. Comparisons of outcome measures between the control
[in this window] and SAT groups
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In the initial phase of antimicrobial therapy, all patients in both SAT and control groups
were treated with iv therapy. Thirty-four (75.5%) patients were administered one agent
and 11 (24.5%) patients received two agents in the SAT group; while 23 (52%) patients
were given one agent, 19 (43%) patients received two agents and two patients were
treated with three agents in the control group (P= 0.044).
Antimicrobial therapy used included cefotaxime in 34 (75.5%) patients and co-amoxiclav
in 11 (24.5%) patients while flucloxacillin was also included in 11 (24.5%) patients
treated with cefotaxime in the SAT group. The antimicrobial agents used in the control
group were cefotaxime in 24 patients, ceftriaxone in seven, co-amoxiclav in 10,
ampicillin in one, penicillin G in one, flucloxacillin in 20 and cefuroxime in four patients.
The antimicrobial agents that were used following the iv therapy in the SAT group were
cefixime in 34 (75.5%) patients and co-amoxiclav in 11 (24.5%) patients, as
recommended by the SAT protocol; while in the control group the corresponding agents
were co-amoxiclav in eight patients, cefuroxime in three, azithromycin in three,
cephradine in four and ampicillin in one patient.
Because SAT and conventional (control) therapy demonstrated equal clinical
effectiveness, a cost-minimization analysis was used to calculate the saving associated
with the implementation of the SAT protocol.
(i)
Antimicrobial cost
6
Costs related to antimicrobial acquisition costs and hidden costs while patients were
hospitalized were calculated, for both SAT and control groups, based on the actual prices
to the Department of Pharmacy (1995/96 contract prices). The geometric mean ± 95% CI)
antimicrobial acquisition cost was £10.3 ± 2.0) ranging from £6.9 to £19.0, and the
related hidden costs were £6.7 ± 0.6) ranging from £4.0 to £11.8 for the SAT group.
Equivalent costs in the control group were £26.0 >± 2.1) ranging from £9 to £95, and
£17.4 ± 1.9) ranging from £8.5 to £38 for the control group, respectively. These
differences were statistically significant (P < 0.001).
The geometric mean ± 95% confidence intervals) total antimicrobial cost (antimicrobial
acquisition plus hidden costs) was £17.0 ± 3.1) ranging from £12.3 to £30.4 for the SAT
group compared with £43.4 ± 5.5) ranging from £17.5 to £129.0 for the control group (P<
0.001).
(ii)
Laboratory tests costs
Costs related to the laboratory tests performed for individual patients during the
hospitalization were calculated, based on individual laboratory costs from the individual
hospital departments, in both SAT and control groups. The geometric mean ± 95% CI)
costs of haematology, microbiology and radiology tests performed were, respectively,
£4.7 ± 0.4) ranging from £4.4 to £8.4; £17.2 ± 1.4) ranging from £10.6 to £32.0; and
£16.2 ± 0.0) in the SAT group. The corresponding data for the control group were £5.5 ±
0.6) ranging from £4.4 to £8.8; £23.6 ± 1.7) ranging from £20.6 to £32.8; and £18.7 ± 2.0)
ranging from £16.2 to £32.4. There were statistically significant differences in tests costs
for haematology (P= 0.012), microbiology (P< 0.001) and radiology (P= 0.001). The
geometric mean ± 95% CI) costs of biochemistry tests performed was £6.9 ± 1.3) ranging
from £3.4 to £13.5 in the SAT group compared with £5.8 ± 1.5) ranging from £3.4 to
£13.5 in the control group. This difference did not reach statistical significance (P=
0.242). The geometric mean ± 95% CI) costs for all laboratory tests performed was £45.0
± 3.1) ranging from £34.6 to £66.1 in the SAT group compared with £53.6 ± 2.9) ranging
from £44.6 to £70.9 in the control group. This difference was found to be statistically
significant (P< 0.001).
(iii)
Hospital bed costs
Costs related to hospital bed occupancy were calculated based on the daily cost to Antrim
Area Hospital for a patient admitted to the medical paediatric service (March 1996
prices). The geometric mean (± 95% CI) hospital bed cost based on the length of hospital
stay was £1105 (± 95) ranging from £285 to £2850 for the SAT group, compared with
£2366 (± 200) ranging from £1425 to £4560 for the control group. This difference was
statistically significant (P< 0.001).
(iv)
Overall healthcare cost
Mean data have already been presented in the Table. The approximate mean potential
savings per patient using the SAT protocol are as follows: antimicrobial costs £26.4;
laboratory costs £8.6; hospital bed costs £1261.0, giving an overall saving of £1296
7
(52%). Using these data the estimated saving for the 45 patients who entered the SAT
protocol was in excess of £58,000.
Discussion
Patient characteristics
The patient characteristics in the control (retrospective) and SAT (prospective) groups
were almost identical. In the control group, several different oral antimicrobial agents
were selected by the physicians when therapy was changed from iv to oral, including coamoxiclav, cefuroxime, azithromycin, cephradine and ampicillin. In the SAT group,
according to the agreed protocol, all patients were switched to either cefixime (75.5%) or
co-amoxiclav (24.5%) before being discharged to complete the remainder of their oral
course at home.
Bacterial pneumonia is more common in patients aged 6 months to 5 years,7,8 the range
within which >95% of the patients in this study lay. In addition, despite the introduction
of immunization, Haemophilus influenzae infections are more common in this patient
population and as this organism is now more frequently resistant to ampicillin,9 cefixime
and co-amoxiclav were considered to be appropriate therapy because of their ß-lactamase
stability.9,10 In addition cefixime is given od which is a significant benefit to children. It
may be the case, however, that cefixime may not be an optimal compound for treatment
of lower respiratory tract infections in the future for two reasons: (i) its intestinal
absorption is saturable (therefore it is not possible to increase the dose with the hope of
increasing blood levels); and (ii) the increasing resistance of Streptococcus pneumoniae.
Only a small percentage of paediatric pneumonia is bacteraemic, and antigen detection is
not particularly useful in this context.11,12 These data are in agreement with our findings
of only 9% (eight patients) with positive blood cultures. S. pneumoniae and H. influenzae
were the two pathogens isolated in our study.
Clinical outcome measures
Clinical protocols and guidelines have been developed to assist the physician with the
decision of when to hospitalize patients with lower respiratory tract infections. 13 Once
the patient is hospitalized, other important medical decisions must be made with regard to
the duration of treatment with iv antimicrobials and the duration of hospitalization. Many
investigators have suggested a 48 h period to be the preferred timing for converting from
iv to oral treatment.14,15
In this study, defined criteria16,17 ,18,19 (Figure) were used to determine when an adequate
course of iv antimicrobial therapy had been delivered and when the patient was ready to
be switched to an oral antimicrobial. The 45 patients were treated for a mean (geometric)
of only 1.7 days of iv antimicrobial therapy. Patients were changed to oral therapy as
soon as their signs and symptoms improved and they became afebrile (since laboratory
tests were generally done on the admission day only). By the second day of iv therapy,
8
95% of the SAT patients had returned to normal temperatures. Signs and symptoms were
favourable in all patients, indicating that the duration of treatment with the iv
antimicrobial was adequate. This study shows that the resolution of pneumonia, with a
short course of iv antimicrobials and a switch to oral therapy, is comparable to the results
achieved in the control group using longer courses of iv therapy. The data therefore
support the findings of others.7,8,20,21 This study also demonstrates a significant decrease
in the length of hospital stay associated with the use of oral medication following an iv
regimen (geometric mean of 4.0 days in SAT versus 8.3 days in control group; P< 0.001).
Other authors have obtained similar results.8,22,23,24,25In a paediatric pneumonia study
involving 78 children, Shalit and his colleagues7 used WBC count and temperature,
together with chest radiographic findings, as clinical markers. They found that these
parameters supported the change to oral antimicrobial therapy at approximately 48 h
coupled with early discharge from hospital. Reduced length of hospital stay is of benefit
to both the hospital and patient, as the longer the patient remains hospitalized, the greater
is the risk of iatrogenic events or other medical complications.26,27,28 In addition
hospitalization can be a traumatic experience for both the child and the family, and
consequently early discharge is desirable.
The clinical success rates observed in the SAT and control groups were identical. Relapse
or failure has been found to be uncommon in patients receiving sequential antimicrobial
therapy.29 In this study no treatment failures occurred; furthermore no relapses occurred
during the 6-week follow-up period in children from the SAT group.
Pharmacoeconomic analysis
The calculated saving per patient in this controlled study was approximately £1200.
Similar savings per patient have been reported by others.14,30,31 The calculated healthcare
costs for treating lower respiratory tract infection in the hospital were 52% less after
introduction of the SAT protocol. Early conversion to oral antimicrobials has been shown
by others to lead to decreased treatment costs of between 45 and 57%.32,33
From the results of the present investigation it can be concluded that the resolution of
lower respiratory tract infection in children with a short course of iv antimicrobials,
followed by conversion to oral therapy, yields clinical outcomes comparable to those
achieved using longer term iv therapy. Furthermore, SAT is an important costminimization tool for realizing substantial healthcare cost savings associated with the
treatment of paediatric patients hospitalized with severe respiratory tract infections.
Notes
*
Corresponding author. Tel:+44-1232-335-800; Fax:+44-1232-247-947.
References
9
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11
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Received 13 November 1998; returned 1 March 1999; revised 14 May 1999; accepted 25 June 1999
12
Table. Comparisons of outcome measures between the control and SAT groups
Protocol
(geometric
mean)
Ratio
control/
protocol
95% CIa
of
the
ratio
Pvalue
Length of hospital
stay (days)
8.3
4.0
2.1
(1.8–
2.5)
<0.001b
95% CI
(3.5–4.6)
3.3
(2.8–
3.9)
<0.001b
0.9
(0.7–
1.2)
<0.597b
1.9
(1.6–
2.3)
<0.001b
2.1
(1.8–
2.5)
<0.001b
Outcome measures
Control
(geometric
mean)
(7.7–9.0)
IV
antimicrobial
therapy (days)
5.6
1.7
95% CI
(1.5–1.9)
(5.1–6.2)
Oral antimicrobial
therapy (days)
2.0
2.2
95% CI
(1.7–2.5)
(1.8–2.6)
7.9
4.0
(7.2–8.7)
(3.5–4.6)
Duration
antimicrobial
therapy (days)
95% CI
of
Total
healthcarec
costs (£)
2463
1167
95% CI
(1007–1370)
a
(2271–2707)
CI, confidence interval.
b
Student's t-test.
c
Healthcare cost, summation of antimicrobial acquisition costs, hidden costs
(associated with drug administration), laboratory test costs and bed costs.
13
14