Elisabetta Schiaroli1, Maria Bruna Pasticci1, Maria Iris Cassetta2, Stefania Fallani2, Corrado Castrioto3, Matteo Pirro4, Andrea Novelli2, Lucia Henrici De Angelis5, Marco Maria D’Andrea5, Maria Lina Mezzatesta6, Franco Baldelli1 and Antonella Mencacci7
1 Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
2 Department of Health Science, University of Florence, Florence, Italy
3 Unit of Neurosurgery, Hospital Santa Maria della Misericordia, Perugia, Italy
4 Unit of of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
5 Department of Medical Biotechnologies, University of Siena, Siena, Italy
6 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania Italy.
7.Unit of Microbiology, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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This paper reports on a 71-year-old Caucasian male who underwent neurosurgery for an oligodendroglioma, followed by a cranial-sinus fistula and cerebrospinal fluid rhinorrhea. The clinical course was complicated due to an extensively drug-resistant Acinetobacter baumannii meningitis. The patient was treated with colistin methanesulfonate, intrathecal for 24 days and intravenous for 46 days. In addition, the patient received meropenem and teicoplanin to treat a urinary tract infection and a bacterial aspiration pneumonia. Cerebrospinal fluid trough colistin levels resulted above the MIC of A. baumannii. Colistin cerebrospinal fluid concentration did not increase over the treatment period. Meningitis was cured and A. baumannii eradicated. No side effects from the antimicrobial therapy were observed.
In conclusion, this case highlights the issues in treating infections caused by resistant Gram negative bacteria and supports previous findings on the efficacy, pharmacokinetic and tolerability of intravenous and intrathecal colistin treatments.
Over the last decade, extensively drug- resistant Gram-negative bacteria, including Acinetobacter baumannii, have become a serious cause of hospital-acquired infections. A. baumannii
has also emerged as a cause of central nervous system (CNS) infections,
which are often associated with the use of external cerebrospinal fluid
(CSF) catheters.[1-3] The treatment of these
infections can often be extremely complex due to antimicrobial
resistance and the inadequate antimicrobial concentration at the site
of infection.[1-6] The increased rate of infections
due to multi drug-resistant Gram-negative bacteria has been reported to
lead to a revival in the use of “forgotten” antibiotics, such as
Colistin, a polymyxin antibiotic that is administered intravenously (IV) as colistin methanesulfonate, is a prodrug that is converted in vivo and in vitro into its active form colistin.[4,6] Colistin methanesulfonate and colistin poorly cross the brain blood barrier,[4,6] thus in order to treat CNS infections, colistin methanesulfonate needs to be administered either intrathecally (IT) or intraventricularly (IVT).[3,6]
The authors report on a case of meningitis caused by multi-drug resistant A. baumannii treated with IV and IT colistin.
A 71-year-old Caucasian male was admitted to our hospital with cerebrospinal fluid rhinorrhea one month after having undergone neurosurgery for an oligodendroglioma. Ten days after admission (Table 1), the patient manifested acute meningitis caused by methicillin-resistant Staphylococcus aureus (MRSA) and Corynebacterium striatum, treated with vancomycin IV 750 mg TID and imipenem IV 500 mg QD. At the same time, the cranial-sinus fistula was repaired. The clinical course was complicated by pneumonia and acute respiratory insufficiency requiring assisted mechanical ventilation (Table 1). A week later, the patient was extubated and re-admitted to the floor. The following day, the patient manifested a low-grade fever and blood tests evidenced increased leukocyte and neutrophil counts; whereas the C-reactive protein (C-RP) and erythrocyte sedimentation rate (ESR) values were 15.4 mg/dL (normal <0.5mg/dL) and 8 mm 1st h (normal 1-30), respectively. Due to a persistent drowsiness and a suspected hydrocephalus, an external CSF lumbar catheter was positioned. The CSF from the catheter resulted having normal cell and glucose values, and the microbiological investigations were negative. Additionally, Enterobacter cloacae urinary infection was treated with meropenem (Table 1). Five days later, the patient’s temperature rose to 38.8°C, the leukocyte, neutrophil, C-RP and ERS values also increased, the patient manifested a more depressed level of consciousness and the patient complained of neck stiffness. Simultaneous CSF findings from the lumbar catheter were consistent with acute Gram-negative bacterial meningitis. In addition, the SeptiFast real-time PCR (SF) (Roche Diagnostics, Monza, Italy) performed on the CSF sample from the lumbar catheter resulted positive for A. baumannii and K. pneumoniae, while the CSF mass spectrometry by matrix-assisted laser desorption/ionization time-of-light (MALDI-TOF) (Bruker Daltonics, Bremen, Germany) was negative. CSF culture yielded A. baumannii and a few colonies of K. pneumoniae, both susceptible only to colistin. Antimicrobial therapy was administrated: intravenous colistin methanesulfonate 4.500.000 International Unit (IU) (equal to 150 mg of colistin based activity) BID (infused over 30’), meropenem 2 g TID, rifampin 600 mg OD and teicoplanin 600 mg OD after the loading dose plus colistin methanesulfonate IT 125.000 IU (equal to 4.16 mg of colistin based activity) a day.[3,10] Rifampin had to be discontinued soon after due to an allergic reaction. Two days later, after three doses of IV colistin and a single dose of IT colistin, a repeated culture of CSF, from both the lumbar catheter and rachicentesis, evidenced A. baumannii. Whenever IT colistin was administered (range of time ± 4h), the catheter was kept closed for 3 hours after. CSF samples for laboratory investigations and concentrations were collected from the lumbar catheter before colistin was administered. Colistin concentrations were evaluated on samples (stored at -20°C until testing) using an HPLC method having fluorimetric detection and netilmicin as an internal standard. Linear calibration curves were obtained by the concentrations of colistin sulfate from 0.30 to 5.0 mg/L in plasma. On day four of therapy, the patient was without fever, CSF cell count was decreased, and the culture resulted negative. After a total of 24 days of therapy, the lumbar catheter was removed, while a lumbar-peritoneal catheter was positioned to treat a hydrocephalus that had developed. Results of CSF findings are reported in Table 2. IT colistin was discontinued while IV colistin, meropenem, and teicoplanin were continued for a further 22 days, followed by meropenem 3 g and oral doxycycline 200 mg per day for another 11 days. During this period, the patient was without fever but multiple episodes of acute respiratory insufficiency occurred, along with alternatively reduced or increased neutrophils values, C-RP values, and lung infiltrates. Repeated bronchoscopic aspirations were performed, and a percutaneous endoscopic gastrostomy (PEG) was positioned (Table 1). Repeated respiratory secretion cultures evidenced MRSA and K. pneumoniae resistant to colistin, but fosfomycin susceptible (Table 1). Despite fosfomycin therapy, the patient had a fatal episode of acute respiratory insufficiency leading to his death.
|Table 1. Clinical course and microbiological findings.|
|Table 2. Cerebrospinal fluid findings.|
We thank Thomas Charles Kilcline for his important editorial assistance.