Salvage Therapy with Ceftolozane-Tazobactam for Multidrug-Resistant Pseudomonas aeruginosa Infections

ABSTRACT

Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) present a major problem for therapeutic management. We report here our experience with 12 patients with a severe MDRPA infection (6 of which were pneumonia) who received salvage therapy with ceftolozane-tazobactam after inappropriate empirical treatment and/or suboptimal targeted treatment. Although 10 of the 12 patients (83.3%) experienced septic shock, only 3 patients (25%) died during the follow-up period. Microbiological cure in 7 patients (58.3%) was observed.

TEXT

The increase in infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) in recent years has hindered the selection of an appropriate antibiotic treatment, leading to an increase in the morbidity and mortality rates in patients with such an infection (1, 2).

In patients with MDRPA infection, resistance to widely used antibiotics, such as antipseudomonal beta-lactams or quinolones, has led to the use of alternative treatment, such as colistin or aminoglycosides, which confer a high risk of nephrotoxicity (3, 4).

To overcome this problem, new antibiotics, such as ceftolozane-tazobactam (C-T), which can be an effective and safe alternative for the treatment of MDRPA infections (5, 6), were recently developed. C-T is a new combination of an antipseudomonal cephalosporin and a beta-lactamase inhibitor. The drug exhibits potent in vitro activity against MDRPA strains and other Gram-negative microorganisms, including extended-spectrum beta-lactamase-producing (ESBL) Enterobacteriaceae (although activity against ESBL Klebsiella is lower than that against other ESBL-producing Enterobacteriaceae) (7, 8). The efficacy of C-T was evaluated in two pivotal phase III trials that resulted in the drug being approved for the treatment of complicated urinary tract infection, including acute pyelonephritis (9), and in the treatment of complicated intra-abdominal infections associated with metronidazole (10).

In spite of the results of these clinical trials, experience regarding the clinical and microbiological efficacy of C-T in other indications has been limited, especially in patients with severe infection in whom this antimicrobial has been used due to the lack of response to previous antibiotic treatment.

We conducted a retrospective, descriptive, multicenter study of consecutive patients in a series of compassionate uses of C-T in Spain between September 2015 and June 2016. Each patient received C-T as salvage therapy. Included in the study were patients who (i) were 18 years or older and (ii) had an MDRPA infection that was unresponsive to previous antibiotic treatment. Strains were considered to be MDR when resistance to at least three of the following antimicrobials was present: antipseudomonal cephalosporin (cefepime), piperacillin-tazobactam, meropenem, ciprofloxacin, and aminoglycosides.

Infections were classified according to the criteria of the Centers for Disease Control and Prevention (11). The MIC of C-T was determined using an MIC test strip assay (Liofilchem, Italy). To determine the sensitivity or resistance of P. aeruginosa to antibiotic treatment, (EUCAST) breakpoints were used.

A total of 12 patients with different severe MDRPA infections were included (Table 1). The median age of the patients was 67 years (range, 54 to 75 years), and most of them had significant comorbidities. All cases were hospital-acquired infections with a median time from admission to the isolation of MDRPA of 28 days (range, 10 to 56 days). All patients produced isolates resistant to antipseudomonal beta-lactams (including meropenem), ciprofloxacin, and piperacillin-tazobactam, and 9 of them (75%) were resistant to aminoglycosides. The isolates from 8 patients (66.6%) were sensitive to colistin. In contrast, all isolates obtained after initial clinical failure were sensitive to C-T. Prior to obtaining the culture results, empirical treatment was initiated in 11 patients for a median duration of 7 days (range, 2 to 9 days) and later changed to targeted therapy (mainly with colistin) for a median duration of 7.5 days (range, 9 to 18 days). Finally, when clinical failure of the initial targeted therapy was detected, treatment with C-T was initiated for a median duration of 12 days (range, 9 to 18 days) from the start of empirical treatment.

TABLE 1.

Patient characteristics and clinical outcomes of ceftolozane-tazobactam treatment as salvage therapy for MDRPA infection

Patient no.	Age (yrs), sex	Comorbidity(ies)	Treatment susceptibility (MIC [mg/liter])a	Primary focus(es) of infection	Procedure	Presence of bacteremia	Initial presentation of infection	Prior antibiotic therapy	Duration (days), dose of C-T treatment (g/8 h)	Outcome
										Clinicalb	Microbiologicalc
1	65, female	Diabetes mellitus	C-T (0.25), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (4)	Abdominal	Drainage of abscess	Yes	Septic shock	Empirical: MEM 2 g/8 h; targeted: CST 4.5 mIU/12 h	14, 1.5	Cure	Eradication
2	75, female	None	C-T (0.5), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (<4)	Respiratory	None	Yes	Septic shock	Empirical: TZP 4.5 g/8 h; targeted: CST 4.5 mIU/12 h	10, 3	Cure	Eradication
3	37, male	Bronchomalacia	C-T (0.5), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (<4)	Respiratory	None	No	Severe sepsis	Empirical: TZP 4.5 g/8 h; targeted: CST 4.5 mIU/12 h	10, 3	Cure	Eradication
4	70, male	None	C-T (0.5), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (<4)	Abdominal	Drainage of abscess	No	Septic shock	Empirical: MEM 2 g/8 h; targeted: CST 4.5 mIU/12 h	21, 1.5	Cure	Eradication
5	45, male	Burkitt lymphoma, severe neutropenia	C-T (2), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Otitis and mastoiditis	Drainage	No	Sepsis	Empirical: FEP 2 g/8 h + amikacin 1 g/24 h; targeted: C-T 1.5/0.5 g/8 h	21, 3	Cure; late recurrence	Eradication; late recurrence
6	74, male	Lung cancer, diabetes mellitus, COPD,d acute renal failure	C-T (2), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Respiratory	None	Yes	Septic shock	Empirical: none; targeted: TZP 4.5 g/6 h + inhaled CST 2 mIU/8 h	15, 3	Death	Eradication
7	53, male	Hepatitis C infection	C-T (<4), MEM (>8), CIP (>1), FEP (>8), TZP (64/4), TOB (>4)	Abdominal	Laparotomy	No	Septic shock	Empirical: MEM 2 g/8 h + daptomycin 600 mg/24 h; targeted: C-T 1 g/8 h	11, 1.5	Death	Persistence
8	76, female	Diabetes mellitus, COPD	C-T (1), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Biliary	Biliary drainage	No	Septic shock	Empirical: aztreonam 2 g/8 h + tigecycline 100 mg/12 h + fluconazole 400 mg/24 h; targeted: CST 3 mIU/12 h + aztreonam 2 g/8 h + tigecycline 100 mg/12 h + fluconazole 400 mg/24 h	9, 1.5	Cure	Eradication; late recurrence
9	79, male	Diabetes mellitus, COPD, renal failure, chronic heart failure	C-T (1), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Venous Central Catheter	Catheter removal	Yes	Septic shock	Empirical: MEM 500 mg/12 h; targeted: MEM 2 g/8 h + amikacin 15 mg/kg/24 h	14, 1.5	Cure	Eradication
10	79, male	None	C-T (1), MEM (>8), CIP (>1), FEP (8), TZP (>16), TOB (>4)	Respiratory	None	No	Septic shock	Empirical: MEM 2 g/12 h + CST 4.5 mIU/12 h; targeted: C-T 1.5/0.5 g/8 h	14, 1.5	Cure	No data
11	61, male	Immunosuppression	C-T (1), MEM (8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Respiratory	None	Yes	Septic shock	Empirical: MEM 2 g/8 h; targeted: CST 2 mIU/8 h	3, 1.5	Death	Persistence
12	58, male	Lung transplantation, acute renal failure, immunosuppression, mediastinitis	C-T (1), MEM (>8), CIP (>1), FEP (>8), TZP (>16), TOB (>4)	Respiratory	None	No	Septic shock	Empirical: ceftazidime 6 g/day (continued infusion) + amikacin 1 g/24 h; targeted 1st line: ceftazidime 6 g/day (continued infusion) + amikacin 1 g/24 h; targeted 2nd line: CST 3 mIU/8 h	21, 1.5	Cure	Persistence

^aC-T, ceftolozane-tazobactam; MEM, meropenem; CST, colistin; CIP, ciprofloxacin; FEP, cefepime; TZP, piperacillin-tazobactam; TOB, tobramycin.

^bThirty days after isolation of P. aeruginosa. Clinical outcome was considered “cure” when the attending physician observed resolution of signs and symptoms and there were no radiologic findings of infection.

^cThirty days after end of therapy with ceftolozane-tazobactam.

^dCOPD, chronic obstructive pulmonary disease.

Although infection presented as septic shock in 10 of the 12 patients (83.3%), only 3 out of the 12 patients (25%) died during the follow-up period despite the initial severity, inappropriate empirical treatment, and delayed initiation of C-T. One of these patients underwent a pulmonary lobectomy for a Pancoast tumor that required a long stay in the intensive care unit, although due to bone metastasis, aggressive measures were limited (patient 6). However, results of blood and bronchial aspirate cultures performed before death were confirmed to be negative in this patient. The other 2 patients with septic shock who died had significant comorbidities. One of them (patient 11) received C-T at doses of 1.5 g/8 h despite having pneumonia.

In 6 of the 12 patients (50%) C-T was used for the treatment of pneumonia, although this antibiotic is not currently approved for this indication. In all these cases, C-T was administered as salvage therapy, given the presence of severe sepsis or septic shock unresponsive to initial treatment with meropenem, colistin, ceftazidime, or piperacillin-tazobactam, depending on the case. Previous studies have shown that C-T has good lung penetration (12), and it has been used to treat patients with MDRPA pneumonia with good results (13, 14), although the efficacy of C-T in this indication should be evaluated through clinical trials, which are currently in progress (ClinicalTrials.gov registration no. NCT02387372).

C-T was used safely in most patients, although treatment had to be suspended in one patient (patient 6) due to the development of dissociated cholestasis.

In 10 patients (83.3%), microbiological eradication was observed 30 days after completion of treatment with C-T, which is similar to observations in previous studies (8). In these patients, the median duration of treatment with C-T was 14 days (range, 9 to 21). However, 2 of these patients (patients 5 and 8) produced C-T-resistant MDRPA isolates in cultures taken subsequent to this period (the MIC for C-T was 48 mg/liter in both cases). Only one of these two patients (a patient with Burkitt lymphoma and profound neutropenia who had otomastoiditis) experienced clinical recurrence despite having been treated with high doses of C-T (3 g/8 h), which were given because of uncertainty about its penetration into the focus of infection. Therefore, the possibility of acquiring resistance to C-T should be considered in patients with previous exposure to beta-lactams and with recurrence or poor response to this antibiotic (15). For this reason, it might be advisable to test the MIC of C-T in patients with severe infection, a history of infection, and previous treatment against P. aeruginosa (even if the isolation is multisensitive).

In conclusion, the results of our series provide encouraging evidence of the efficacy of C-T in patients with serious infection (especially pneumonia) caused by MDRPA. This evidence needs to be confirmed in larger patient cohorts and ultimately in randomized trials.