Cefepim in empiric therapy of ventilator-associated pneumonia
*Jowita Biernawska, Maciej Żukowski, Małgorzata Zegan-Barańska, Agnieszka Żukowska
Department of Anaesthesiology, Resuscitation and Intensive Therapy with Unit of Acute Intoxications, Teaching Hospital no. 2 in Szczecin
Background. The most common infection following surgical treatment, when mechanical ventilation and tracheal intubation are used, is ventilator-associated pneumonia (VAP) induced by Gram-negative and Gram-positive bacteria. Its treatment is difficult due to increasingly high antimicrobial drug resistance observed recently.
Case report. A 73-year-old patient was admitted to undergo coronary artery bypass grafting and cardiac aneurysm excision. Additionally, chronic circulatory insufficiency (NYHA 2) with ejection fraction of 30% together with hypertension and type 2 diabetes were diagnosed. After extracorporeal circulation, she was given adrenaline/noradrenaline and intra-aortic balloon pump. Postoperatively, elevated levels of CRP (70 mg L-1 ) and of procalcitonin (22.4 ng mL-1) were detected. Empiric therapy with cefepime 1 g × 2 iv was started. X-ray revealed atelectasis in the middle left lung lobe and Enterobacter cloacae was isolated from the bronchial tree. Patient was intubated and mechanically ventilated. Antibiotic therapy with cefepime was continued for 10 days and resulted in improvement of patient’s general condition. On postoperative day 7, she was transferred from ITU to the cardiac surgery ward.
Conclusion. Cefepime applied empirically to a VAP patient can effectively treat the lung infection and improve his/her general condition.
In recent years, drug resistance of hospital pathogens has become an increasingly important problem. The main causes of this phenomenon include widespread use of broad-spectrum antibiotic therapy leading to increased resistance of the environmental bacteria as well as more and more invasive procedures performed in patients with numerous diseases (mainly those affecting the cardiovascular and respiratory system), with impaired immunity and susceptible to nosocomial infections. Such infections substantially prolong the therapeutic process and hospitalization, which is reflected in treatment-related costs .
Pathogens inducing the commonest therapeutic problems in hospitalized patients are mainly Gram-negative bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The mechanism of antibiotic resistance of Gram-negative bacteria results mostly from the production of ß-laktamases, enzymes of expanded-substrate profile - ESßL, inactivating all penicillins and most of cephalosporins, and Amp C cephalosporinases (breaking down all penicillins and cephalosporins, third generation ones included) [2,3].
Empiric choice of antibiotics depends on a variety of factors, e.g. location of the infection, age and general status of a patient, coexisting diseases, recent hospitalizations and surgeries, present pharmacotherapy (including types of antibiotics and drugs affecting the immune system) as well as kinds and resistance of pathogens characteristic of a hospital ward. Therefore, initial broad-spectrum antibiotics are recommended, which Gram-negative and Gram-positive bacteria as well as anaerobes are susceptible to. The therapy should be verified as soon as possible once microbiological findings are available; narrower-spectrum antibiotics targeted at a particular pathogen have to be administered to avoid the selection of resistant strains.
One of the most common complications following surgery is pneumonia resulting from impaired respiratory mechanics after surgical procedures as well as mechanical lung ventilation in patients requiring such management due to surgical reasons or general status. Ventilator-associated pneumonia (VAP) accounts for half of all hospital acquired infections in ITUs . This specific form of infection, associated with ventilation and endotracheal intubation occurs in 8-28% of patients  with the mortality rates of 24-50%. Colonization of microorganisms is affected by many factors: severity of the underlying disease, past surgeries, antibiotics received, other drugs used, contact with devices for invasive procedures. Bacteria invade the airways mainly through aspiration from the upper pharynx or leakage of the secretion around the endotracheal tube cuff. The presence of infected biofilms in the endotracheal tube may also be relevant . VAP is often caused by Gram-negative rods and Gram-positive staphylococci; anaerobic bacteria are rare.
Prognosis in VAP developing early (within the first 4 days of hospitalization) is better as it is more frequently induced by antibiotic-susceptible bacteria. VAPs of late onset (≥ 5 days after admission) are usually caused by pathogens resistant to many drugs, thus are associated with worse prognosis [6, 7]. The recommendations concerning empiric antibiotic therapy in VAP patients are presented in the available guidelines .
The objective of the study was to present a case of effective treatment of VAP after cardiac surgery.
A 73-year-old patient underwent cardiac surgery due to three-vessel coronary artery disease (CCS 3). The additional risk factors included two myocardial infarcts, circulatory failure (NYHA 2), impaired contractility of the left ventricle (ejection fraction about 30%), arterial hypertension, type 2 diabetes mellitus, dyslipidemia and nicotinism.
The pre-surgery examination did not reveal features of infection; the respiratory and circulatory systems were efficient. The results of laboratory tests were within normal limits and the concentration of procalcytonine was <0.05 ng mL-1. The patient underwent the aorto-coronary bypass procedure with extracorporeal circulation and blood cardioplegia. After the completion of extracorporeal circulation, proper flows in the arterial and sequential venous bypasses were found and only trace flow in the right coronary artery bypass (Quantix flowmeter). This resulted in hypotension, which did not respond to intravenous infusion of adrenaline and extracorporeal circulation was restarted. After the period of prolonged reperfusion, due to unstable circulatory system despite the infusion of adrenaline and noradrenaline, intraaortal balloon pumping (IABP) was applied. Then the patient received analgosedation; mechanical lung ventilation was carried out; circulation was supported with the infusion of catecholamines and IABP. No myocardial infarction was observed. Metabolic acidosis, hyperglycemia and postoperative ischemia were effectively corrected with appropriate therapy.
The physical examination demonstrated normothermia, vesicular murmur above lung fields, sinus tachycardia, hypotension despite adequate fluid therapy, normal hourly diuresis. Several hours after the procedure, the surgical field was revised due to excessive hourly drainage from the wound; however, no evident site of bleeding was found. The findings after re-surgery were as follows: the concentration of C-reactive protein - 70 mg L-1 of procalcitonine – 22.4 ng mL-1, WBC - 10 G L-1 (neutrophils 82%, lymphocytes 8.8%). Considering instability of the circulatory system (despite adequate filling of the vascular bed and lack of bleeding manifestations) and prolonged mechanical lung ventilation as well as subfebrile condition and increased concentration of procalcytonine, which might have been suggestive of SIRS or developing infection, the samples of blood, urine and bronchial secretion (BAL) were collected for microbiological tests.
Prophylactic antibiotic therapy (at present the hospital epidemiological team prescribes cefazolin) was abandoned and empiric therapy with i.v. cefepime 1.0 g x 2 instituted. Several hours later, the circulatory function gradually stabilized; the infusion of catecholamines and IABP were discontinued. Chest X-ray showed impaired aeration of the medial left lung field, slight amounts of fluid in the pleural cavity on the left side and the normal right lung (Fig.1).
The cultures of blood and urine carried out two day later did not show any pathogens; however, in the bronchial sample Enterobacter cloacae amp C. was detected. For these reasons, intravenous therapy with cefepime was continued for 10 days even when the concentration of procalcytonine declined to < 0.01 ng mL-1, together with colistine used for nebulization.
The postoperative period was additionally complicated with ischaemic cerebral stroke with left-sided hemiparesis.
On postoperative day 3, the examination findings showed normothermia, stable circulatory function, normal hydration and good hourly diuresis, slight hemiparesis. Leucocytosis was 13.8 G L-1, concentration of procalcytonine 19 ng mL-1, C-reactive protein 252 mg L-1. The remaining laboratory results (blood cell count, ionogram, arterial blood gasometry, clotting parameters, renal and hepatic parameters) were normal. The general condition of the patient improved, and she was extubated on postoperative day 4. In successive days, inflammation parameters normalized: WBC - 6 G L-1, procalcytonine - 6.03 ng mL-1, C-reactive protein - 247mg dL-1. Repeated chest X-ray disclosed improved aeration of the left lung, normal picture of the right lung and trace amounts of fluid in the left pleura (Fig. 2).
On postoperative day 7, the patient was transferred from ITU to the department of cardiac surgery and after 2 weeks discharged home in good general condition.
Cefepime is a forth-generation cephalosporin for parental use characterized by broad spectrum of activity, mainly against Gram-negative rods and Gram-positive cocci. It has a particularly high activity against Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii producing derepressed chromosomal cephalosporinase. The drug penetrates easily the cell wall of Gram-negative bacteria, shows low affinity to chromosomally-encoded β-lactamases, although there are some resistant pathogens producing plasmic enzymes of an expanded spectrum (ESβL), which inactivate cefepime. Its biological activity in vitro is associated with marked resistance to chromosomal β-lactamases and particular ability to penetrate the pore channels, thanks to its small molecular weight, shape and charge of the drug molecule as well as affinity to three penicillin–binding proteins. The penetration coefficient of cefepime to the cells of Escherichia coli and Enterobacter is five to twenty times higher than that of cefotaxime or ceftraixone. High affinity to penicillin-binding proteins is responsible for quick bactericidal effects and activity against strains resistant to other β-lactam antibiotics. It should be underlined that cefepime is not active against the majority of Stenotrophomonas maltophilia, Bacteroides fragilis, Clostridium difficile, enterococci (e.g. Enterococcus faecalis) and methicillin-resistant staphylococcus aureus [8, 9, 10].
The main indications for cefepime include infections of the lower airway, urinary system, skin, soft tissues and those affecting the abdominal cavity (including peritonitis, biliary infections). Moreover, cefepime is indicated for neutropenic and febrile patients. It is also recommended to prevent infections in patients undergoing abdominal surgeries [1, 7, 8, 11, 12, 13]. The drug is well tolerated by patients.
Cefepime appears to be a good alternative to carbapenems for empiric broad-spectrum antibiotic therapy, especially when strains resistant to carbapenems are detected in the ward. It should be remembered that cefepime shows synergism of action with aminoglycosides. The cefepime combined therapy has been accepted for nosocomial pneumonia (including Pseudomonas aeruginosa pneumonia) [14, 15].
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Received: 20.06. 2009.