This report describes a significant clinical case where TAZ/CTLZ and low-dose TOB combination therapy was successfully used to treat XDR-P. aeruginosa infection in a patient with severe burns. To our knowledge, this treatment approach has not been previously reported.

In patients with severe burns, infection is the most common complication that is associated with an increased mortality risk [3]. The burn wound is initially colonized by a higher proportion of Gram-positive bacteria with continued antimicrobial therapy, these bacteria are often replaced by Gram-negative ones [12]. A 50% increase in mortality has been reported in patients with burns having Gram-negative bacteremia compared with those without bacteremia [13]. Moreover, due to the increasing antibiotic resistance, the treatment of infections has become difficult and has contributed to the increased mortality rate. Furthermore, MDR-P. aeruginosa causes 4–60% of nosocomial infections, which leads to high mortality and morbidity in patients with burns [14, 15]. Therefore, controlling P. aeruginosa and preventing the development of antibiotic-resistant strains is crucial for infection control in burn wards and successful treatment of burns. In this case, XDR-P. aeruginosa was detected within 1 month after the first positive blood culture, and bacteremia caused by this isolate persisted; thus, controlling XDR-P. aeruginosa was necessary for the successful treatment of this patient.

Combination therapy with more than two antibiotics with anti-P. aeruginosa activity is recommended for the treatment of severe P. aeruginosa infections to decrease the risk of treatment failure. Among the effective regimens, the β-lactam and aminoglycoside combination is frequently used, and this combination is effective against MDR-P. aeruginosa infections [16, 17]. In this case, the MEPM and AMK combination therapy used to treat XDR-P. aeruginosa infection did not result in any clinical improvement. A possible cause of treatment failure was that this patient had AKI and was receiving low doses of MEPM and AMK. In support of this, a synergistic study of antibacterial activity against resistant P. aeruginosa showed that the combination of MEPM and AMK at low doses did not show a synergistic effect (Fig. 2).

A recent study reported that TAZ/CTLZ therapy is more effective than colistin, polymyxin, or aminoglycoside-based regimens, in severe P. aeruginosa infections. The CEFTABUSE registry results showed that the 14-day clinical cure rates of TAZ/CTLZ administration were more effective than those of aminoglycosides and polymyxin, although the difference was not statistically significant [18]. A retrospective cohort study showed that TAZ/CTLZ administration was independently associated with clinical cure compared with colistin- or aminoglycoside-based regimens [19]. These two studies indicated that the incidence of AKI was significantly lower with the TAZ/CTLZ treatment group, indicating that TAZ/CTLZ can be an effective option for patients with renal dysfunction or those with a high risk of nephrotoxicity. However, in this case, treatment with TAZ/CTLZ monotherapy failed to suppress the persistent bacteremia caused by resistant P. aeruginosa. This could be due to the fact that retrospective P. aeruginosa drug susceptibility testing had revealed a TAZ/CTLZ-resistant strain.

In our case, persistent bacteremia caused by resistant P. aeruginosa was controlled after initiation of combination therapy with TAZ/CTLZ and low-dose TOB. We believe that the fact that blood cultures became negative on two consecutive follow-up evaluations after the start of combination therapy with TAZ/CTLZ and TOB proves the effectiveness of the combination therapy. The success of this combination therapy supported two previous reports [10, 11].　An in vitro study has assessed the efficacy of a combination therapy of TAZ/CTLZ and an aminoglycoside [10], demonstrating that the TAZ/CTLZ and AMK combination therapy has synergistic effects and may therefore be useful in treating MDR-P. aeruginosa infections. In another study conducted on febrile neutropenic patients with concurrent TAZ/CTLZ -resistant P. aeruginosa infection, the combination of TAZ/CTLZ and TOB synergistically decreased the respective minimal inhibitory concentration values [11]. Thus, in our case, the addition of TOB improved the anti-microbial effects and possibly enhanced the efficacy of TAZ/CTLZ. One difference between these two previous reports and the present case is the dosage of TOB. In these two previous studies, the dosing settings were 25 mg/kg/q24h for AMK and 7 mg/kg/q24h for TOB, which were capable of reaching the target peak concentrations required for therapeutic effects. In our case, TOB was initiated at a dose of 3 mg/kg, which is much lower than the dose required to achieve the target peak concentration to produce a therapeutic effect (5–7 mg/kg/q24h). Furthermore, renal function at the time of TOB initiation in this patient was eGFRcreat > 130 mL/min/1.73 m2, a condition suspicious for augmented renal clearance (ARC). Previous reports suggest that the recommended dose of TOB in patients with ARC is 7 mg/kg/day to achieve pharmacodynamic goals [20]. It has also been reported that split doses or higher doses may be required to reach target peak concentrations in severe burn patients with increased volume of distribution and increased clearance [21, 22]. Generally, when TOB is administered at a low dose for its synergistic effects against Gram-negative bacteria, its peak concentration is not routinely measured. However, actual measured TOB trough concentrations (Table S2) and patient factors also suggest that the effective peak concentration has not been reached. Despite a low dose of TOB for persistent bacteremia, the success in achieving negative blood culture results suggests an enhanced synergistic efficacy of the TAZ/CTLZ and TOB combination therapy.

We did not select quinolones as an antibiotic treatment option for XDR-P. aeruginosa. Although quinolones constitute effective therapeutic options for P. aeruginosa infections, a meta-analysis indicated that the use of quinolones increased the risk of MDR- or XDR-P. aeruginosa compared with that of resistant or susceptible P. aeruginosa [23]. Therefore, the use of quinolones was avoided here to prevent P. aeruginosa from acquiring multidrug or extensive drug resistance.

In our case, TAZ/CTLZ susceptibility testing of P. aeruginosa-resistant strains was performed retrospectively, which has rarely been reported of P. aeruginosa strains that acquired resistance prior to TAZ/CTLZ exposure in Japan. The stability of TAZ/CTLZ against the main resistance mechanisms of P. aeruginosa, such as OprD deficiency, increased AmpC production, and drug excretion proteins [6, 24], underscores that TAZ/CTLZ resistance can result from the intense use of other β-lactam antibiotics that can induce or inhibit AmpC production, independently of TAZ/CTLZ use [25]. Therefore, it is possible that the use of multiple β-lactam antibiotics during the 1-month burn treatment period contributed to the development of TAZ/CTLZ resistance. However, the mechanisms driving TAZ/CTLZ resistance need to be further explored. Notably, the combination of TAZ/CTLZ and low-dose aminoglycoside antibiotics may be an effective antimicrobial treatment option, even in P. aeruginosa strains that exhibit TAZ/CTLZ resistance.

A limitation of this study is that no antimicrobial synergism study of TAZ/CTLZ and TOB was conducted; therefore, TOB monotherapy may have been more effective than TAZ/CTLZ and TOB synergistic therapy. Therefore, future antimicrobial synergistic studies of TAZ/CTLZ and low-dose aminoglycosides in vitro should be conducted to clearly distinguish between additive and synergistic effects. However, we consider it a clinically serious finding that in the present case, treatment with TAZ/CTLZ and low-dose TOB resulted in negative blood cultures for XDR-P. aeruginosa bacteremia resistant to TAZ/CTLZ.

In conclusion, this case highlights the efficacy of a combination therapy with TAZ/CTLZ and low-dose TOB in managing persistent XDR-P. aeruginosa bacteremia in patients with severe burns. Furthermore, the combination of TAZ/CTLZ with low-dose TOB is a promising antimicrobial option for TAZ/CTLZ-resistant P. aeruginosa infections. Further research is warranted to validate the findings of this study and explore the potential benefits and limitations of this regimen.