Clinical Effect and Efficacy Factors of Modified Piperacillin-Tazobactam Dosing Regimens in Abdominal Tumor Patients with Post-Operative Pneumonia

Abstract

Background:

This study was conducted to observe the clinical efficacy of long-term piperacillin-tazobactam (TZP) infusion and identify the factors affecting its curative effect against pneumonia in patients who had undergone surgery for abdominal tumor.

Methods:

The 100 patients were divided into four clinical groups according to the severity of their infection: Simple pneumonia, pneumonia with pleural effusion, pneumonia and atelectasis, and severe pneumonia. Each group of patients was then divided into control and treatment groups using a completely random design. The control group received TZP as a regular infusion, and the treatment group received TZP as a long-term infusion. The cure time in the different groups was compared according to the administration regimen, and stratified analysis was carried out to identify the efficacy factors of long-term TZP infusion for patients with each kind of pneumonia.

Results:

The average cure time for TZP differed significantly among the groups. In particular, the average cure times in the simple pneumonia, pneumonia with pleural effusion, pneumonia and atelectasis, and severe pneumonia groups were 6.800 ± 0.342, 7.320 ± 0.304, 10.840 ± 0.571, and 15.942 ± 0.973 d (p < 0.001). In each group, the usage time of antibiotics in the treatment groups was significantly shorter than in the control group (8.87 ± 0.64 vs. 15.95 ± 2.02 d; p < 0.001). The cure times (d) for simple pneumonia and pneumonia and atelectasis were conspicuously lower in the treatment groups than in the control group (5.667 ± 0.256 vs. 7.846 ± 0.451; p < 0.001; 9.667 ± 1.432 vs. 11.923 ± 0.947; p = 0.024). The factors associated with continuous treatment effectiveness were being male, age <70 years, Acute Physiology and Chronic Health Evaluation score ≥17 points, minimum inhibitory concentration of the pathogen 8 mcg/mL, oxygenation index >200 mm Hg, serum procalcitonin concentration >4 ng/mL, and serum albumin <25 g/L.

Conclusion:

Long-term TZP infusion exhibited better clinical efficacy than did traditional treatment in patients with pneumonia after abdominal tumor surgery.

With the widespread use of antibiotics and the constant increase in drug-resistant strains, resistance has become the main barrier to clinical anti-infection treatment. Therefore, recent studies have focused on formulating a rational antibiotic dosage regimen that prevents the emergence of drug resistance. Piperacillin/tazobactam (TZP) is a compound preparation of beta-amide and beta-lactamase inhibitors. It exhibits anti-bacterial activity against various aerobic and anaerobic bacteria and is recommended by the American Thoracic Society (ATS) as a first-line agent for hospital-acquired pneumonia (HAP) pneumonia [1]. The anti-bacterial effect of TZP, as a time-dependent antibiotic, depends on the percentage of time the free drug concentration in the serum is higher than the minimum inhibitory concentration (MIC) during a given dosing interval (%fT>MIC). When %fT>MIC is 40%–50%, bacterial clearance exceeds 85% [2]. In the present study, the administration of TZP was extended in order to prolong the duration of %fT>MIC.

Patients and Methods

Ethical approval

This study met medical ethical standards and was approved by the Medical Ethics Committee of Tianjin Medical University Cancer Hospital. Each patient signed an informed consent before participating in the study. This study was registered at and approved by Clinical Trial with Registration Certificate No. NCT01796717.

Inclusion criteria

Patients aged 18–70 years who underwent surgery for an abdominal tumor and had post-operative HAP and who were treated in the intensive care unit of Tianjin Cancer Hospital from January 1, 2013, to September 30, 2013, were eligible. All had pneumonia diagnosed in accordance with the Chinese “Diagnosis Standard of Hospital-Acquired Pneumonia, 1999” [3] and “New Guidelines for Diagnosis and Treatment of HAP,” issued jointly by the ATS and the Infectious Diseases Society of America in February 2005 [4]. They exhibited no pre-operative heart or lung disease, lung injury, or respiratory dysfunction during the operation or anesthesia, and they had no lung metastasis. The patients underwent radical excision of their abdominal tumor and had no post-operation bleeding, fistula formation, abdominal infection, or cardiac dysfunction. Drug susceptibility testing showed an MIC of 4, 8, or 16 mcg/mL for TZP.

Exclusion criteria

Patients who had clinical manifestations of infection or had received anti-infective therapy for more than 48 h before admission were excluded, as were those with kidney injury (urinary volume <20 mL/h or <80 mL/4 h, acute renal failure that necessitated dialysis, or creatinine clearance rate <40 mL/min); infection caused by TZP-insensitive bacteria; or recurrent pulmonary infection caused by previously existing factors such as bronchial obstruction, obstructive pneumonia, lung cancer, pulmonary abscess, empyema pleurae, or active tuberculosis; or penicillin allergy. We also excluded pregnant or lactating females; those with any factor likely to increase patients' risk or interfere with the clinical trial; and patients with a gastrointestinal fistula after abdominal surgery with or without complication by a severe abdominal infection.

Data collected

We enrolled 100 patients with pneumonia after abdominal tumor surgery. There were 58 males and 42 females aged 48–70 years with an average age of 68.34 years. Among these patients, 16 had renal cancer, 20 had cardiac carcinoma, 38 had gastric cancer, 4 had pancreatic cancer, 12 had colon cancer, and 10 had liver cancer. None of the patients had been given pre-operative neo-adjuvant therapy. The patients were divided into four groups (n = 25 each): Simple pneumonia, pneumonia with pleural effusion, pneumonia and atelectasis, and severe pneumonia.

Treatment

The antibiotic TZP was selected in consideration of the sputum culture and drug susceptibility results. The patients in each group were divided randomly into a control group (traditional therapy; 12 cases) and a treatment group (continuous therapy; 13 cases). The control groups received TZP 4.5 g q 6 h by regular infusion for 30 minutes; the treatment group received the same dose over 3 hours using an infusion pump. In cases in which the pathogenic bacteria were eliminated, the clinical effect was rated excellent, and a clinical pulmonary infection score of <6 was considered successful, with TZP treatment being discontinued. A hydrocarbon enzyme was used as a remedy in cases of ineffective treatment and worsening pneumonia.

Clinical observations and curative effect judgment

The clinical and bacteriologic effects were determined in accordance with the “Guiding Principles for Clinical Application of Antimicrobial Agents,” released by the Ministry of Health, the General Logistics Department of Health and State Administration of Traditional Chinese Medicine.

Statistical analysis

The enumeration data were compared by the χ² or Fisher exact test to determine the statistical significance of any difference; measurement data were compared with the t-test. Clinical parameters in the groups were compared by variance or χ² analysis. Multi-factor correlation analysis was conducted by logistic regression to determine any statistical significance. Statistical significance was considered to be present at p < 0.05. Data were processed by SPSS V. l7.0 software.

Results

In general, the average time to cure differed significantly among the groups. In particular, the average cure times (d) of the simple pneumonia, pneumonia with pleural effusion, pneumonia and atelectasis, and severe pneumonia groups were 6.800 ± 0.342, 7.320 ± 0.304, 10.840 ± 0.571, and 15.942 ± 0.973 (χ² = 85.192; p < 0.001; Fig. 1). Among the different groups, an equal variance of antibiotic cure time was observed between the treatment and control groups (F = 0.393; p = 0.532). The cure time (d) in the treatment group was considerably shorter than that in the control group (8.87 ± 0.64 vs. 15.95 ± 2.02; χ² = 13.058; p < 0.001; Fig. 2). A comparison among the groups with different types of lung infection showed that prolonged TPZ infusion significantly reduced the cure time of simple pneumonia and pneumonia and atelectasis (Table 1).

FIG. 1.

Cure time differed significantly among various types of post-operative pulmonary infection after abdominal tumor surgery (χ² = 85.192; p < 0.001).

FIG. 2.

Cure time was significantly shorter in the treatment (continuous PIP/TAZ infusion) than in the control (standard therapy) group (χ² = 13.058; p < 0.001).

Table 1.

Analysis of Two PIP/TAZ Administration Modes for Different Types of Post-Operation Hospital-Acquired Pulmonary Infection

Disease	PIP/TAZ therapy	Average cure time (d)	χ² value	p
Simple pneumonia	Treatment	5.667 ± 0.256	11.769	0.001
	Control	7.846 ± 0.451
Pneumonia complicated with pleural effusion	Treatment	6.917 ± 0.433	1.805	0.179
	Control	7.629 ± 0.499
Pneumonia complicated with atelectasis	Treatment	9.667 ± 1.432	5.106	0.024
	Control	11.923 ± 0.947
Severe pneumonia	Treatment	14.833 ± 1.466	0.736	0.391
	Control	16.878 ± 1.293

Determination of Efficacy Factors through Stratified Analysis of Prolonged TPZ Treatment

The healing time of male lung infection patients was significantly shorter in the treatment group than in the control group (9.17 ± 0.78 vs. 12.39 ± 1.40 d; χ² = 4.122; p = 0.042; Supplemental Fig. 1). The healing time of patients aged less than 70 years also was significantly shorter in the treatment group (9.30 ± 0.84 vs. 12.38 ± 1.52 d; χ² = 3.920; p = 0.048; Supplemental Fig. 2). The healing time of patients with an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥17 was significantly shorter in the treatment than in the control group (10.32 ± 0.81 vs. 13.40 ± 1.13 d; χ² = 5.203; p = 0.023; Supplemental Fig. 3). The healing time of patients whose infecting organism had an MIC of 8 mcg/mL was significantly shorter in the treatment than in the control group (8.94 ± 0.64 vs. 11.57 ± 1.20 d; χ² = 4.160; p = 0.041; Supplemental Fig. 4). The healing time of patients with an oxygenation index >200 mm Hg was significantly shorter in the treatment than in the control group (7.00 ± 0.39 vs. 9.20 ± 0.64 d; χ² = 8.183; p = 0.004; Supplemental Fig. 5). The healing time of patients with a serum procalcitonin (PCT) concentration >4 ng/mL was significantly shorter in the treatment than in the control group (9.67 ± 0.94 vs. 12.76 ± 1.73 d; χ² = 4.095; p = 0.043; Supplemental Fig. 6). The healing time of patients with a serum albumin concentration <25 g/L was significantly shorter in the treatment than in the control group (8.78 ± 0.81 vs. 13.37 ± 1.76 d; χ² = 6.474; p = 0.011; Supplemental Fig. 7).

Correlation analysis of continuous TZP treatment and clinical curative effect of different types of pneumonia patients

Stratified multivariable correlation (logistic regression) analysis revealed that the prolonged TZP injection mode was the key factor in the cure of severe post-operative pneumonia (odds ratio [OR] = 0.017; p = 0.038) but not in the curative effect in a separate group of patients with simple pneumonia, pneumonia with pleural effusion (p = 1.000), or pneumonia (p = 0.076) and atelectasis (p = 0.327) having non-abdominal tumor operations.

Influence of surgical complications on the effects of different regimens of TZP

Abdominal bleeding was observed, in 18 cases, incision infection in 15, and gastrointestinal dysfunction secondary to malnutrition in 23. It should be explained that these complications were not necessarily isolated; some patients had more than one.

For the incidence of complications of the two groups, we conducted a statistical analysis (Supplemental Fig. 8). We utilized the Mann-Whitney U test and found that there was no significant statistical difference between the surgical complications of the two groups (p = 0.927). We also utilized the Mann-Whitney U and Kruskal-Wallis tests to evaluate whether there existed differences in surgical complications between the four groups of patients with different kinds of pneumonia with and without antibiotic infusion. There was no significant difference in surgical complications in the control and treatment groups (Table 2).

Table 2.

Comparisons of Surgical Complications in Four Groups of Patients by Antibiotic Administration Mode

	Complication
Group	None	Hemorrhage	Incision infection	Malnutrition	H+I	H+M	I+M	H+I+M	P
Overall (n = 100)									0.927
Treatment group (n = 48)	27	6	4	5	3	1	0	2
Control group (n = 52)	30	3	7	7	0	4	1	0
Comparison by disease (n = 100)									0.117
Simple pneumonia (n = 25)	17	2	2	1	0	1	2	0
PPE (n = 25)	11	0	4	6	0	4	0	0
PA (n = 25)	17	3	2	3	0	0	0	0
Severe pneumonia (n = 25)	11	4	4	2	0	1	1	2
Simple pneumonia (n = 25)									0.152
Treatment group (n = 12)	6	1	2	1		1	1
Control group (n = 13)	11	1	0	0	0		1
PPE (n = 25)									0.406
Treatment group (n = 12)	4	0	2	4	0	2	0	0
Control group (n = 13)	7	0	2	2	0	2	0	0
PA (n = 25)									0.979
Treatment group (n = 12)	8	2	1	1	0	0	0	0
Control group (n = 13)	9	1	1	2	0	0	0	0
Severe pneumonia (n = 25)									0.574
Treatment group (n = 12)	5	2	0	2	0	0	1	2
Control group (n = 13)	6	2	4	0	0	1	0	0

H+I = hemorrhage complicated by incision infection; H+M = hemorrhage complicated by malnutrition; H+I+M = three complications in single patient; I+M = incision infection complicated by malnutrition; PA = pneumonia complicated by atelectasis; PPE = pneumonia complicated by pleural effusion.

Through logistic regression analysis, we found that only the different administration mode had an influence on curative effectiveness (p = 0.001), but surgical complications had no significant influence on clinical efficacy: Hemorrhage (p = 0.149), incision infection (p = 0.525), malnutrition (p = 0.561), hemorrhage and malnutrition (p = 0.058), incision infection and malnutrition (p = 0.956), and all of these complications together (p = 0.161).

Discussion

Surgery for tumor changes the local anatomic structure and causes failure of some physiological barriers. Therefore, potentially dangerous factors such as malnutrition and low immunologic function render these patients at high risk of HAP. Among the patients undergoing surgery for abdominal tumors and having HAP, the healing time with long-term TZP infusion was significantly shorter in the patients with simple pneumonia or pneumonia and atelectasis than in the control groups. This result is similar to that of Roberts et al. [6], who used a Monte Carlo model for the dose simulation of pharmacokinetics and found that long-term TZP infusion improved the treatment effect in sepsis. Lodise et al. [7] also showed that long-term TZP infusion could enhance the cure rate of patients with severe Pseudomonas aeruginosa infection. A recently published meta-analysis [8] has revealed that long-term infusion of β-lactam antibiotics benefits sepsis patients and that the mechanism is related to the pharmacokinetic properties of these drugs. Beta-lactam antibiotics deactivate the active part of the bacterial cell wall assembly through acylation and maintain the stability of the inactive part through permanent modification, thus causing the bacteria to disintegrate. Antibiotics can achieve acylation only at a few points in the wall, so that the bactericidal action will not improve further when the acylation of these points reaches saturation, and a higher dose will have no effect. The above MIC duration rather than the peak concentrations of time-dependent antibiotics may better reflect their bactericidal abilities. The optimization of beta–amide therapy requires maximizing the drug exposure time by prolonging drug administration or intravenous infusion time instead of increasing the dose to reach the target value (%T>MIC required for the optimal therapeutic effect). To achieve the best antibacterial effect of penicillin, the %>TMIC should be at least 40–60 [9]. With the constant appearance of multi-drug-resistant bacteria, the MICs of many antibiotics have increased. For moderately susceptible high-MIC bacteria, the current dosing interval cannot fully guarantee a %T>MIC above 50. Thus, we prolonged the infusion time to increase the 50%fT>MIC rate, control infection, and optimize the utility of the antibiotic. This method of administration proved to be safe and effective.

Stratified analysis of the results showed that the cure time of long-term infusion in males was short. However, the underlying mechanism remains unknown and might be related to immune function differences by gender. Croce et al. showed that the differences in immunologic function between males and females cause different morbidities and mortality rates from sepsis [10]. In addition, the underlying mechanism might be related to testosterone and estrogen. Furthermore, the bioavailability of drugs may have some gender differences. Antibiotic-related studies of this issue are few. Sowinski et al. analyzed the bioavailability of ofloxacin (steady state/whole body) and reported that the distribution volume (V(SS)/F) is significantly smaller in females than in males and that the median peak concentration is 27% lower in females than in males despite a lack of significant difference in total body weight [11]. A second finding was that the cure time for long-term infusion was significantly shorter in patients younger than 70 years, possibly because of the decreased cellular and humoral immune function and sputum drainage obstacle caused by weakened respiratory ciliary movement and airway clearance in older patients. Meanwhile, the pneumonia of elderly patients was latent because of delayed diagnosis in the absence of obvious respiratory symptoms. Furthermore, elderly patients usually have reduced functioning of other organs. Tumbarello et al. pointed out that age is an independent risk factor for P. aeruginosa pneumonia [12]. A third finding was that the cure time of patients with APACHE II scores ≥17 was significantly shorter in the treatment than in the control groups. In addition, the improved infusion method was highly effective in critically ill patients. Thomas et al. obtained a similar result [13]. The reason might be because most of these patients had immunosuppression and required an increase in the %T>MIC time to achieve good bactericidal action. A fourth finding was that the cure time of long-term infusion in patients with an MIC of 8 mcg/mL was significantly shorter, indicating that the long-term infusion was highly effective in these patients. When the MIC was 4 mcg/mL, both infusion methods produced a Tf%>MIC time >50%, indicating no difference in effectiveness. When the MIC value was 16 or 32 mcg/mL, although the organism still was considered sensitive, neither method could guarantee %T>MIC time >50. This result also explains the ineffectiveness of prolonging the TZP infusion time in the study by Li et al., who did not perform a stratified analysis by MIC value [14]. Our fifth significant finding was that the cure time of long-term infusion in patients with an oxygenation index >200 mm Hg was short. This result proves that serious lung injury occurred in patients with an oxygenation index <200 mm Hg, some of whom needed mechanical ventilation. Many factors could interfere with the cure rate. Aside from the anti-infective therapy, factors such as lung protection, mechanical ventilation, and nutritional support influenced the clinical effect to some extent. Also, in recent years, PCT has been a widely used measure for diagnosing and monitoring inflammatory bacterial infection. In infection and sepsis, a large amount of PCT is formed and released into the blood; thus, the serum PCT concentration increases, and the degree of elevation correlates with the severity of the disease. Persistent elevation suggests a poor prognosis [15 –17]. In the present study, the cure time of long-term infusion in patients with PCT >4 ng/mL was significantly reduced. This result indicates that long-term infusion is effective in patients with severe sepsis. However, whether the critical MIC value is 4 ng/mL needs further study. Finally, the cure time with long-term infusion in patients with a serum albumin concentration below 25 g/L was short. The serum concentration of the antibiotics decreased with decreasing serum albumin. Moreover, the low serum albumin concentration influenced colloid osmotic pressure and thus affected fluid therapy. Multiple factors hinder effective %T>MIC time, and long-term infusion remedies these weaknesses and enhances clinical effectiveness to some extent.

Supplementary Material

Reasons for the choice of patients with abdominal tumors as experimental subjects

In post-operative patients, HAP and the mortality rate for this kind of pneumonia are high, especially 5 ± 4 days after surgery [18], Sabate et al. [19] and others have found that the incidence of pneumonia after surgery is as high as 2%–40%, and the mortality rate is as high as 48%. The incidence of pneumonia after abdominal surgery is especially high: 10%–25%. The research by Guan and Tang [20] showed that changes in pulmonary function and chest wall mechanical force after abdominal surgery, especially weakened diaphragmatic function, induces lung volume reduction and functional residual capacity decline, especially after upper abdominal surgery. The incidence rate of post-operative pneumonia and the distance between the surgical site and the diaphragm are negatively correlated. Thus, the incidence rate of pneumonia after upper abdominal and lower abdominal surgery are 17%–76% and 0–5%, respectively.

The number of patients admitted to our department for abdominal tumor surgery was nearly 750 in 2010–2015. Among them, nearly 200 patients had pneumonia and were transferred to our department, which was as high as 26.6% of the patient population. Our hospital is a cancer institution and hospital, and after a long period of observation, we found that a large number of tumor patients having pneumonia after surgery had been treated for primary thoracic and abdominal tumors. The thoracic tumors often violated the lungs, and the patients more often suffered pneumonia/atelectasis, which was associated with respiratory dysfunction. Thus, there were many influences favoring the development of pneumonia post-operatively. Although patients with abdominal tumors usually had normal respiratory function pre-operatively, because of their post-operative supine position, pain, gastrointestinal dysfunction, aspiration of digestive juices, and other factors could still lead to pneumonia. Therefore, there was more one influence in thoracic tumor patients. For these reasons, our study enrolled patients with abdominal tumors. As everyone knows, upper abdominal surgery has more complications than lower abdominal surgery, but we did not use digestive tract surgery as an enrollment standard. At the same time, the chief physician had a treatment for related complications except pneumonia, and the side effects of complications were controlled within an acceptable range. Therefore, the surgical complications had no influence on the clinical efficacy of the different administration modes of TZP, and abdominal tumor patients with pneumonia were enrolled in our study.

Upper abdominal complications generally are more common than those in the lower abdomen, and the incidence of pneumonia after upper abdominal operations is higher. However, the control and treatment groups showed no significant difference, and the operative site had no effect on clinical efficacy. Therefore, we did not distinguish between upper and lower abdominal operations.

Main pathogenic bacteria

The bacteriologic results of 100 cases of pneumonia showed P. aeruginosa in 18 cases, Escherichia coli in 23, Klebsiella pneumoniae in 31, Acinetobacter baumannii in 11, and Serratia marcescens in 17. All MIC values were below 16 mcg/mL. Susceptibility results usually revealed susceptibility to TZP (Supplemental Fig. 9). We utilized the Mann-Whitney U and Kruskal-Wallis tests and found no significant difference in primary pathogens between the treatment and control groups (p = 0.784). The four groups likewise had no difference in the numbers of the various primary pathogens (p = 0.886). In a comparison of the different administration modes, there was no significant statistical difference: Simple pneumonia (p = 0.979), pneumonia complicated by atelectasis (p = 0.376), pneumonia complicated by pleural effusion (p = 0.894), and severe pneumonia (p = 0.123). Importantly, the bacteriologic efficacy in the treatment group was superior to that in the control group (p = 0.001; Supplemental Fig. 9).

In summary, this study adopted an optimized dosage regimen by prolonging the infusion time of TZP in patients with nosocomial pneumonia caused by a gram negative bacterium. The treatment group, receiving TZP by infusion for 3 h, achieved better clinical results than the control groups having traditional therapy. The factors encouraging good results in the treatment group were being male, age <70 years, APACHE II score ≥17 points, MIC 8 mcg/mL, oxygenation index >200 mm Hg, PTC >4 ng/mL, and serum albumin <25 g/L.

Footnotes

Acknowledgments

The study was supported by a grant from the Science and Technology Fund of the Tianjin Municipal Health Bureau, China (No. 2013KZ091) and the Science Foundation of Tianjin Medical University, China (No. 2014KYQ10).

Author Disclosure Statement

The authors declare that they have no competing interests.

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Supplementary Material

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