Abstract
In intensive care units (ICUs), infection rates range from 18 to 54%, which is five to ten times higher than those observed in other hospital units, with a mortality rate of 9% to 60%. In recent decades, the susceptibility pattern has changed and Gram-Negative Bacteria (GNB) have become a threat due to their high frequency of multidrug resistance associated with a scarcity of therapeutic options. However, the drugs Ceftolozane/Tazobactam (C/T) and Ceftazidime/Avibactam (C/A) are demonstrating good clinical and microbiological response in the treatment of severe nosocomial infections. Therefore, this study aims to evaluate the clinical outcome of patients with severe infections caused by Multidrug-Resistant (MDR) GNB treated with C/T and C/A. Our study evaluates a total of 131 patients who received treatment with C/T and C/A due to infections caused by MDR GNB within the period from 2018 to 2021. The main infections were urinary tract (46,6%) and respiratory (26,7%) infections. Pseudomonas aeruginosa was the prevailing agent in the sample evaluation (34.3%), followed by Klebsiella pneumoniae (30,1%). About 54,9% of patients showed a favorable response, with culture negativation in 66,4% of the samples, with no discrepancy in negativations when comparing ages: 67,7% in young and 66% in elderly patients. Among the patients, 62,6% received monotherapy with C/T and C/A with a better response observed with monotherapy compared to combination therapy (58,6% vs 41,4%). The overall mortality rate was 45%, with MDR GNB infections responsible for 33,9% of these deaths, and the others (66,1%) due to factors such as oncological, hematological, and degenerative neurological diseases. In regards to hematological aspect, 35,1% of patients showed changes, with 28,2% of them presenting anemia, 4,5% thrombocytopenia, and 2,5% thrombocytosis. Concerning the use of invasive devices, higher mortality was observed in patients on mechanical ventilation (52%). In this manner, it was possible to observe that therapy with C/T and C/A yielded a favorable clinical outcome in patients with severe infections caused by MDR GNB in the study. These drugs also demonstrated good tolerability regardless of age or the presence of preexisting comorbidities and were deemed safe when assessing adverse effects. Our data also demonstrate the importance of determining the mechanism of resistance to carbapenems so that these drugs can be used more effectively and rationally.
Keywords: Klebsiella pneumoniae carbapenemases, Extended-spectrum β-lactamases, Multidrug-resistant bacteria, Gram-negative bacteria
Introduction
Gram-Negative Bacteria (GNB) are one of the leading causes of nosocomial infections in critically ill patients [1], particularly those with pre-existing comorbidities [2]. Carbapenems, a class of β-lactam antibiotics, have been considered one of the options for treating infections caused by Multidrug-Resistant (MDR) GNB, especially in cases where other antibiotics have failed [3]. However, the spread of carbapenem-resistant GNB, mainly due to the production of β-lactamases, is a serious public health concern. Therefore, there is an urgent need for new and effective antibacterial therapies, as current options involve high doses of medication and combination strategies with polymyxins, tigecycline, fosfomycin, and aminoglycosides to maximize treatment response [4–6].
The main mechanisms responsible for carbapenem resistance in Enterobacteriales are highlighted by the production of β-lactamase enzymes [7]. These resistance mechanisms are spreading globally and consequently raising serious public concerns [8].
Ceftazidime/Avibactam (C/A) is a cephalosporin combined with a β-lactamase inhibitor that has demonstrated efficacy in the treatment of infections caused by extended spectrum β-lactamase (ESBL) producing Enterobacteriales and Gram-Negative Bacteria Pseudomonas aeruginosa [9]. Unlike other available β-lactamase inhibitors, Avibactam is reversible, allowing it to bind to multiple classes of β-lactamases, such as A, C, and D [10]. Its microbiological response has shown success in isolates of Klebsiella pneumoniae and Escherichia coli producing ESBLs in patients with low sensitivity to ertapenem, meropenem, and ceftazidime [8].
Ceftolozane/Tazobactam (C/T) is a combination of an antipseudomonal cephalosporin with a β-lactamase inhibitor [11], exhibiting powerful action against GNB, particularly against P. aeruginosa. It has high affinity with penicillin-binding proteins (PBP1b and PBP3), high outer membrane permeability, stability against AmpC β-lactamase, and is less affected by efflux pumps compared to other antibiotics [12, 13]. The drug has a good response in the treatment of complex urinary tract infections, intra-abdominal infections, and nosocomial pneumonia [12].
In a comprehensive systematic review conducted using the Meta-analyses of Observational Studies in Epidemiology (MOOSE), examining clinical outcomes and therapeutic efficacy associated with C/A and C/T therapy in the majority of European and North American articles, it was revealed that these pharmaceutical interventions achieved an impressive therapeutic success rate of 73% among patients afflicted with diverse infections attributed to Gram-negative bacilli in healthcare-associated settings. Furthermore, the study observed a relatively low adverse effects rate, with only 10% of cases experiencing such complications [14].
In Latin America, including Brazil, there is a gap in articles that address studies related to clinical and microbiological data and in vivo results of therapy with these combined drug regimens in patients [15]. Some articles focus on in vitro analysis of GNB susceptibility profiles to C/A and C/T [16, 17].
Therefore, obtaining clinical and microbiological data from Brazilian patients with GNB infections who were treated with C/A and C/T therapy is essential to improve the understanding and treatment of these infections.
Materials and methods
For the present study, a cross-sectional analytical cohort clinical trial was conducted to evaluate the clinical outcomes of patients infected with MDR GNB who were admitted to the intensive care units (ICUs) of a private high-complexity hospital in the metropolitan region of Recife, PE, Brazil and treated with C/T and C/A drugs during hospitalization from 2018 to 2021.
The antimicrobial susceptibility profile was evaluated by the infection control committee of the selected hospital for the research. This profile evaluation was made available for consultation in the electronic medical record, as well as the bacterial species related to the various infections of the included patients selected for the study.
The selected patients were all over 16 years of age, who had been admitted to the ICUs from 2018 to 2021 with infections caused by MDR GNB at various infection sites and were treated with C/T and C/A drugs during their hospital stay. Patients with co-infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or who had previously been diagnosed with SARS-CoV-2 were excluded from this study to avoid interference in the obtained results.
The evaluation of the clinical outcome and clinical response to treatment with C/T and C/A drugs was performed using the electronic medical record provided by the hospital. Information such as gender, age, mortality rate, infection site, previous antibiotic therapy, use of invasive devices, length of hospital stay, and previous comorbidities were collected. Similarly, laboratory evaluation was also performed, where information such as creatinine, urea, glutamic oxaloacetic transaminase (GOT), glutamate pyruvate transaminase (GPT), hemogram, platelets, leukogram, C-reactive protein (CRP), international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) were evaluated. It was possible to observe changes present before the start of treatment and changes that could be caused by the use of the drugs under study. The response to antibiotic use was also evaluated by the negation of the culture of the collected samples.
The statistical analysis of the data evaluated in this study was performed using Matlab R2022a, specifically the statistics and machine learning toolbox. The expected value, i.e., mathematical expectation, of the variables investigated consisted of applying the arithmetic mean. The variance was calculated by taking the mean of the squared deviations with respect to the mean value of the variable. Frequencies and percentages of parameters were analyzed with a 95% confidence interval (95% CI).
This study was approved by the Human Research Ethics Committee of the Federal University of Pernambuco (CAE: 45633621.1.0000.5208).
Results
A total of 293 medical records were evaluated, of which 131 were eligible for cohort analysis. The remaining cases were excluded for presenting co-infection or previous infection with SARS-CoV-2, for being under 16 years old, and/or for not having received treatment with the drugs under study during ICU hospitalization.
The study included 65 (49,6%) male and 66 (50,4%) female patients, with a mean age of 70 years and 8 months and a standard deviation of 18.1 years. Most of these patients had pre-existing comorbidities, with the most prevalent being Systemic Arterial Hypertension (81; 61,8%), followed by Diabetes Mellitus (42; 32,06%).
Regarding the presence of comorbidities, 103 (78,6%) patients exhibited underlying health conditions, as documented in Table 1. In the comorbidities subgroup, culture negativation was achieved in 72 (69,9%) instances. Specifically, 33 (45,8%) negativations were achieved with C/A treatment, and 39 (54,2%) with C/T treatment. These findings suggest that C/A may offer a potential benefit in treatment response among patients with comorbidities.
Table 1.
Description of the frequency of variables sex, mean age, comorbidities, and microbiological cultures
| Variables | N (%) |
|---|---|
| Male | 65 (49,6%) |
| Female | 66 (50,4%) |
| Mean Age | 70y.8 m |
| Comorbities | |
| Hypertension | 81 (61,8%) |
| Diabetes Mellitus | 42 (32,1%) |
| Chronic Kidneys Disease | 26 (19,8%) |
| Conorary Artery Disease | 25 (19,1%) |
| Obesity | 22 (16,8%) |
| Heart Failure | 15 (11,4%) |
| Chronic Liver Disease | 0 (0%) |
| Microbiological cultures | |
| Urinary Culture | 61 (46,6%) |
| Tracheal Secretion | 35 (26,7%) |
| Blood Culture | 17 (13%) |
| Rectal Swab | 11 (8,4%) |
| Peritoneal Fluid | 5 (3,8%) |
| Transcatheter | 4 (3%) |
| Operative Wound | 2 (1,5%) |
| Renal Abscess | 1 (0,8%) |
| Bone Fragment | 1 (0,8%) |
Conversely, among patients without comorbidities (28; 21,4%), there were 15 (53,6%) instances of culture negativation. Within this subgroup, 4 (26,7%) cases achieved negativation with C/A treatment, while 11 (73,3%) cases demonstrated a potentially superior response to C/T treatment. These observations suggest that C/T may yield a more favorable response in patients without underlying health conditions.
The hospitalization period had a mean of 7,44 weeks (with a standard deviation of 9,44 weeks) and the mortality rate was 59 deaths (45%), with 20 deaths (33,9%) caused by MDR GNB infection and 39 (66,1%) due to other causes, such as oncological, hematological, and degenerative neurological diseases.
The majority of patients were admitted to the ICU due to urinary tract infection 61 (46,6%), pneumonia 35 (26,7%), 17 (13%) patients presented bloodstream infection, and 5 (3,8%) presented peritoneal fluid infection.
The main isolated bacterium was P. aeruginosa in 49 patients (34,3%), followed by K. pneumoniae in 43 (30,1%) and E. coli in 28 (19,6%). However, the most prevalent bacterium when compared to the mortality rate was K. pneumoniae in 26 (44%) patients. The bacterial resistance profile described in the medical records was the occurrence of β-lactamases in the Gram-negative bacilli isolated from the patients included in this study, which were ESBL 57 (35,6%) enzymes followed by Metallo-β-lactamase (MβL) in 53 (33,1%) isolates. The frequency of Gram-Negative Bacilli and their correlated enzymes are described in Table 2.
Table 2.
Description of the frequency of Gram-negative bacilli and β-lactamase enzymes detected in clinical samples from patients. KPC: Klebsiella pneumoniae carbapenemase
| Gram negative bacilli (%) | Enzymes (%) | ||
|---|---|---|---|
| P. aeruginosa | 49 (34,3%) | ESBL | 3 (6,1%) |
| KPC | 0 (0%) | ||
| MβL | 36 (73,5%) | ||
| Uninformed | 10 (20,4%) | ||
| K. pneumoniae | 43 (30,1%) | ESBL | 32 (52,4%) |
| KPC | 4 (6,5%) | ||
| MβL | 14 (22,9%) | ||
| Uninformed | 11 (18%) | ||
| E. coli | 28 (19,6%) | ESBL | 21 (75%) |
| KPC | 0 (0%) | ||
| MβL | 2 (7,1%) | ||
| Uninformed | 5 (17,8%) | ||
| Enterobacter cloacae | 6 (4,2%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 6 (100%) | ||
| Proteus mirabilis | 5 (3,5%) | ESBL | 1 (20%) |
| KPC | 0 (0%) | ||
| MβL | 1 (20%) | ||
| Uninformed | 3 (60%) | ||
| A. baumannii | 4 (2,8%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 4 (100%) | ||
| Burkholderia cepacia | 2 (1,4%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 2 (100%) | ||
| S. marcescens | 2 (1,4%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 2 (100%) | ||
| Morganella morganii | 2 (1,4%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 2 (100%) | ||
| K. oxytoca | 1 (0,7%) | ESBL | 0 (0%) |
| KPC | 0 (0%) | ||
| MβL | 0 (0%) | ||
| Uninformed | 1 (100%) | ||
During ICU hospitalization, 68 (51,9%) patients had used a central venous catheter (CVC), 45 (34,3%) had inserted an orotracheal tube (OTT), 37 (28,2%) underwent tracheostomy (TQT), and 28 (21,4%) had installed a PICCLINE. Other devices can be evaluated in Table 3. When comparing the mortality rate with the use of invasive devices, the highest percentage was found in the use of OTT (69; 52%).
Table 3.
Use of invasive devices
| Use of invasive devices | N (%) |
|---|---|
| Central Venous Catheter | 68 (51,9%) |
| Orotracheal Tube | 45 (34,3%) |
| Tracheostomy | 37 (28,2%) |
| PICCLINE | 28 (21,4%) |
| Nasoenteral Tube | 26 (19,8%) |
| Foley Catheter | 25 (19%) |
| Gastrostomy | 13 (9,9%) |
| Hemodialysis Catheter | 4 (3%) |
From the hospitalized patients, 82 (62,6%) received monotherapy with C/T or C/A and 49 (37,4%) received combination therapy with other antimicrobials, with concomitant use of meropenem (12), ertapenem (8), polymyxin B (4), linezolid (3), piperacillin (3), and teicoplanin (3) being most prevalent. Other antibiotics that have also been used are found in Table 4.
Table 4.
Combination antibiotic therapy with the drugs under study in patients during hospitalization from 2018 to 2021
| Previous antibiotic therapy | N |
|---|---|
| Meropenem | 12 |
| Ertapenem | 8 |
| Polymyxin B | 4 |
| Linezolid | 3 |
| Piperacillin | 3 |
| Teicoplanin | 3 |
| Vancomycin | 2 |
| Ceftazidime | 2 |
| Gentamicin | 1 |
| Tigecycline | 1 |
| Norfloxacin | 1 |
| Sulfamethoxazole + Trimethoprim | 1 |
| Azithromycin | 1 |
| Cefepime | 1 |
| Ceftaroline | 1 |
| Levofloxacin | 1 |
| Metronidazole | 1 |
Among the patients who received antimicrobial treatment, 58,6% achieved microbiological cure with the use of monotherapy and 41,4% with combination therapy. In the case of patients with K. pneumoniae infections, 27 (62,8%) were treated with C/A, with 14 (51,8%) receiving monotherapy and 13 (48,1%) undergoing combination therapy with other antimicrobials. Among those exclusively treated with C/A, 9 (64,3%) did not survive. However, 10 (71,4%) out of the 14 patients achieved microbiological cure, including 3 ESBL, 5 MβL, and 2 of unknown enzyme origin cases. Similarly, among the 13 patients on combination therapy, 6 (46,1%) did not survive. However, 10 (76,9%) achieved culture clearance, including one ESBL and 5 MβL cases. From the 4 patients whose isolates presented KPC-producing K. pneumoniae, all were treated with C/A, with 3 (75%) receiving combination therapy and only one (25%) receiving monotherapy.
Of the 3 patients treated with combination therapy, one (33,4%) survived and had negative cultures after evaluation, and 2 (66,6%) died, but one (33,4%) of them had negative cultures after evaluation. The patient who received monotherapy did not die and had negative cultures at the end of the evaluation.
For patients receiving C/T, 7 (43,7%) underwent monotherapy, and 9 (56,2%) underwent combination therapy. All 7 patients under exclusive C/T treatment did not survive. Nevertheless, 4 (57,1%) still achieved culture clearance, including one ESBL and 3 cases of unknown enzyme origin. Among those on combination therapy (9; 56,2%), 4 (44,4%) patients did not survive, while 8 (88,9%) achieved culture clearance, including 4 ESBL and 4 cases of unknown enzyme origin.
Moving on to patients infected with E. coli, 5 (17,8%) were treated with C/A, of which 2 (40%) received monotherapy, and 3 (60%) underwent combination therapy. The remaining 23 (84,1%) patients were treated with C/T, with 15 (65,2%) receiving monotherapy and 8 (34,8%) undergoing combination therapy. Among those receiving monotherapy with C/A, one (50%) did not survive, whereas among those on combination therapy, 2 (66,7%) did not survive. However, when analyzing culture clearance, even after the unfortunate outcomes, the microbiological cure rate with monotherapy was 100%, while with combination therapy, it stood at 33,3%.
Regarding mortality among patients who received monotherapy with C/T, 3 (20%) did not survive, while among those who received combination therapy, one (12.5%) did not survive. As for microbiological cure, we observed a 66,7% microbiological cure rate with monotherapy using C/T, while with combination therapy, this percentage was 62.5%. The lower microbiological cure rate in P. aeruginosa strains can be attributed to the production of MβL-type enzymes.
Moving on to patients infected with P. aeruginosa, 18 (36,7%) were treated with C/A, and 31 (63,3%) with C/T. Among those treated with C/A, 13 (72,2%) received monotherapy, and 5 (27,8%) underwent combination therapy. Of the patients who received monotherapy with C/A, 2 (15,4%) did not survive, and those who received combination therapy, 2 (40%) deceased. Regarding microbiological cure, we observed a 46,1% microbiological cure rate with monotherapy using C/A, while with combination therapy, this percentage was 80%.
When analyzing patients treated with C/T, 25 (80,6%) received monotherapy, and 6 (19,4%) underwent combination therapy. Evaluating the mortality rate in monotherapy, we found 12 (48%) deaths, whereas among those who received combination therapy, one (16,7%) did not survive. As for microbiological cure, we observed a 60% microbiological cure rate with monotherapy using C/T, while with combination therapy, this percentage was 50%. The low percentage of microbiological cure in P. aeruginosa strains is attributed to the production of MβL-type enzymes.
From the 131 patients analyzed, only 7 did not receive prior antibiotic therapy (taking into account treatments performed up to 3 months before the current hospitalization). Therefore, the most commonly used antimicrobials were meropenem (66), piperacillin + tazobactam (60), teicoplanin (52), amikacin (17), ciprofloxacin (17), polymyxin B (16), vancomycin (16), metronidazole (15), ertapenem (9), ceftriaxone (8), azithromycin (7), clindamycin (5), linezolid (4), levofloxacin (4), ceftaroline (4), and tigecycline (3).
During hospitalization, 59 (45%) patients died. However, when cultures were analyzed, 87 (66,4%) had negative results after the use of the antibiotics under study (C/T or C/A), indicating microbiological success. Out of these microbiological responses, 37 (42,5%) had negative results with the use of C/A, and 50 (57,5%) had negative results with the use of C/T. When analyzing patient age, there was no difference in response between young and elderly groups, as culture negativity occurred in 67,7% of young patients and 66% of elderly patients who used the drugs. Within the cohort of patients aged between 16 and 60 years, culture negativations were observed in 21 cases, constituting 67,7% of the cohort. Among these negativations, 11 (52,4%) resulted from treatment with Compound A (C/A), while 10 (47,6%) were associated with Compound T (C/T). Importantly, no significant discrepancy in treatment efficacy was discernible within this younger patient population.
In contrast, among patients aged 60 years and above, culture negativation was achieved in 66 cases, corresponding to 66% of the cohort. Notably, 26 (39,4%) cases were attributed to the administration of C/A, while 40 (60,6%) were linked to the use of C/T. This trend underscores the potential superior response to C/T treatment within this older patient group.
Regarding the mortality rate after therapy with C/A compared to patients treated with C/T, a -value was calculated based on a binomial distribution, where = 0.035 was obtained, indicating that therapy with C/A was more effective than therapy with C/T due to the reduction in mortality.
Regarding laboratory analysis, it was found that 28 (21,4%) people had elevated urea, 13 (9,9%) had elevated creatinine, 9 (6,9%) had elevated GOT, 9 (6,9%) had elevated GPT, 6 (4,5%) had elevated white blood cells, 37 (28,2%) had anemia, 9 (6,9%) had platelet abnormalities (6 patients had thrombocytopenia, and 3 had thrombocytosis), 3 (2,3%) had elevated INR, and no patients had abnormalities in aPTT or PT.
Discussion
The present study represents an important real-life experience regarding the use of C/T and C/A drugs in patients hospitalized in ICUs due to infections caused by MDR GNB, with a favorable clinical response observed in 66,41% of patients. This is consistent with a study conducted by Balandin et al. [13], which observed that C/A showed a good clinical response in 73,5% of patients, and with another analysis performed by Cultrera et al. [8], which showed 81,1% microbiological cure of the analyzed patients with C/T treatment. These findings are supported by the results obtained in a meta-analysis study developed by Wilson et al. [14] which analyzed 29 clinical studies including 1620 patients treated mainly with C/T, C/A, or meropenem/vaborbactam for MDR microorganism infections or rescue therapy, and a high clinical success rate of 73,3% was observed. The clinical success rates for C/T and C/A were similar.
In this study, it was observed 67,3% culture negativation rate among isolates from patients treated with C/A and 65,79% of negativation rate in patients treated with C/T. From the 131 isolates, 28,2% were ESBL producers. Of theses isolates, 54 (41,2%) exhibited the presence of the MβL enzyme was present, a factor possibly contributing to therapeutic failure and unfavorable clinical outcomes (resulting in patient mortality) in 21 (35,6%) individuals within the study cohort.
These findings are consistent with a prior research by Tsivkovski et al.[18], which reports that Avibactam does not effectively target group B β-lactamases, and with another study by Hirsch et al. [19], which shows that C/T is more stable against the action of ESBLs and AmpC-producing bacteria, providing insight into the potential causes of therapeutic failure observed in these patients.
Regarding the detection of β-lactamases in this study, we observed a higher occurrence of ESBL in K. pneumoniae and E. coli isolates, which is consistent with the findings from Barrios et al. [20]. Notably, we identified four K. pneumoniae isolates in our study that produced the KPC enzyme, aligning with the results reported by Carvalho et al. [21]. In a study conducted by Rossi et al. [22], it was shown that out of 30 K. pneumoniae isolates carrying the KPC enzyme, none were susceptible to Ceftazidime alone, however 96,7% displayed susceptibility to the combination of C/A. The selection of appropriate medication for effective treatment in patients infected with KPC-producing strains is challenging [23], underscoring the necessity for urgent and accurate laboratory diagnosis [24]. Futhermore, it is of utmost importance to detect the resistance mechanism for more appropriate medical interventions, which was a limiting factor of the study since it was retrospective relying on data extracted from medical records. Therefore, it was not possible to detect the genes related to β-lactam resistance mechanism.
Nevertheless, since C/A is a new drug on the market, K. pneumoniae still has a low incidence of resistance to it, with a potential cure rate of up to 55%, as indicated in the study conducted by Bassetti et al. [25]. Despite the limitations present, our study still observed a 100% cure rate in patients infected with K. pneumoniae carrying the KPC enzyme and treated with monotherapy, alongside a 66,6% culture negation rate in combination therapy in combination with other drugs.
Concerning monotherapy or combined therapy, in this study, 58,6% of microbiological samples tested negative with monotherapy (62,7% with C/T and 37,2% with C/A), and 41,4% tested negative with combined therapy (50% with C/T and 50% with C/A). Some studies propose that combining these antimicrobials with other antibiotics such as meropenem, amikacin, or polymyxin B may enhance microbiological efficacy and clinical response in patients [26]. However, in a study conducted in 2019 by Onorato et al. [27] found no significant changes in clinical and microbiological responses in patients treated with monotherapy or combined therapy with these drugs. This was corroborated by Balladin et al.’s study. [13], where in the analysis of 95 critically ill patients, the proportion of response to monotherapy with C/T was almost the same when compared to its combined use with colistin and amikacin (30,9% vs. 30,1%).
In this investigation, we demonstrated a higher cure rate and lower morbidity when employing monotherapy with C/T or C/A. The negative results associated with combination therapy in our study are attributed to the necessity for high doses of medications, which potentiate their adverse effects, as demonstrated by Bassetti et al. [28], where the dose of Tigecycline needed to approach the maximum dose (up to 100 mg/day) for a satisfactory effect. Additionally, Tsuji et al. [29] demonstrated the nephrotoxic potential of colistin and polymyxin B, contributing to a significant confusion in choosing the appropriate dose for the patient, configuring a higher risk of morbidity.
Regarding the clinical origin of bacterial isolates in the present study, 43% were from UTIs and 23% from pulmonary infections. Other studies report a higher frequency of lower respiratory tract infections, such as the data from Wilson et al. [15] and Jorgensen et al. [30], with 50% and 62%, respectively. In a clinical study conducted in China [31], pneumonia was described as the most prevalent infection (60%), along with intra-abdominal and bloodstream infections. Zaragoza et al. [32] and Wilson et al. [14] in a review and meta-analysis study, respectively, also note high prevalence of samples from patients with pneumonia, similar to our study, where this sample type ranked as the second most prevalent. These authors also highlight that pneumonia caused by MDR microorganisms presents a worse prognosis and is more difficult to treat. For this reason, the results observed in the present study on the success rates of C/A and C/T drugs in the treatment of MDR microorganism pneumonia are particularly encouraging.
The most frequente isolated microorganism found in the present study was P. aeruginosa (34,3%), aligning with microbiological data from a Brazilian multicenter study by Rossi et al. [22] and Jorgensen et al. [30]. However, Kuang et al. [31] described K. pneumoniae as the most frequent bacterial isolate. It is noteworthy that in the present study, K. pneumoniae was associated with a higher mortality rate among patients. In a case report study by Meschiari et al. [33] C/A and C/T were used for the treatment of extensively drug-resistant P. aeruginosa (XDR-PA) post-neurosurgical infections. Theses infections have become a major concern due to limited therapeutic options. Although not approved for these indications, new combinations of β-lactams with β-lactamase inhibitors may represent a valid rescue treatment. The authors describe a case of nosocomial meningitis and two cases of cervical osteomyelitis caused by XDR-PA that were successfully treated with C/A and C/T, underscoring that potenctial of these drugs against challenging post-neurosurgical infections caused by P. aeruginosa.
In the present study, 41 patients exhibited renal function alterations, 21 undergoing monotherapy and 20 reciving combination therapy, which corroborates with the evaluation by Gorham et al. [34]. Although they evaluated the clinical response of C/A, it was necessary to adjuste the drug dosage to avoid renal damage, which impacted its efficacy compared to the use of meropenem. In contrast, patients in the same study who used C/T did not require dose adjustment for renal function, only the infusion time of the drug. Nevertheless, Cluck et al. [35] observed that only one patient out of a total of 40 patients (2,5%) treated with C/T needed to descontinue therapy due to increased renal function markers. In our study, the majority of patients who showed renal function alterations while using the evaluated drugs had a previous history of chronic kidney disease (62,3%). Regardless, no patient needed a dose adjustment due to renal function, and no patient needed to start hemodialysis during treatment. This demonstrates the safety of employing these drugs, even in patients with preexisting renal disease.
In our investigation, only 9 (6,8%) patients displayed transaminase abnormalities. Since the excretion of the drugs under study is predominantly renal [36], changes in liver enzymes are relatively infrequent, as demonstrated by Barcelona et al. [37], where only 1% of patients exhibited alterations in these enzymes. In contrast, it was observed that 46 (35%) patients showed hematological alterations, with 37 (28%) developing anemia, 9 (6,8%) encountering platelet irregularities (6 patients with thrombocytopenia and 3 with thrombocytosis), and 3 (2,3%) with changes in INR. This differs from other literature reports, such as the one conducted by Mazuski et al. [38] which evaluated only 2,5% of anemia with the use of C/A, while approaching the platelet evaluation present in the studies by Barcelona et al. [37].
An analysis conducted by Wilson et al. [15] reports in a meta-analysis study that the most common adverse effects include acute kidney or liver injury (38%), gastrointestinal issues (35%), and skin rash (6%). No fatal adverse effects were linked to any of the studied antibiotics.
The data from the present study emphasize the significance of utilizing drugs such as C/A and C/T in empirical therapy to reduce mortality stemming from infections caused by MDR microorganisms, with early and adequate therapy being crucial. Zaragoza et al. [32] point out the importance of early and appropriate initiation of empirical therapy, however, insufficient knowledge about the susceptibility profile of MDR microorganisms results in inadequate empirical therapy and consequently increased mortality in these patients. Hence, understanding the mechanism of resistance to β-lactams produced by MDR GNB strains is vital to enable the adoption of appropriate empirical therapy including the use of C/A and C/T. It is important to note that numerous methods for detecting β-lactamases exist for laboratory routines, with the choice of methodology associated with factors related to cost, time of performance, accuracy, and information it yields [39]. The detection of resistance mechanisms, in addition to providing better therapeutic efficacy, will also provide epidemiological data on circulating resistance mechanisms in hospital units, which is essential for mediating preventive actions [32, 39].
As a retrospective study without a control group, some characteristics, microbiological data and detailed patient information could not be systematically collected, which does impose some limitations on the study. Nevertheless, given its comprehensive analysis performed in seven ICUs with 131 patients with diverse characteristics, it is possible to accurately evaluate the efficacy and clinical outcome of the selected patients.
Conclusion
Based on the study’s findings, we can conclude that patients administered C/A and C/T drugs showed good clinical and microbiological outcomes, with no discernible disparity between the drugs concerning microbiological cure evaluation. Both drugs demonstrated safety, with minimal adverse effects reported, such as renal function and anemia, but without influencing the prognosis of the patients, making these drugs suitable for elderly patients and those with previous comorbidities. With the scarcity of effective drugs available on the market to combat MDR GNB, it is important to comprehend the effectiveness of the clinical, laboratory, and microbiological response with the use of new eligible drugs, taking into account the epidemiological and microbiological profile of the studied region for a more assertive medical approach with reducer side effects and preventing the exacerbation of microbial resistance.
Acknowledgements
The authors are thankful to Dr. Noel Guedes Loureiro and Dr. Tiago Luiz Lagedo Ferraz for providing the support and access to medical records of the patients. They would also like to thank the Conselho Nacional de Desenvolvimento Científico e Technológico (CNPq) for the financial support.
Declarations
Conflict of interest
The authors of this article declare that they have no conflict of interest that could interfere with the impartiality of the scientific work. Furthermore no competing financial interests exist.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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