Introduction
Chronic obstructive pulmonary disease (COPD) is a
chronic respiratory disease. The incidence of the disease is on the
increase annually. The disease is characterized by limitations in
airflow, incomplete reversibility, and is rapidly progressive. It
is the leading cause of respiratory failure. COPD is caused and
aggravated by bacterial pneumonia, especially severe pneumonia
(1). With the increasing age of the
population in China, COPD with severe pneumonia has become an
important cause of mortality (2).
The associated clinical symptoms include septic shock and multiple
organ dysfunction.
The rational use of antibiotics is key to treatment,
and is important for inhibiting bacterial reproduction and
controlling progression of the disease. However, antibiotics are
also the main cause of bacterial resistance and corresponding
decrease in effectiveness of treatment (3). Mutations in bacterial genes are an
important cause of bacterial resistance (4). According to statistics (5) on COPD with pneumonia, after 10–14 days
of antibiotics application, the rate of relief of clinical symptoms
was 50–75%, and the rate of bacterial resistance was 5–10%.
Although antimicrobial susceptibility tests can help select
sensitive antibiotics, long training cycles and hysteresis of
clinical application limit the application value. Based on this,
the antibiotic de-escalation principle emphasizes early coverage of
the bacterial spectrum, adequate sterilization, timely sensitivity
enhancement, and reduction in resistance, which significantly
improves the treatment efficiency and shortens the treatment course
(6,7).
The present study followed the antibiotic
de-escalation principle to treat elderly patients with COPD
complicated with severe pneumonia, to provide a reference for the
rational use of antibiotics in clinic.
Patients and methods
Patients
A total of 86 elderly patients who were hospitalized
and diagnosed with COPD combined with severe pneumonia from
January, 2015 to January, 2016 were consecutively selected. The
inclusion criteria were: i) Conforming to the diagnostic criteria
of COPD and severe pneumonia, ii) able to provide samples of sputum
and blood for bacterial culture, iii) sensitive to currently
available antibiotics, and iv) achieved effective clinical
treatment. The exclusion criteria included: i) Respiratory failure,
consciousness disorder, severe disease condition, and expected
survival time of <1 month, ii) combined with other lung
diseases, such as bronchiectasis, lung cancer, and tuberculosis,
iii) underlying diseases such as heart, brain, liver, kidney, and
other organ dysfunctions and iv) allergic to antibiotics.
The present study obtained approval of the Ethics
Committee of The Affiliated Hospital of Qingdao University
(Shandong, China) and informed consent of patients and their
families. According to the parity method of hospitalization number,
patients were divided into control and observation groups, with 43
cases each. Baseline parameters of patients in the two groups were
comparable (Table I).
 | Table I.Baseline parameters of patients in the
two groups. |
Table I.
Baseline parameters of patients in the
two groups.
| Group | No. of cases | M/F | Age, years | Course of disease,
year | Smoking | Hypertension | Diabetes | Mild COPD | Moderate | Severe | PRSP | Klebsiella
pneumoniae |
Staphylococcus | Other |
|---|
| Control | 43 | 23/20 | 72.6±10.3 | 5.2±2.4 | 10 (23.3) | 12 (27.9) | 8 (18.6) | 8 (18.6) | 29 (67.4) | 6 (14.0) | 20 (46.5) | 10 (23.3) | 10 (23.3) | 3 (7.0) |
| Observation | 43 | 24/19 | 73.2±14.5 | 5.3±2.3 | 12 (27.9) | 11 (25.6) | 9 (20.9) | 6 (14.0) | 30 (69.8) | 7 (16.3) | 18 (41.9) | 12 (27.9) | 11 (25.6) | 2 (4.7) |
| t/χ2 |
| 0.047 | 0.126 | 0.251 | 0.244 | 0.059 | 0.073 |
| 0.380 |
|
| 0.536 |
|
| P-value |
| 0.829 | 0.724 | 0.628 | 0.621 | 0.808 | 0.787 |
| 0.827 |
|
| 0.911 |
|
Research methods
Patients in the two groups underwent routine
examinations, including liver and renal functional tests, routine
blood tests, blood gas analysis, and antibiotic sensitivity tests.
The medical history and history of use of antibiotics were noted
and the conditions of patients were comprehensively assessed. The
patients received targeted treatment according to the results of
assessment. Based on empirical application of antibiotics, patients
in the control group were treated with levofloxacin and
cephalosporin. Patients in this group received 200 mg levofloxacin
two times per day, and 2 g cefoperazone sulbactam three times per
day. Three days later, if treatment was effective, the treatment
regimen continued. If the effect was poor, the regimen was adjusted
and the next round of medication was chosen. Antibiotics active
against Gram-positive (G+) and Gram-negative (G-) bacteria, such as
third or fourth generation cephalosporin antibiotics combined with
aminoglycoside, or macrolide antibiotics were chosen. After 3–7
days the effect of treatment was re-evaluated. If effective, the
original regimen was continued, and if the effect was poor, the
regimen was adjusted. Broad-spectrum antibiotics such as imipenem
were chosen, or bacterial cultures and drug sensitivity tests were
performed to adjust the treatment regimen.
Patients in the observation group were treated
according to the principle of antibiotic de-escalation therapy.
Antibiotics active against G+ and G- bacteria such as piperacillin,
ceftriaxone sodium, and ciprofloxacin were chosen as the first
round of medication. For inefficient cases, 3 days later,
broad-spectrum antibiotics, such as imipenem, were administrated as
supplement. After remission of symptoms for 7 days, the treatment
was changed to narrow spectrum antibiotics, and bacterial cultures
and drug sensitivity results were combined to adjust the antibiotic
regimen. The patients were given symptomatic treatment, such as
combined mechanical ventilation, rehydration, nutritional support,
and airway management. Adverse reactions, such as allergies, liver
and kidney functional damage, and ototoxicity were monitored during
the treatment.
Observational indicators and
evaluation criteria
The rate of mechanical ventilation, course of
antibiotics, number of antibiotics used, and mortality of the two
groups were compared. Improvements of lung function, including
forced expiratory volume in 1 sec (FEV1), forced vital capacity
(FVC), FEV1/FVC, and maximum expiratory flow rate (PEER) were
compared. Improvements in blood gas indexes, including arterial
partial pressure of carbon dioxide (PaCO2), partial
pressure of oxygen (PaO2), and blood oxygen saturation
(SpO2) were compared. Curative effects, including the
ratio of peripheral blood neutrophils and white blood cells
(N/WBC), the ratio of respiratory failure index (RFI)
(PaO2) and FiO2 (inspired oxygen
concentration) (PaO2/FiO2 = RFI) were
compared as well as C-reactive protein (CRP) levels.
Statistical analysis
SPSS 19.0 (IBM SPSS, Armonk, NY, USA) software was
used for statistical analysis. The measurement data are presented
as mean ± standard deviation. Comparisons between and within groups
were all conducted by t-test. Countable data are presented as rate
and tested by χ2; ranked data comparisons were tested by
sum of ranks. P<0.05 was considered to indicate a statistically
significant difference.
Results
Comparison of mechanical ventilation
usage, course of antibiotic treatment, number of antibiotics used,
and death rate
Mechanical ventilation usage, course of antibiotic
treatment, the number of antibiotics used, and death rate of the
observation group were lower than those of the control group, and
the differences were statistically significant (P<0.05)
(Table II).
| Table II.Comparison of mechanical ventilation
usage, course of antibiotic treatment, number of antibiotics used,
and mortality rate. |
Table II.
Comparison of mechanical ventilation
usage, course of antibiotic treatment, number of antibiotics used,
and mortality rate.
| Group | No. of case | Mechanical
ventilation usage [case (%)] | Course of antibiotic
treatment (days) | No. of
antibiotics | Mortality rate [case
(%)] |
|---|
| Control | 43 | 26 (60.5) | 16.2±3.4 | 5.6±0.8 | 13 (30.2) |
| Observation | 43 | 16 (37.2) | 10.6±2.3 | 3.4±0.6 | 5 (11.6) |
| t/χ2 |
| 4.654 |
5.245 | 5.728 | 4.497 |
| P-value |
| 0.031 |
0.026 | 0.023 | 0.034 |
Comparison of pulmonary function
improvement
Comparing the FEV1, FVC, FEV1/FVC, and PEER between
the two groups before treatment, the differences were not
statistically significant (P>0.05). The above parameters of the
two groups were significantly increased after treatment.
Furthermore, the improvements in these parameters in the
observation group were more pronounced, and the differences were
statistically significant (P<0.05) (Table III).
| Table III.Comparison of pulmonary function
improvement. |
Table III.
Comparison of pulmonary function
improvement.
|
| FEV1 (%) | FEV1/FVC (%) | FVC (l) | PEER (l/sec) |
|---|
|
|
|
|
|
|
|---|
| Group | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment |
|---|
| Control | 52.6±7.2 | 63.8±6.5 | 62.3±8.3 | 70.5±10.2 | 1.2±0.5 | 1.7±0.7 | 2.0±0.6 | 3.3±0.8 |
| Observation | 50.8±7.3 | 71.8±7.4 | 63.4±9.0 | 77.2±11.5 | 1.1±0.6 | 2.3±0.8 | 2.1±0.8 | 3.9±0.7 |
| t-test | 0.123 | 5.293 | 0.326 | 5.627 | 0.162 | 5.168 | 0.324 | 5.524 |
| P-value | 0.864 | 0.030 | 0.724 | 0.023 | 0.827 | 0.032 | 0.627 | 0.028 |
Comparison of blood gas index
improvement
Comparing PaO2, PaCO2 and
SpO2 between the two groups before treatment, the
differences were not statistically significant (P>0.05).
PaO2 and SpO2 of the two groups increased
after treatment, while PaCO2 decreased. Furthermore, the
improvements were more pronounced in the observation group, and the
differences were statistically significant (P<0.05) (Table IV).
| Table IV.Comparison of blood gas index
improvement. |
Table IV.
Comparison of blood gas index
improvement.
|
| PaO2
(mmHg) | PaCO2
(mmHg) | SpO2
(%) |
|---|
|
|
|
|
|
|---|
| Group | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment |
|---|
| Control | 56.2±6.8 | 76.6±8.6 | 69.8±7.8 | 55.7±9.3 | 86.9±5.3 | 92.7±4.6 |
| Observation | 54.8±6.6 | 82.3±7.3 | 70.2±7.9 | 42.3±8.6 | 84.7±5.5 | 96.4±6.5 |
| t-test | 0.524 | 5.632 | 0.426 | 6.328 | 0.965 | 6.258 |
| P-value | 0.632 | 0.025 | 0.721 | 0.013 | 0.214 | 0.015 |
Comparison of clinical curative
effect
Comparing N/WBC, RFI, and CRP between the two groups
before treatment, the differences were not statistically
significant (P>0.05). N/WBC and CRP of the two groups
significantly decreased after treatment, while RFI increased.
Furthermore, the observation group had more pronounced
improvements, and the differences were statistically significant
(P<0.05) (Table V).
| Table V.Comparison of clinical curative
effect. |
Table V.
Comparison of clinical curative
effect.
|
| N/WBC (%) | RFI (mmHg) | C-reactive protein
(mg/l) |
|---|
|
|
|
|
|
|---|
| Group | Before
treatment | After
treatment | Before
treatment | After
treatment | Before
treatment | After
treatment |
|---|
| Control | 82.3±10.6 | 72.5±9.6 | 326.5±24.6 | 432.5±63.8 | 13.6±5.4 | 8.2±1.2 |
| Observation | 84.6±13.4 | 64.2±8.5 | 316.4±30.5 | 465.9±56.6 | 14.3±5.7 | 6.3±1.4 |
| t-test | 0.562 | 6.207 | 0.562 | 6.259 | 0.148 | 6.532 |
| P-value | 0.648 | 0.022 | 0.428 | 0.020 | 0.629 | 0.010 |
Discussion
The current status of COPD in elderly
patients
COPD is primarily caused by type B
Haemophilus influenza, Streptococcus pneumonia and
Staphylococcus aureus. COPD is characterized by apoptosis of
alveolar epithelial cells, vascular remodeling, structural damage,
complications of airway infection, and severe pneumonia (8). The incidence of COPD is relatively
higher in the older population. The course of disease is long,
which causes weakness, respiratory failure, decline of immune
function, and decrease of tolerance to various drugs. COPD combined
with nosocomial pneumonia is very common, and is difficult to treat
effectively.
Application of antibiotics
COPD complicated with severe pneumonia is usually
treated with broad-spectrum antibiotics, such as the third
generation of cephalosporins, and levofloxacin. Antibiotics are
widely used, and their use is abused. Approximately 30% of patients
worldwide have succumbed because of drug resistance caused by
irrational drug use (9). The rate of
use of antibiotics in China is significantly higher than the
recommended rate used internationally. The overuse of antibiotics
is one of the most serious public health problems in China. The
abuse of antibiotics has resulted in the appearance and spread of
multidrug resistant and pandrug resistant strains of bacteria
(10). Although empirical antibiotic
application effectively controlled COPD in the short-term, with the
recurrent attacks of the disease, increased frequency of use of
antibiotics, and prolonged medication time, a large number of
sensitive strains could not be selectively killed. Simultaneously,
drug-resistant strains appear and reproduce to replace sensitive
strains, which increases the incidence of drug resistance, adverse
reactions, and complications. Consequently, pulmonary infection is
difficult to control effectively, the course of disease will be
delayed, and may even lead to mortality (11).
The importance of the de-escalation
principle
The disease conditions of patients with COPD
complicated with severe pneumonia progress rapidly. If no
antibiotics are effective in the early treatment period, there will
be a delay in recovery. Antibiotic resistance was associated with
β-lactamase, which negated its effects (12). In the stage of early delay, rapid
disease progression can change the target proteins on cell
membranes, and reduce the affinity between the antibiotic and its
binding site, so that antibiotics cannot bind. The following
antibiotic failure and double infection make the conditions of the
patients improve slowly (13).
Therefore, in clinical practice, if the infection persists, the
condition becomes worse after the improvement, which proves to be
the improper choice of antibiotics. The de-escalation principle
emphasizes early and comprehensive coverage of possible pathogens,
uses one-step principle of the broad-spectrum antibiotics to
inhibit G+ and G- pathogens, and combines sensitive antibiotics to
adjust the regimen after control of the disease (14,15). The
de-escalation principle not only avoids bacterial resistance,
reduces the production of resistant strains and microflora
disorders, but also reduces the incidence of adverse reactions in
patients, shortens the time of treatment, and achieve favorable
prognosis (16).
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