General AML

Ciprofloxacin versus colistin prophylaxis during neutropenia in AML: two parallel patient cohorts treated in a single center

Neutropenia is a frequently observed complication of intensive myelosuppressive chemotherapy in Acute Myeloid Leukemia (AML) patients. Chemotherapy-induced neutropenia can be severe and prolonged, resulting in patients being hospitalized for treatment of fever or at risk of fatal infections.

According to Peter E. Newburger and David C. Dale, neutropenia is typically defined as the following:

  • An Absolute Neutrophil Count (ANC) below 1.5 × 109/L (1500/mm3)
  • ANC of 0.2–0.5 × 109/L is associated with an increased risk of infections in most patients.
  • ANC of 0.2 × 109/L or less (often referred to as “agranulocytosis”)
  • Patients with a count of lower than 100 are considered to be at the highest risk of infection1


Besides the myelosuppressive therapy AML patients receive to destroy malignant cells, the alteration of the patient’s bone marrow and can adversely affect the patient’s immune system making them more susceptible to bacterial infections.

Bacterial infections are a serious problem. M. Pohlen from the University Hospital of Muenster, Germany, and colleagues state that bacterial infections are the most common cause of treatment-related mortality in patients with neutropenia after chemotherapy.

Interventions that prevent the risk of bacterial infection and do not interfere with the patients’ treatment for the underlying leukemia are crucial. However, the search to identify the most appropriate treatment paradigm can be problematic; namely due to the indiscriminate use of antibiotics and the rise of associated drug-resistant and multidrug-resistant pathogens. In addition, if antibiotics are to be used prophylactically in AML patients the most beneficial time to initiate treatment has to be identified i.e. during induction/relapse versus consolidation cycles.

Pohlen et al. conducted a retrospective evaluation of 172 AML patients in order to try and resolve the aforementioned issues. They analyzed patients whom had received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of more than seven days. The investigators compared the effects of the frequently used antibiotic prophylactic regimens colistin and ciprofloxacin. The investigation was carried out in a single institution in Germany. The study was published in Haematologica in October 2016. 

The key findings were:

  • The infection rates observed during the induction and relapse re-induction courses were 96.9% and 100% in the colistin group compared with 88.7% and 75.0% in the ciprofloxacin group.
  • Infection rates during consolidation courses with colistin and ciprofloxacin were 54.9% and 3%, respectively (P<0.0001). Furthermore, in a subset analysis, mucositis was identified as a predictor of infection during the consolidation courses.
  • With regards to the effects of the antibiotic prophylactic treatment on patient outcomes, there was 7.0% mortality among patients who received prophylaxis versus0% among patients who did not receive prophylaxis ( P=0.4219)
  • In terms of antibiotic resistance, the percentage of prophylaxis-resistant pathogens observed in ciprofloxacin and colistin were 79.5% versus5%, respectively. 

In summary, the authors state that, in addition to the therapy stage and the local distribution of resistant pathogen, the risk of mucositis has to be considered in the prevention of bacterial infection in AML patients.

Furthermore, they reported that the results from this single institution indicated that ciprofloxacin prophylaxis could be used during induction and relapse chemotherapy for AML. However, during consolidation cycles, colistin could provide a suitable alternative.

 

Abstract

Patients undergoing intensive chemotherapy for acute myeloid leukemia are at high risk for bacterial infections during therapy-related neutropenia. However, the use of specific antibiotic regimens for prophylaxis in afebrile neutropenic acute myeloid leukemia patients is controversial. We report a retrospective evaluation of 172 acute myeloid leukemia patients who received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of more than seven days. The patients were allocated to antibiotic prophylaxis groups and treated with colistin or ciprofloxacin through 2 different hematologic services at our hospital, as available. The infection rate was reduced from 88.6% to 74.2% through antibiotic prophylaxis (vs. without prophylaxis; P=0.04). A comparison of both antibiotic drugs revealed a trend towards fewer infections associated with ciprofloxacin prophylaxis (69.2% vs. 79.5% in the colistin group; P=0.07), as determined by univariate analysis. This result was confirmed through multivariate analysis (OR: 0.475, 95%CI: 0.236–0.958; P=0.041). The prophylactic agents did not differ with regard to the microbiological findings (P=0.6, not significant). Of note, the use of ciprofloxacin was significantly associated with an increased rate of infections with pathogens that are resistant to the antibiotic used for prophylaxis (79.5% vs. 9.5% in the colistin group; P<0.0001). The risk factors for higher infection rates were the presence of a central venous catheter (P<0.0001), mucositis grade III/IV (P=0.0039), and induction/relapse courses (vs. consolidation; P<0.0001). In conclusion, ciprofloxacin prophylaxis appears to be of particular benefit during induction and relapse chemotherapy for acute myeloid leukemia. To prevent and control drug resistance, it may be safely replaced by colistin during consolidation cycles of acute myeloid leukemia therapy.

References
  1. Newburger P.E. & Dale D.C. Evaluation and Management of Patients with Isolated Neutropenia. Semin Hematol. 2013 Jul; 50(3):198–206. DOI: 10.1053/j.seminhematol.2013.06.010
  2. Pohlen M. et al. Ciprofloxacin versus colistin prophylaxis during neutropenia in acute myeloid leukemia: two parallel patient cohorts treated in a single center. Haematologica. 2016 October; 101(10): 1208–1215; DOI:10.3324/haematol.2016.147934.