Efficacy of a Fosfomycin-Containing Regimen for Treatment of Severe Pneumonia Caused by Multidrug-Resistant Acinetobacter baumannii: A Prospective, Observational Study

This was a prospective, observational study conducted in Italy: three 300-bed hospitals in Rome and one 1200-bed tertiary hospital in Udine. From January 2017 to June 2020, all consecutive hospitalized patients with pneumonia caused by MDR-AB were included in the study. The inclusion criteria were: (1) age ≥ 18 years; (2) culture positive for MDR-AB; (3) clinical signs and symptoms consistent with pneumonia [17]. Polymicrobial etiology was excluded; only one episode of MDR-AB infection for each patient was reported in the study period. The prospective nature of the study was based on the consecutive enrollment of patients. However, all complete data were afterwards retrospectively extracted, and the Ethics Committee (Policlinico Casilino) waived the need for informed consent. The study was conducted according to the principles stated in the Declaration of Helsinki. Patient data were collected from medical charts and from hospital computerized databases or clinical charts according to a pre-established questionnaire. The following information was reviewed: demographics; clinical and laboratory findings; comorbid conditions; microbiologic data; duration of ICU and hospital stay; any MDR infection during hospitalization; treatment and procedures (e.g. non-invasive ventilation [NIV], mechanical ventilation, continuous renal replacement therapy [CRRT]) carried out during hospitalization and/or in the 30 days prior to infection; class of antibiotics received on admission and/or during admission before a positive culture of a biologic sample was obtained; the Simplified Acute Physiology Score (SAPS II); sequential organ failure assessment (SOFA) at time of infection; anamnestic MDR-AB colonization or during hospitalization; antibiotic regimens used for MDR-AB infection; development of septic shock; 30-day mortality.

Infections were defined according to the standard definitions of the European Centers for Disease Control and Prevention (eCDC) [18].

Infection was defined as the presence of at least one positive culture from the lung for MDR-AB in individuals with signs and symptoms consistent with pneumonia [17‐19]; concomitant isolation of MDR-AB in other sites such as the blood, urine, skin swabs or biopsies, or abdomen was also recorded. Infection onset was defined as the date of development of signs and symptoms of pneumonia.

HAP was considered pneumonia occurring 48 h or more after admission that did not appear to be incubating at the time of admission. VAP was considered HAP developing > 48 h after endotracheal intubation. The diagnosis of severe pneumonia was based on the Infectious Diseases Society of America/American Thoracic Society consensus guidelines, i.e., one major criterion (invasive mechanical ventilation or septic shock with the need for vasopressors) or three minor criteria (respiratory rate of > 30 breaths/min, partial pressure of arterial oxygen {PaO₂]/fraction of inspired oxygen [FiO2] ratio of < 250, multilobar infiltrates, confusion/disorientation, uremia [blood urea nitrogen (BUN) level of > 20 mg/dl], leukopenia [white blood cell (WBC) count of < 4,000 cells/mm³}, thrombocytopenia [platelet count of < 100,000 cells/mm³], hypothermia [core temperature  < 36 °C], or hypotension requiring aggressive fluid resuscitation) [20].

Septic shock was defined according to international definitions [21]. The severity of clinical conditions was determined by using SAPS II, and SOFA scores calculated at the time of infection onset. The length of hospital and ICU stay was calculated as the number of days from the date of admission to the date of discharge or death.

The identification of MDR-AB strains was based accordingly with local laboratory techniques. From positive cultures, gram staining and a rapid identification protocol were adopted. The bacterial pellet obtained directly from positive cultures was used for MALDI-TOF MS (Bruker Daltonics) identification and for molecular analysis. The SensiTitre™ system (Thermo Fisher Scientific) or the Vitek 2 automated system (bioMérieux, Marcy l’Etoile, France) were used for isolate identification and antimicrobial susceptibility testing. Minimum inhibitory concentrations (MICs) were established according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints [22].

Empiric antibiotic regimens were selected according to clinical judgment by infectious disease specialists and were subsequently modified according to blood culture results. During the study period, the usual antimicrobial dosages, adopted for the most used antibiotics were the following: for colistin, a loading dose of 9 million IU followed by 4.5 million IU every 12 h; for tigecycline, a loading dose of 150–200 mg followed by 100 mg every 12 h; for gentamicin, a dosage of 5 mg/kg every 24 h; for rifampin, a dosage of 10 mg/kg/day; for meropenem, a dosage of 2 g every 8 h or 1.5 g every 6 h; for fosfomycin 12–24 g/day divided every 6–8 h; for ampicillin/sulbactam 3 g every 6 h; for trimethoprim/sulfamethoxazole 15–20 mg/kg/day divided every 6 h; for vancomycin 40 mg/kg/day divided every 12 h.

Depending on the number of drugs used (1 or > 1), treatment regimens were classified as either monotherapy or combination therapy. Initial antibiotic therapy, defined as antimicrobial chemotherapy implemented within 24 h after the onset of infection, was assessed along with definitive antibiotic therapy, defined as antimicrobial treatment based on in vitro MDR-AB isolate susceptibility. Drugs in definitive therapy must have been administered for at least 50% of the total duration of therapy (except for patients who died while on definitive therapy, who were included if they received at least 1 complete day of therapy). Time to initial definitive therapy was the period between the infection onset and initial definitive therapy.

The primary endpoint of the study was to evaluate risk factors associated with survival or death at 30 days from pneumonia onset.

To detect significant differences between groups, we used chi-square test or Fisher exact test for categorical variables, and the two-tailed t test or Mann-Whitney test for continuous variables, when appropriate. In a multivariate analysis of survival, the Cox regression model was tested using a proportional hazards model analysis with backward stepwise selection and p < 0.05 for all variables to determine the effects of all anamnestic, clinical, and therapeutic variables on 30-day survival. A propensity score for receiving therapy with fosfomycin was added to the model. The propensity score was calculated using a nonparsimonious multivariate logistic regression model in which the outcome variable was the treatment with fosfomycin. Kaplan-Meier curves were used to determine survival at 30 days in patients treated with either a fosfomycin-containing regimen or other antibiotic regimens. Survival curves for time-to-event variables, constructed using Kaplan-Meier estimates, were based on all available data and were compared with the use of the log-rank test. Wald confidence intervals and tests for the hazard ratio were computed based on the estimated standard errors. Possible confounding factors and interactions were weighted during analysis. Statistical significance was established at ≤ 0.05. All reported P values are two-tailed. The results obtained were analyzed using a commercially available statistical software package (SPSS, version 20.0; SPSS Inc, Chicago, IL).