Increasing frequency of Pseudomonas aeruginosa infections during tigecycline use

Introduction: The widespread use of tigecycline raises the question of increasing infection rates of Pseudomonas aeruginosa (PA) in ICUs which are not affected by this antibiotic. Objective: The aim of this study was to determine if treatment with tigecycline is a risk factor for PA infection in ICU patients. Methodology: A retrospective and observational study was conducted at Erciyes University Hospital, Turkey, between 2008 and 2010. The Erciyes University Hospital is a 1300-bed tertiary care facility. The patients included in this study were hospitalized in four adult ICUs. Patients with PA infections (case group) were compared with patients with nosocomial infection other than PA (control group). Results: A total of 1,167 patients with any nosocomial infections were included in the study. Two hundred and seventy eight (23.8%) of the patients had PA infection during their ICU stay. Fifty nine patients (21.2%) in the case group received tigecycline before developing PA infections, which were found to be significantly more frequent than in the controls (p < 0.01). Multivariate analysis showed that risk factors for PA infection were previous tigecycline use (4 times), external ventricular shunt (4.2 times), thoracic drainage catheter (2.5 times) and tracheostomy (1.6 times). Conclusion: Our results contribute to the need for new studies to determine the safety of tigecycline use, especially for the treatment of critically ill patients. Since tigecycline seems to be an alternative for the treatment of multidrug resistant (MDR) microorganisms, rational use of this antibiotic in ICU patients is essential.


Introduction
Tigecycline demonstrates potent broad-spectrum in vitro antibacterial activity against clinically important gram-positive and gram-negative aerobic bacteria and anaerobes, with the exception of the intrinsically resistant Pseudomonas aeruginosa (PA) [1].Tigecycline was approved in 2005 for the treatment of complicated intra-abdominal infections, skin and soft tissue infections and for community acquired pneumonia in 2009 [2].During the same period of time, due to the increase in reported rates of multidrug-resistant (MDR) gram negative bacteria especially among critically ill patients in intensive care units (ICU), the need for new antimicrobial agents has grown.In the search for a solution to the therapeutic limitation of infections due to MDR bacteria, tigecycline became the drug of choice for monotherapy or a component of combined therapies.The widespread use of tigecycline raises the question of increasing infection rates of PA in ICUs which is not affected by this antibiotic.Therefore, we aimed to determine if treatment with tigecycline is a risk factor for PA infection in this study.

Methodology
We performed a retrospective and observational study at Erciyes University Hospital between 2008 and 2010.Erciyes University Hospital is a 1300-bed tertiary care facility.The patients included in this study were hospitalized in four adult ICUs with a 55bed capacity.The types of ICUs included the medical, surgical, neurosurgical and reanimation.All nosocomial infections defined in these ICUs were recorded by a routine surveillance program in our hospital according to Centers of Disease Control (CDC) criteria [3].All microorganisms were isolated from clinical samples, and patients with colonization were excluded from the study.Susceptibility tests were carried out according to the Clinical and Laboratory Standards Institute (CLSI) criteria using the disk diffusion method.
The first episode of each infected patient was recorded.Patients with PA infections (case group) were compared with patients with nosocomial infections other than PA (control group).Patients were analyzed according to whether they had received tigecycline before PA infection and also the following data were collected: gender, age, underlying diseases, infections and invasive procedures.Patients with any exposure to tigecycline regardless of the duration of treatment were included in the study.
The statistical analysis was performed using SPSS software version 15.0 (USA).Univariate and multiple binary logistic regression analyses (model: backward Wald) were performed to analyze the effects of variables.Age, respiratory failure and use of central venous catheter were included in the model; however these variables were not significant.Since length of hospital stay before infection may confound the relationship between previous tigecycline use and Pseudomonas infection, the results were adjusted for this variable.The level of significance was set at p < 0.05 for all tests.
Fifty nine (21.2 %) of the case group patients received tigecycline before PA infection which was found to be significantly more frequent than in the controls (p < 0.01).Table 1 shows the univariate analysis of patients' characteristics and of variables associated with PA infection.Multivariate analysis showed that risk of PA infection is higher in situations including previous tigecycline use (4 times), presence of external ventricular shunts (4.2 times), thoracic drainage catheters (2.5 times) and tracheostomy (1.6 times).

Discussion
PA is a frequent cause of serious infections among hospitalized patients and is associated with considerable morbidity and mortality.Several risk factors have been associated with Pseudomonas infections [4].Results in this study are consistent with those in earlier studies in which invasive devices and procedures were mostly associated with PA infections [4,5].During the last decade, there have been several reports concerning risk factors associated with multidrug-resistant PA [6,7].Such reports have concluded that the use of anti-pseudomonal antibiotics plays the major role in the emergence of resistant PA infections.On the other hand, a recent study reported that exposure to ertapenem, which has no effect against PA, was found to be associated with resistance [8].However, molecular tests regarding the type of resistance were not performed.Also in this study, the PA strains isolated from ICU patients were found to be resistant to most of the antibiotics; however, this study does not include data on whether resistance is associated with prior exposure to tigecycline.Similarly, no molecular tests were performed concerning resistance patterns.
Tigecycline, a broad-spectrum antibiotic but ineffective against PA, represents a therapeutic option in the treatment of multidrug-resistant gram-negative infections.The problem arising with widespread use of tigecycline is the emergence of increased rates of PA infection, or infections by other microorganisms with reduced susceptibility to this antibiotic.A recent study indicates that the risk of superinfection rates, particularly on account of PA, increased during tigecycline therapy [9].The authors reported PA superinfection in 13.7% of 51 patients, a higher rate than previously reported [10,11].Furthermore, a higher number of new infections and bacterial superinfections after treatment with tigecycline have also been reported in subsequent studies [1,12].The most striking finding in this study was that prior exposure to tigecycline was also associated with a fourfold increase in the risk of PA infections.This is probably due to the disappearance of tigecycline sensitive pathogens during the treatment with tigecycline and the increase of tigecycline resistant strains such as "PA".
PA is a highly virulent nosocomial pathogen with a broad clinical spectrum of infections.Resistance to multiple classes of antibiotics in this microorganism is also problematic and a source of growing therapeutic challenges.This is a retrospective study performed in a three year period involving a large number of patients.However, the current study is limited by its retrospective design and consequently flawed with insufficient data (duration of tigecycline treatment, initiation time of tigecycline before infection, resistance rates in years).

Conclusions
Recently, based on a meta-analysis of clinical trials, the FDA announced that tigecycline was associated with higher mortality rates, particularly for severe infections [13].Our results highlight the risks of using tigecycline as monotherapy, especially for the treatment of critically ill patients.Since tigecycline seems to be an alternative for the treatment of MDR gram negative infections, rational use of this antibiotic in ICU patients is essential.