Introduction

Infections caused by highly resistant bacteria are an increasing challenge for physicians. Ceftolozane/tazobactam is a new antibacterial drug product that combines ceftolozane, a cephalosporin, and tazobactam, a beta-lactamase inhibitor, approved for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. One of its most promising targets is multidrug-resistant Pseudomonas aeruginosa.

Case description

In April 2016, a 58-year-old man with past medical history significant for obesity, HIV infection and ischemic heart disease was admitted to the intensive care unit for a community-acquired pneumonia due to influenza A virus with high fever and suffering a severe acute respiratory distress syndrome. He was treated with oseltamivir as well as protective mechanical ventilation, prone position and prolonged neuromuscular relaxation. After six days of treatment without significant improvement 1 mg/kg/day of methylprednisolone was initiated.

In the second week he presented a ventilator-associated tracheobronchitis caused by multiresistant P. aeruginosa that was only susceptible to colistin and amikacin and with intermediate susceptibility to piperacillin–tazobactam. Multiresistant bacteria were not isolated in the previous surveillance cultures but grew in the following ones. This respiratory infection hindered the respiratory progression and was treated with colistin (3 mill U tid) and amikacin (1 g qd). The patient developed a sacral pressure ulcer with necrotic tissue but there were no apparent evidence of infection on physical examination.

The patient condition was improving but in the third week he had fever (39 °C), leukocytosis (16,320 mL−1) and elevated serum C-reactive protein (232 mg/L) and procalcitonin (1.47 ng/mL) levels. Two peripheral vein blood cultures and a catheter hub blood culture were simultaneously drawn, as well as bronchoaspirate and pressure ulcer cultures, and the subclavian venous indwelling catheter was removed and cultured. P. aeruginosa was simultaneously isolated in all three blood cultures (there was no differential time to positivity), and also in bronchoaspirate and in the bed of the pressure ulcer but the catheter was sterile. With the preliminary information of the positivity of blood cultures an empiric treatment with vancomycin (1 g bid) and piperacillin/tazobactam (4/0.5 g every 6 hours) in prolonged infusion had been initiated. The final result was the mentioned isolation of P. aeruginosa; serotype O4, only susceptible to colistin (CMI ≤2) and amikacin (CMI ≤8). A multilocus sequence typing (MLST) study for comparison with other current clones was performed and was identified as ST175, widely distributed and highly pathogenic. We required it to be tested against ceftolozane/tazobactam and CMI was 3, so authorization was requested and granted for compassionate use of ceftolozane/tazobactam. We decided to prescribe intravenous doses of 1/0.5 g tid as creatinine clearance remained over 50 mL/min.

The one day after the start of the new antibiotic regimen the patient presented a clinical improvement and laboratory abnormalities began to normalize and three days later he was successfully extubated. Treatment was continued for ten days and the patient was discharged from the ICU. Colonization by P. aeruginosa in respiratory samples and rectal swab persisted at that point.

Discussion

This case highlights a challenge in many intensive care units, which is the treatment of multiresistant bacteria infections. Sometimes bacteria are resistant to all antibiotics tested. In the present case P. aeruginosa was susceptible only to two antibiotics, both of them were prescribed and during the treatment the patient presented bacteremia by the same microorganism. This may be because the bacterium becomes resistant to prescribed antibiotics or because the antibiotics could not penetrate and reach adequate concentration in certain tissues. Secondary effects of these antibiotics are also worrisome pitfalls. In this context, new antibiotics are promising.

Ceftolozane/tazobactam is a novel cephalosporin combined with a beta-lactamase inhibitor. It provides coverage against many Gram-positive and Gram-negative organisms including some multidrug-resistant species. It is active against extended spectrum beta-lactamase-producing bacilli, ampC beta-lactamases of Enterobacter spp. and P. aeruginosa and it is not affected by other resistance mechanisms as loss of the porin OprD or overexpression of efflux pumps. It has been recently approved only for abdominal and complicated urinary tract infections including pyelonephritis and there is an ongoing phase 3 study on patients with respiratory infection (NCT02070757) [1]. Some cases of off-label use of ceftolozane–tazobactam have been reported, including non-bacteriemic ventilator associated pneumonia [2]. As this new agent belongs to the first antibiotic group described, certain pharmacokinetic characteristics can be inferred. The appropriate dosing regimen is still in study and we decided to use the approved dose regimen for intraabdominal infections—1.5 g tid—, although 3 g-tid-dose regimen could also be considered to increase the probability of target attainment with a dismal risk of drug accumulation after multiple intravenous doses [3]. Dosage adjustments are required in patients with moderate to severe renal impairment and in patients on hemodialysis but no adjustment is needed based on age or hepatic impairment. Limited data are available on ceftolozane/tazobactam dosing in patients receiving continuous renal replacement therapy but a dosage of 1.5 g tid should adequately achieve a desired drug concentration [4]. The most common adverse effects occurring in patients receiving ceftolozane/tazobactam were nausea, diarrhea, headache and pyrexia. The only contraindication described is the history of serious hypersensitivity to ceftolozane/tazobactam or other members of the beta-lactam class.

In the present case there were doubts about the primary focus of infection. In the pressure ulcer culture after debridement P. aeruginosa strains grew although colonization was observed in perirectal exudate. The other possible focus was the respiratory tract but the tracheobronchitis due to P. aeruginosa was having a good clinical evolution, so it was unlikely to give rise to bacteremia. None of these options is included in cefotlozane/tazobactam label.

This new agent was used for ten days once blood culture and antibiogram were performed. It could also be considered on an empirical basis in life-threatening infections when risk factors for resistant enterobacteria are present but it will likely need to be used in combination with other agents depending on the focus as its activity against Staphylococci, Enterococci and Clostridium spp. is limited [5]. In complicated intra-abdominal infections, it is recommended to use ceftolozane–tazobactam in combination with metronidazol.

Conclusion

Multiresistant germens causing infections pose an increasing threat. Nevertheless new alternatives continue to emerge as cefotlozane/tazobactam or others like ceftazidime/avibactam. The efficacy of the former has been tested against intra-abdominal and urinary tract infections, based on pivotal studies and clinical experience. Little is known about the use of this agent for the treatment of bacteremia or pneumonia although some phase 3 studies are running and some case series suggest that it may be effective. Although more studies are necessary to provide sufficient scientific evidence in the treatment of multidrug-resistant P. aeruginosa bacteremia, in view of our clinical experience the use of ceftolozane/tazobactam should be considered.