Cancer patients undergo some of the most intense treatments in medicine, including myelosuppressive chemotherapy drugs, radiotherapy and Hematopoietic Stem Cell Transplantation (HSCT). Consequently, these patients, particularly in the pediatric population, become highly vulnerable to the most significant and life-threatening complication: the invasive infections.1

Neutropenia coupled with fever may be the first signs of a life-threatening infection. Once the diagnosis of Febrile Neutropenia (FN) has been made, broad-spectrum intravenous antibiotic therapy is empirically prescribed for these patients2-4 decreasing mortality from invasive infections from 90 % in the 1970s5 to below 1 % in the years 2000.6 With increased survival, these patients now experience two or more episodes of FN during cancer treatment. Over the last decade, there has been an estimated increase of more than 50 % in the number of hospitalizations for febrile neutropenia.6 Consequently, patients with this condition often undergo prolonged and repeated courses of antibiotic therapy. When coupled with factors such as the use of prophylactic antibiotics, multiple and extended hospital stays, care in the Intensive Care Unit (ICU) and the use of invasive devices, these circumstances pose significant risks for the emergence of Multidrug-Resistant (MDR) bacterial infections.7,8

Recently, an increase in the BSI caused by Gram-Negative Bacilli (GNB) has been observed, specifically those caused by Multidrug-Resistant (MDR) which are associated with an increased demand for intensive care, a higher likelihood of progressing to severe conditions and greater morbimortality6,9 making the better understanding of its management and development of new therapies urgent.10

In pediatric onco-hematological patients, the treatment of MDR infections poses greater challenges, including a limited array of therapeutic options, insufficient data on pharmacokinetics/pharmacodynamics, and concerns about drug safety, particularly in the context of chemotherapy regimens and in critical clinical conditions.

To date, in low- and middle-income countries such as Brazil, polymyxins in combination are still the most prescribed antibiotic for treatment of carbapenemase-producing Enterobacterales infections due to its lower cost and greater availability.11 However, the use of polymyxins has been associated with severe adverse events such as nephrotoxicity up to 70 % and neurotoxicity in 3 %.12 In addition, drug interactions and allergic reactions leading to interruption and therapeutic failure are commonly observed especially in oncologic patients, who receive many other therapeutic agents.13,14 For these reasons, safer and more effective antimicrobials as ceftazidime-avibactam, meropenem-vaborbactam and imipenem-relebactam have been recommended by European and American guidelines as the first choice for treatment of carbapenem-resistant GNB.15,16

In Brazil, among the new therapeutic options, ceftazidime-avibactam is the only approved option for pediatric patients. The Brazilian National Health Surveillance Agency (Anvisa) granted approval for Ceftazidime-Avibactam (CAZ-AVI) for children over 3 months to 18 years of age in 2020 for urinary tract and intra-abdominal infection. While studies in the pediatric population have demonstrated the safety and efficacy of the drug, there is a notable scarcity of research focused on pediatric oncologic patients.

To date, there are only two case series in children with cancer.17,18 This case series aimed to describe the use of ceftazidime-avibactam to treat other complicated infections caused by GNB children undergoing antineoplastic treatment and Hematopoietic Stem Cell Transplantation (HSCT) in Brazil. This population diverges from phase two studies19,20 because they are critically ill, due to the infection severity and present comorbidities related to cancer.

This is a retrospective observational study that includes all pediatric cancer patients hospitalized at the Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), who received CAZ-AVI for the treatment of GNB infections between 01 January 2021 and 30 June 2022.

IOP is a pediatric oncology hospital recognized as a leading institution in Latin America. It has 56 beds with 10 intensive care unit beds, treating approximately 430 new cancer cases annually and conducting around 80 bone marrow transplants each year. The institute supports a technical and scientific partnership with the Universidade Federal de São Paulo. The IOP Infection Prevention and Control team (IPC) diligently checks all GNB infections within the facility, documenting all cases of infections data. The cases described in this study were identified by the IPC database. The data collection was obtained through review of clinical charts.

The study included children and adolescents patients aged between 3-months and 18-years with cancer who underwent or not to HSCT receiving CAZ-AVI for more than 72-hours to treat documented GNB infection. The 3-day period is commonly used in intention to treat analysis and is important to assess the choice and review the severity of the illness if the patient's condition worsens or there's no improvement in a antimicrobial stewardship program.21

Infection was defined by the presence of BGN associated with one or more clinical symptoms. Patients whose clinical data could not be obtained or had been in use of CAZ-AVI for less than three days of treatment or empirical use were excluded.

Treatment success was defined as resolution of signs and symptoms related to the infection, microbiologic negative control and improvement of laboratory test results at the end of therapy course. Clinical failure was defined as laboratory and clinical worsening of the symptoms that required additional intervention as therapy change due to infection.

Patients were followed for 30-days, and a clinical form was completed, capturing demographic and clinical information, underlying disease, history of HSCT, use of antibiotic prophylaxis, prior antimicrobial treatments, history of previous surgery, presence of indwelling devices, earlier MDR GNB colonization, time to cultures become negative, details of empirical and definitive therapy, mortality at 14- and 30-days. Additionally, concurrent infections with potential impact on clinical outcomes were assessed. Laboratory data, including neutrophil count, C-Reactive Protein (CRP), urea, creatinine, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) were also evaluated.

Our analysis included thirteen episodes of GNB infections in eleven patients treated with CAZ-AVI. Notably, two patients experienced two episodes of infections more than thirty days apart. Among the patients, five patients were female (45 %), with an average age of 7 years (ranging from 4 to 16-years of age, mode of 4-years). The oncological diagnoses encompassed three cases of Acute Lymphoid Leukemia (ALL), three cases of Acute Myeloid Leukemia (AML), two cases of Non-Hodgkin's Lymphomas (NHL), and 3 solid tumors (23.0 %). Allogeneic HSCT was performed for two AML patients. In 10/13 (76 %) of the episodes, the patient was neutropenic when the infectious diagnosis was made and treatment with ceftazidime-avibactam was started. Relevant comorbidities were detailed in Table 1.

Clinical and laboratory evolution

Seven patients were neutropenic when CAZ-AVI was prescribed. Four of them remained neutropenic during GNB infection treatment. Only in episode #1, the patient persisted neutropenic and perished. In three episodes patients resolved the neutropenia by day 12th, 5th and 5th of treatment with clinical improvement and CPR demotion (Figs. 1–4).

Fig. 1.

CPR level in K. pneumoniae cases.

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Fig. 2.

CPR level in E. cloacae cases.

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Fig. 3.

CPR level in S. maltophilia.

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Fig. 4.

CPR level in Pseudomonas spp. cases.

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No fever was observed in six episodes. Among the seven episodes associated with fever, the time to become afebrile varied from one to four days, with the most common being within 72 hours (80 %). Four of these episodes occurred in neutropenic patients. In two episodes the fever persisted until Day 10 and Day 16 despite the antibiotic treatment leading to patient death.

Figs. 1–4 illustrates the CRP evolution during the infection episode and CAZ-AVI treatment. Notably, only one episode exhibited a tendency for increased CRP during treatment, and unfortunately, this patient succumbed due to the progression of the oncological disease. In six episodes, a continuous drop in CRP was seen shortly after the introduction of CAZ-AVI. In three episodes, there was an increase up to 72 hours after the start of the antimicrobial with a progressive decrease afterwards and in another three there was an increase in CRP during treatment between D7 and D14 with a decrease afterwards. Patient number 7 presented a progressive drop in CRP to 10 mg/dL but died due to massive gastrointestinal bleeding. Growth of Trichosporon asahii in blood cultures was identified after his death.

In five episodes, hypoalbuminemia (<3g/dL) was observed before CAZ-AVI prescription, which was resolved during treatment of three cases. Albumin measurement was not performed in three episodes.

The World Health Organization (WHO) estimates that multidrug resistant microorganisms will be responsible for top 3 leading causes of death by 2050 killing up to 10 million people annually.26 This raises even greater concern in high-risk populations such as pediatric oncology patients.

Agud et al. evaluated the risk factors for colonization by MDR in children with complex conditions in Spain and found that the main risk factors were use of prophylactic antibiotics, use of immunosuppressive medication, skin lesions, greater number of surgeries and prolonged stay in hospital in the last 12-months.27 Patients included in this study had all risk factors for MDR described in the literature such ICU stay, previous use of broad-spectrum antibiotics, skin wound, invasive devices and colonization with MDR GNB.

In this study, the average age was 7 years with a prevalence of hematological diseases such as ALL, AML and NHL (72 %), compatible with literature data on MDR GNB infections in pediatric oncology patients.28 In a Brazilian study, Costa et al. found that MDR GNB infections in oncology children had a mean age of 7 years and hematological disease and healthcare-associated infection were also risk factors.29 Casseli et al. observed in a multicenter study with oncology children a higher average age of 7 years at infection when associated with Pseudomonas aeruginosa MDR compared to non-MDR Pseudomonas spp. of 4 years of age. They also found a higher prevalence of hematological diseases up to 70 % in infections caused by Pseudomonas spp.28

In this study, the prescription of CAZ-AVI was primarily due to MDR GNB infection, especially to those resistant to carbapenemases, secondly to therapeutic failure of the first regimen with good clinical response.

The main site of infection was the bloodstream, with blood cultures showing negative results in all BSI cases at the first control test. A systematic review and meta-analysis support the security and efficacy of CAZ-AVI in BSI due to carbapenem-resistant Enterobacteriaceae finding lower 30-day mortality and lower nephrotoxicity when compared to other antibiotic regimens such as colistin.30

This study highlights that pediatric oncology patients present peculiarities such as an important history of colonization and previous MDR infection, use of broad-spectrum antibiotics during prolonged hospitalizations, progression to severe conditions requiring extended intensive care unit stays.

This population is deeply immunocompromised by baseline disease, chemotherapy, neutropenia or in critical ill status that may lead to no classical symptoms of infection. The presence of fever, clinical alteration and laboratory changes may be the only signs of infection.31

In view of this, the support of microbiology to prompt identification of the infectious agent as well as its resistance mechanisms and phenotypes becomes of foremost importance, enabling the adequate targeted therapy.

Among the isolated agents, the most prevalent were Enterobacteriaceae, Klebsiella pneumoniae and Enterobacter cloacae carbapenem resistant. The resistance to carbapenems in Enterobacteriaceae is generally due to the production of enzymes Class A Serine Carbapanemase type, with KPC-2 being the most prevalent in Brazil. According to a national report, since 2020, an increase in the frequency of NDM producer isolates and NDM/KPC co-producers has been documented, accelerated by the COVID-19 pandemic.32

CAZ-AVI was also prescribed for infections caused by Pseudomonas spp. and Stenotrophomonas maltophilia. In addition to the enzymatic resistance mechanisms, antimicrobial resistance in non-fermenting gram-negative bacilli has specific characteristics that make their treatment particularly challenging.

Pseudomonas aeruginosa stands out for its ability to acquire multiple resistance mechanisms and is classified as Difficult to Treat (DTR) by the CLSI criteria when they present a phenotype of resistance to first-line antimicrobials: ceftazidime, aztreonam, cefepime, piperacillin-tazobactam, imipenem, meropenem and quinolones. Its resistance can be explained by mutation of its ampC, PDC (Pseudomonas-Derived Cephalosporinases), hyperproduction of PDC, increase in the efflux system due to increase in MexAB-OprM and entry deficiency due to porin reduction OprD, in addition to the acquisition of enzymes such as metallocarbapenemases.32,33

In the study, Pseudomonas spp. BSI showed resistance solely to meropenem and polymyxin B. This finding suggests a non-aeruginosa Pseudomonas infection, since the colistin resistance may be intrinsic in Pseudomonas fluorescens complex (e.g., P. chlororaphis or P. koreensis) or adaptive by genes emrA, lpxA, lpxD, pgsA, phoP and phoQ leading to the addition of cationic compounds such as L-ara-4n to the lipopolysaccharide of the outer bacterial membrane.34 It was not possible to identify the species of Pseudomonas found and the possibility of Pseudomonas aeruginosa infection is unlikely since the prevalence of resistance to colistins by P. aeruginosa is low, less than 2 %.35 The P. aeruginosa strains presented an indeterminate Blue-Carba test and a positive blaSPM-1 gene test. The Blue Carba test demonstrated a sensitivity of 93.6 % and a specificity of 100 % for detecting carbapanemase producing Pseudomonas spp. However, this text has shown important limitations in detecting class B carbapanemase. Although the frequency of SPM-1 producing P. aeruginosa has declined over the years in Brazilian centers, P. aeruginosa carrying blaSPM gene are still recovered in our hospital, where it was firstly reported.36

Case number 6, the patient presented an invasive infection by Stenotrophomonas maltophilia, a non-fermenting GNB in the bloodstream and tracheal aspirate culture. Risk factors for this infection included invasive devices, urinary tract infection, and extensive prior antimicrobial use, as meropenem and aminoglycosides. Notably, the patient had a history of severe SARS-CoV-2 infection that progressed to MIS-C (Multi-Inflammatory Syndrome in Children)37 with coronary dilation. Secondary infection by S. maltophilia was recurrent complication associated to SARS-CoV-2 infection during the pandemic.38

For severe S. maltophilia infections, the Infectious Diseases Society of America (IDSA) recommends combination therapy with first-line antibiotics such as levofloxacin, minocycline, sulfamethoxazole-trimethoprim, and ceftazidime. Stenotrophomonas maltophilia exhibits resistance to carbapenems and other beta-lactams due to the presence of Serine beta-lactamases L2, conferring an ESBL-like resistance profile. Additionally, resistance to aztreonam can occur through the production of metallo-beta-lactamase L1. Furthermore, S. maltophilia possesses RND, MFS, and ABC efflux systems, enabling resistance to aminoglycosides, quinolones, tetracyclines, macrolides, and chloramphenicol.39

Ceftazidime and avibactam, while active against serine carbapenemases, are inactivated by metallo-beta-lactamase. On the other hand, aztreonam is a monobactam that is not hydrolyzed by metallo beta lactamases, but is inactivated by extended spectrum betalactamases and serinecarbapenemases. This complementary activity enables effective combination therapy against the increasingly prevalent bacteria that co-produce metallo-beta-lactamases and extended-spectrum serine beta-lactamases. Consequently, the combination of ceftazidime-avibactam with aztreonam emerged as a therapeutic possibility. Furthermore, the aztreonam-avibactam combination appears to be active against carbapenem-resistant Stenotrophomonas maltophilia and Burkholderia cepacia complex.40

In the study, the combination of CAZ-AVI with aztreonam proved to be effective in treating GNB that co-produces metallo and other class A beta-lactamases. CAZ-AVI combined with aztreonam showed to be synergistic by disc approximation testing and proved to be clinically efficacious in treating a patient with a disease caused by SPM-1 producing Pseudomonas aeruginosa. This combination also proved to be a therapeutic option for infection caused by S. maltophilia. Falcone et al. demonstrated higher rates of therapeutic success, lower mortality and lower nephrotoxicity in the treatment of BSI in adults caused by metallo-beta lactamase-producing Enterobacterales with the combination CAZ-AVI and aztreonam when compared to regimens using other antibiotics showing in vitro activity such as polymyxin B, aminoglycosides, fosfomycin and tigecycline.16,41

The use of CAZ-AVI in the treatment of ventriculitis due to K. pneumoniae in a 7-year-old patient showed a good therapeutic response, expanding the possibilities of using the medication. Despite the negative cultures even after prior administration of intravenous and intrathecal polymyxin B, the patient-maintained CSF altered parameters and persistent drowsiness. After switching to CAZ-AVI, there was progressive clinical and laboratory improvement. Case series have demonstrated success in the treatment of CNS infection caused by Enterobacteriaceae and Pseudomonas aeruginosa MDR with ceftazidime-avibactam in adults and children. Although robust data are limited, recent studies suggest that there is approximately 38 % penetration of CAZ-AVI in the CNS, levels sufficient for its bactericidal action.42-44

The patient with endocarditis had a good clinical evolution with the use of two weeks of CAZ-AZI and after his stabilization. CAZ-AVI was maintained in combination with polymyxin B and meropenem for two more weeks resulting in clinical cure. He kept progressively improving ultrasound image and anti-coagulation due to the associated hypothesis of thrombus. Data on its use in the treatment of infective endocarditis is scarce, restricted to case reports in adults.45

A systematic review of CAZ-AVI use in severe MDR GNB infections in adults highlights its effectiveness in a landscape of rising resistance and limited therapeutic options. However, more data on its pharmacodynamics are needed to refine its use across different patient profiles and types of infections.46

The study revealed two unrelated deaths that were not attributed to the bacterial infection or medication and no other adverse events related to the use of the antimicrobial were seen, such as gastrointestinal complaints, rash and other altered laboratory parameters.

In the case series, it was possible to observe that patients often presented hypoalbuminemia (serum albumin less than 3g/dL) and an increase in the estimated glomerular filtration rate with CrCl above 130 mL/min/1.73m2, common findings in oncology and critically ill patients.47 Although one study found usual dose might achieved adequate pharmacodynamic target in children older than 3-months, further research is necessary to set up the best antimicrobial combination as well as pK/pD parameters for optimization of antimicrobial regimens in critical ill children.48

All patients responded to the CAZ-AVI therapy. Despite being a relatively new antibiotic, resistance to CAZ-AVI has already been described. The most common mechanisms involve the co-existence of carbapenemases such as metallocarbapenemase or other class D oxacillinases such as Oxa-24/40. Other mechanisms may be due to hyperproduction of extended spectrum beta-lactamase such as VEB (Vietnamese Extended-spectrum Beta-lactamase) and carbapenemases, gene mutation Ex: KPC-2 omega loop mutation. In non-fermenting BGN such as Pseudomonas aeruginosa, resistance can additionally arise from mutation in genes encoding beta-lactamases such as ampC, increase in the efflux system and entry deficiency due to reduction of porins.49

In life-threatening infections due to MDR or XDR GNB, studies suggest a possible benefit of combining CAZ-AVI with other antibiotics. The combination of CAZ-AVI with meropenem, amikacin and aztreonam appears to significantly reduce the MIC for ceftazidime up to fourfold in MDR strains of Klebsiella pneumoniae and in the case of Pseudomonas aeruginosa, the combination with meropenem or colistin has shown a similar, albeit less pronounced, effect.50

This study presents some limitations as a retrospective observational study with few subjects, limited microbiologic investigation and access to CAZ-AVI at the period also led to previous selection of patients with documented GNB infection that can arise risk of bias and caution with interpretation of results. Nonetheless, this study exposes a real-life scenario in developing countries and challenges in treatment of MDR BGN infection in children with cancer. Molecular resistance mechanisms were done only in blood culture, and other limitations of this study were considered

We reported our experience with 13 courses of CAZ-AVI to treat infection by BGN in oncologic patients. In this cohort (92 %) recovered and achieved microbiological cure. No adverse events were attributed. CAZ-AVI may be a choice for treating BGN infections in the pediatric cancer setting.