Clinical success of anti-infective combination therapy compare to monotherapy in patients with carbapenem-resistant Pseudomonas aeruginosa infection: a 10-years retrospective study

Pseudomonas aeruginosa (P. aeruginosa) is a ubiquitous microorganism that causes different types of infections, primarily in immunosuppressed patients, critical care patients, or those with comorbidities [1]. P. aeruginosa is also one of the most common pathogens that causes nosocomial infections, including central line-associated bloodstream infections, ventilation-associated pneumonia [1].

For clinicians, selecting an appropriate antibiotic regimen for Carbapenem-resistant P. aeruginosa (CRPA) infections is a global challenge. Instead of carbapenems, other antibiotics, such as ceftolozane-tazobactam, aminoglycoside, and fosfomycin, can be used against CRPA [2, 3]. The rationale for combination anti-infective therapy against CRPA is based on the possibility of achieving a higher rate of bacterial killing. Current clinical guidelines suggest using combination therapy to treat patients with severe CRPA infections [2, 3]. However, it is a conditional recommendation for use, and insufficient evidence is available for this recommendation. Current guidelines do not provide a specific method to identify severe CRPA infections [2, 3]. Additionally, recent studies have demonstrated that the effects of monotherapy and combination therapy on the prognosis of CRPA infection remain controversial [4‐7].

Furthermore, there is growing evidence of harm caused to individual patients by unnecessary antimicrobial use. More antibiotic use risks higher costs, and it is more likely to cause drug-related adverse events such as allergic or hypersensitivity reactions and kidney injury [8]. In addition to adverse drug reactions and drug toxicity, antimicrobial resistance is one of the most widely recognized mechanisms of antimicrobial-associated harm [8]. A prospective observational study found that concomitant use of several antimicrobials is associated with an excess mortality risk compared to monotherapy [9].

Sepsis is characterized by fatal organ dysfunction caused by an overwhelming host response to an infection. The sequential organ failure assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction and the severity of septic shock in sepsis [10, 11]. The primary objective of this study is to determine the effectiveness of anti-Infective combination therapy compared to monotherapy in achieving clinical success in patients with CRPA infection and risk factors of clinical failure of monotherapy.

The primary objective of this study is to determine the effectiveness of anti-Infective combination therapy compared to monotherapy in achieving clinical success in patients with CRPA infection and risk factors of clinical failure of monotherapy. In this study, we found that combination therapy is recommended for CRPA infection patients, especially those whose SOFA score was ≥2 or whose Charlson comorbidity index was ≥6. Regarding all-cause 28-day mortality, we did not find any differences between the monotherapy and combination therapy groups.

CRPA has emerged and caused many nosocomial outbreaks, leading to millions of deaths each year [13, 14]. As the carbapenem-resistance mechanisms are complicated, selecting an effective and safe antibiotic regimen remains a challenge. Traditional antipseudomonal β-lactams, including cefepime, ceftazidime and piperacillin/tazobactam and new BLBLIs (ceftazidime-avibactam and ceftolozane-tazobactam), have been found to be effective for CRPA [2, 3]. To increase the success rates of treatment, researchers have attempted to identify the most effective antibiotic regimens against CRPA. In this study, we also found that combination therapy was more effective than monotherapy in patients with CRPA infection. However, the effectiveness of combination therapy for CRPA infections remains controversial. One way of assessing the effectiveness of antibiotic regimens involves in vitro methods based on bacterial killing and antibiotic synergism [15, 16]. According to Ramos JF [4] et al., meropenem with colistin demonstrated superior performance compared to other antibiotic regimens. In vivo CRPA models were also created to test the efficacy of antibiotic regimens. In an intraperitoneal murine CRPA infection model, combination therapy involving colistin and rifampicin exerted a synergistic effect [17]. A previous study demonstrated that the combination of caspofungin and polymyxin exhibited superior efficacy compared to caspofungin alone in reducing mixed biofilm biomass and fungal and bacterial viability in CRPA strains [18]. Similarly, the combination of ceftazidime/avibactam (CZA) with aztreonam (ATM) showed synergistic bacteriostatic or bactericidal activity against NDM-, IMP-, KPC+IMP-, and KPC+NDM-producing carbapenem-resistant Enterobacterales (CRE) strains. This combination therapy not only reduced mortality but also prolonged the lifespan of mice infected with these strains [19]. Furthermore, a combination therapy involving aggressive doses of polymyxin B and tigecycline displayed synergistic or additive effects in treating multidrug-resistant carbapenem-resistant Acinetobacter baumannii(CRAB) infections in humans [20]. In a previous retrospective cohort study included critically ill patients with CRAB infections, they found that patients who received the combination therapy of colistin plus meropenem had a significantly lower adjusted odds ratio (aOR) for 30-day mortality compared to those who received colistin monotherapy. The aOR for 30-day mortality was 0.43, with a 95% confidence interval (CI) ranging from 0.23 to 0.82 [21]. The results of previous study showed that CRAB infections patients who received loading dose (LD) colistin-imipenem had a lower 30-day survival rate (adjusted HR = 0.57, 95% CI: 0.37-0.90; p = 0.015) and a lower clinical response (aHR = 0.56, 95% CI: 0.35-0.90; p = 0.017) compared with those who received LD colistin-meropenem [22].

However, combination therapy did not improve clinical outcomes in all patients with carbapenem-resistant bacteria infection. In a study by Mical Paul [12] et al., which included 406 patients, no significant difference was observed in clinical failure at 14 days after randomization between the colistin monotherapy group (156/198, 79%) and the combination therapy group (152/208, 73%) (risk ratio [RR] 0.93, 95% CI 0.83-1.03). Regarding infections caused by CRAB, the combination of colistin with vancomycin did not show any significant differences in 30-day mortality, clinical response, or microbiological response compared to colistin alone. The rates of nephrotoxicity were similar in both groups, suggesting that colistin combination therapy with vancomycin may not be necessary for managing CRAB infections [23]. A recent meta-analysis that involved 11 studies and 396 patients with carbapenem-resistant gram-negative bacteria (CRGNB) receiving ceftazidime/avibactam alone or in combination was conducted. There was no significant difference in the mortality rate and microbiological cure rate between combination therapy and monotherapy (38.1% vs. 30.9%; 64.9% vs. 63.4%), according to the meta-analysis [24]. In Western China, a retrospective study of 355 patients with Carbapenem-resistant Gram-negative bacterial bloodstream infections (CRGNB-BSI) found that Combination antimicrobial therapy was not superior to monotherapy (P = 0.387) and appropriate therapy was associated with lower treatment failure and 28-day in-hospital mortality rates [25]. Another retrospective study of 164 CRE bloodstream infection cases in China, highlighted the importance of early detection of carbapenemase type and timely initiation of appropriate combination therapy for improving survival [26]. A randomized clinical trial investigated the association between mortality in Acinetobacter baumannii infections and colistin resistance, showed that colistin monotherapy yielded better outcomes compared to colistin-meropenem combination therapy for patients with colistin-resistant isolates [27]. Current guidelines do not take a definitive stance on whether to recommend or discourage the use of combination therapy with new antibiotics (ceftazidime-avibactam and ceftolozane-tazobactam) or cefiderocol for CRPA infections [2, 3]. Overall, these studies underscore the importance of exploring combination therapies to combat carbapenem-resistant bacterial infections. While some combinations show promising results and improved outcomes, it's essential to recognize that not all combination therapies may be effective in every case. The severity of the infection, the specific bacterial strain, and individual patient factors may influence the success of combination therapies. Further research and clinical trials are necessary to identify the most effective treatment strategies for combating carbapenem-resistant bacteria infections.

In addition to finding the most effective antibiotic regimens, identifying the patients who benefit most from monotherapy is also important. Antibiotics can harm patients by various mechanisms: drug toxicity, mitochondrial dysfunction and organ dysfunction, adverse drug reactions, and antimicrobial resistance [8]. Therefore, in order to prevent harm caused by antimicrobials, doctors should limit their use to only when necessary. For patients with non-severe CRPA infections, current guidelines also recommend individualized selection of in vitro-active monotherapy based on the source and type of infection. However, current guidelines do not provide specific tools to evaluate the severity of CRPA infections [2, 3]. SOFA is one of the most frequently used tools to screen and evaluate the severity of sepsis and is also shown to be closely related to the outcomes of sepsis patients [28]. The SOFA score is required for accurate assessment [29]. Combination therapy consisting of two antimicrobials with gram-negative coverage for empiric treatment is recommended for patients with sepsis or septic shock and a high risk for multidrug-resistant (MDR) organisms [30]. In our study, we also found that combination therapy is beneficial for CRPA-infected patients whose SOFA score was ≥ 2 points to control infection. Similarly, SOFA is recommended to help physicians evaluate clinical CRE infection severity before meropenem-based combination therapy is performed [31].

In addition to organ dysfunction, disease burden should be taken into consideration when physicians evaluate the outcomes of infection. The Charlson comorbidity index has been a useful, simple, and readily applicable tool for physicians in their effort to assess and underline complicated diseases and an indicator of disease burden. Its weighted score was assigned to 17 comorbidities and ages, which were found to be associated with long-term mortality [32]. Patients with weakened immune systems or existing health conditions are more vulnerable to P. aeruginosa and are at greater risk of developing severe infections like septic shock or sepsis [33‐35]. The presence of comorbidities is a crucial factor that affects the prognosis of respiratory system infections. Comorbidities such as cardiovascular disease and cancer, which are included in the Charlson comorbidity index, were associated with worse outcomes in cases of acute respiratory infections [36, 37]. The administration of appropriate antimicrobials is one of the most important interventions to control the infection.

In this study, we also explored which antimicrobial regimen (monotherapy or combination therapy) was beneficial to achieving clinical anti-infection treatment success for those patients who had more comorbid diseases. According to the subgroup analysis results, we further found that combination therapy is more suitable for CRPA-infected patients whose Charlson comorbidity index is not less than 6 to control infection.

Our study has the following limitations. First, it is a retrospective study from a large database, and further random control trials are needed. Second, the data was obtained from the MIMIC-IV database,which may limit the generalizability of the findings to other settings. Different hospitals or regions may have variations in patient populations, treatment protocols, and antimicrobial resistance patterns, which could affect the outcomes. Third, the study included a relatively small sample size (279 subjects), which may limit the statistical power and generalizability of the findings. A larger sample size would provide more robust results and allow for more detailed subgroup analyses. Forth, there are some P. aeruginosa antibiotic susceptibilities results that do not include β-lactam agent, so we do not know if β-lactams are effective against these P. aeruginosa bacteria in vitro.Fifth, potential unmeasured confounders: Despite adjusting for various factors in the multivariate analysis, there may still be unmeasured confounding variables that were not accounted for. These variables could potentially influence the outcomes and introduce bias into the results. Sixth,we had no access to the specific carbapenem-resistance mechanisms of CRPA isolated from patients in our study. Seventh, we did not find the most effective combination therapy regimens for CRPA due to the limitation in the original data.

Combination therapy is more effective for CRPA infection patients, especially those whose SOFA score is ≥ 2 or whose Charlson comorbidity index is ≥ 6. SOFA and Charlson comorbidity index may help clinicians to decide antibiotic regimen and to avoid using unnecessary antibiotics.