Pseudomonas aeruginosa (P. aeruginosa) is a common nosocomial pathogen that often causes pneumonia in hospitalized patients [ 1,2]. Due to the fact that P. aeruginosa is a virulent organism that is susceptible to only a limited number of antibiotic agents, infections caused by this organism are difficult to cure and often require combination therapy. Although the definition of multidrug-resistant P. aeruginosa (MDRP) has not been standardized internationally, it is defined as P. aeruginosa resistant to ceftazidime, ciprofloxacin, piperacillin, imipenem, and amikacin [ 3,4]. In Japan, it is usually defined as P. aeruginosa resistant to carbapenems, such as imipenem or meropenem, fluoroquinolones, and amikacin by the Japan Nosocomial Infections Surveillance (JANIS), a program of the Ministry of Health, Labour and Welfare [ 5]. The increasing resistance of P. aeruginosa is a growing threat to the clinical management of such infections [ 6].

Piperacillin/tazobactam (PIPC/TAZ) and ceftolozane/tazobactam (CTLZ/TAZ) are antibiotic regimens that combine a beta-lactamase inhibitor with an anti-pseudomonas agent, either penicillin or cephem, and their use for treating P. aeruginosa has increased, which has contributed to inhibiting carbapenem and fluoroquinolone overuse in Japan [ 7,8]. Therefore, PIPC/TAZ and CTLZ/TAZ are named ‘carbapenem-alternative drugs’ and are recommended for P. aeruginosa pneumonia to decrease the emergence of carbapenem-resistant P. aeruginosa [ 8,9]. However, the appearance of P. aeruginosa resistant to these two antibiotics is also a concern, and how to use these antibiotics, especially CTLZ/TAZ, may be controversial and unclear, because world-wide use of CTLZ/TAZ has recently started[ 8].

In this report, two cases of P. aeruginosa pneumonia are presented. Both cases had malignant tumors as the underlying diseases and were treated by PIPC/TAZ followed by CTLZ/TAZ after surgery. CTLZ/TAZ was effective, after PIPC/TAZ became ineffective. However, the first case had bacteremia and died, and CTLZ/TAZ-resistant P. aeruginosa was isolated after 14 days of treatment, and the second case without bacteremia survived after 10 days of treatment by CTLZ/TAZ.

These cases and the related study were approved as #2022-072 by the Institutional Review Board of Saitama Medical University International Medical Center on September 07, 2022 and registered as UMIN000047992, and the patients whose specimens were used provided written, informed consent to have their case details and any accompanying images published.

A 76-year-old man with esophageal cancer underwent esophagectomy after chemotherapy for 2 months, but he developed hospital-acquired pneumonia (HAP) 6 days after the operation (Figure 1A). Infiltration shadows in both lung fields were found on chest X-rays, and arterial oxygen saturation (SpO₂) was 95% (O₂ 10-L mask). P. aeruginosa was isolated, and TAZ/PIPC drip infusion 4.5 g three times per day and high-flow nasal canula (HFNC) management were started from this day (day 0). Laboratory data on day 0 were as follows: white blood cell (WBC) count, 14.56 x 10³/F06DL, with 93.1% neutrophils, 3.3% lymphocytes, 3.4% monocytes, 0.1% eosinophils, and 0.1% basophils; platelet count, 13.2 × 10⁴/F06DL; hemoglobin, 8.5 g/dL; blood urea nitrogen, 14.3 g/L; serum creatinine, 0.66 mg/dL; aspartate aminotransferase (AST), 21 U/L; alanine aminotransferase (ALT), 61 U/L; and C-reactive protein (CRP), 21.930 mg/dL.

After 10 days, his condition, including respiratory status, chest X-rays, and laboratory data, had improved, and PIPC/TAZ was switched to sulbactam/ampicillin (Figure 1B). However, on day 14, his respiratory condition, including chest X-ray, deteriorated, and septic shock developed (Figure 1C). Ventilator management and vasopressors were started. P. aeruginosa was isolated from the sputum and blood, and the isolated P. aeruginosa was found to show resistance to PIPC/TAZ (Table 1, left column). CTLZ/TAZ was started instead on day 28, and the pneumonia improved (Figure 1D). CTLZ/TAZ was then switched to levofloxacin, but his condition worsened again on day 32, and P. aeruginosa resistant to CTLZ/TAZ was isolated from his blood (Table 1, right column). Finally, he died due to septicemia and renal failure.

A 51-year-old woman received a tracheotomy because of tracheobronchial injury following surgery for a brain tumor, and PIPC/TAZ was used to treat the isolated P. aeruginosa, which showed good susceptibility to most antibiotics (Table 2, left column). Seven days later, she developed ventilator-associated pneumonia (VAP) and then pneumothorax. Chest X-ray and computed tomography (CT) showed a massive infiltration shadow in the right lower lung field after expansion by drainage (Figure 2A and B). Laboratory data on that day (day 0) were as follows: white blood cell (WBC) count, 7.93 x 103/F06DL, with 82.0% neutrophils, 15.5% lymphocytes, 1.6% monocytes, 0.1% eosinophils, and 0.8% basophils; platelet count, 23.1 × 104/F06DL; hemoglobin, 7.9 g/dL; blood urea nitrogen, 18.3 g/L; serum creatinine, 0.29 mg/dL; aspartate aminotransferase (AST), 62 U/L; alanine aminotransferase (ALT), 117 U/L; and C-reactive protein (CRP), 12.963 mg/dL. Since the isolated P. aeruginosa became resistant to TAZ/PIPC (Table 2, right column), she was switched to CTLZ/TAZ. Ten days later (day 10), she recovered, and her chest X-ray and CT were improved (Figure 2C and D). Her pneumonia improved smoothly without bacteremia.

P. aeruginosa is a Gram-negative, aerobic, rod-shaped, polar-flagella bacterium, and an opportunistic pathogen responsible for VAP. VAP due to P. aeruginosa is usually multidrug-resistant and associated with severe infection and increased mortality, and it has been associated with higher rates of treatment failure, relapse, and death [ 10].

In this report, two cases of pneumonia, one HAP and one VAP, due to P. aeruginosa were presented. Both cases were treated by PIPC/TAZ first and then switched to CTLZ/TAZ treatment after 7-10 days because of relapse or exacerbation of the pneumonia. PIPC/TAZ is known as the penicillin to cover P. aeruginosa and is usually recommended for P. aeruginosa pneumonia, and a duration of treatment of 7-10 days may be appropriate [ 9]. Although it was previously recommended that antibiotics be continued for a minimum of 14–21 days to reduce the chance of relapse, the recent guidelines recommended a 7-day course of therapy for VAP, regardless of causative pathogen. To support their recommendation, the expert consensus panel performed a meta-analysis of studies comparing a short course (7–8 days) versus a long course (10–15 days) of therapy and found no differences in mortality or VAP recurrence [ 9,11]. However, in the present cases, PIPC/TAZ-resistant P. aeruginosa was isolated after 7-10 days of therapy, which suggests that PIPC/TAZ might easily induce resistant bacteria in P. aeruginosa pneumonia.

Furthermore, CTLZ/TAZ was used after failure of the PIPC/TAZ therapy in the present two cases, with good clinical effectiveness according to the microbiological results that showed that the isolated P. aeruginosa was susceptible. Ceftolozane (CTLZ) is a β-lactam, novel cephalosporin antibiotic that exhibits broad-spectrum activity against P. aeruginosa, especially when combined with tazobactam (TAZ), a β-lactamase inhibitor, and it has been reported that 75% of carbapenem-resistant P. aeruginosa were susceptible to CTLZ/TAZ, although 81% of the MDRP strains were resistant [ 12]. CTLZ/TAZ was thus non-inferior to meropenem (MEPM) in terms of both 28-day all-cause mortality and clinical cure at test of cure, and it has been used as a ‘carbapenem-alternative antibiotic’ to reduce the emergence of carbapenem-resistant bacteria from the perspective of antimicrobial stewardship [ 13,14]. In fact, CTLZ/TAZ was effective, although the isolated P. aeruginosa became resistant to PIPC/TAZ, which has a similar spectrum to the carbapenem antibiotics, in the present cases. However, in case 1, the isolated P. aeruginosa also became resistant to CTLZ/TAZ after 14 days of treatment for pneumonia, and the patient showed bacteremia. In contrast, the case 2 patient completed the treatment for pneumonia without bacteremia within 10 days and ultimately survived. These data suggest that CTLZ/TAZ be used for P. aeruginosa pneumonia treatment within 7-10 days, the same as PIPC/TAZ and carbapenems to reduce the risk of the development of resistant strains and bacteremia.

P. aeruginosa and related pseudomonas strains were the second most common Gram-negative organisms in bloodstream infections among adult cancer patients, and one of the most common carbapenem-resistant isolates. Although the incidence of MDR Gram-negative blood stream infection (BSI) increased annually during 2015-2018, the mortality rate of Gram-negative BSI remains unchanged at about 20%; however, the mortality rate was significantly greater (35.4%) in those with resistant Gram-positive BSIs[ 15]. It was reported that the overall mortality rate was 21.5%. Early (7-day mortality) and late mortality (30-day mortality) rates were 10% and 3.4%, respectively. These data suggested that bacteremia was critical in P. aeruginosa infection, and we should take care not to induce bacteremia and resistant strains even when using novel antibiotics, including CTLZ/TAZ, and it might be better to complete the treatment for P. aeruginosa pneumonia within 7-10 days.

Two cases of P. aeruginosa pneumonia treated with PIPC/TAZ followed by CTLZ/TAZ were presented. The case 1 patient received prolonged treatment with PIPC/TAZ and CTLZ/TAZ, and the organism became resistant to both in sequential order. The patient had not only pneumonia, but also bacteremia, and finally died. The case 2 patient completed treatment with CTLZ/TAZ for P. aeruginosa pneumonia within the appropriate period and finally survived without bacteremia. We should take care to use broad-spectrum antibiotics appropriately, even though the drugs might be novel and effective, to avoid creating resistant strains and severe complications including bacteremia.

COI:

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Acknowledgments

The authors would like to thank all healthcare staff, including physicians, pharmacists, nurses, and medical clinical microbiological technicians, for their kind support with respiratory management in Saitama Medical University International Medical Center.