We discussed a patient who underwent IVT tigecycline and polymyxin B therapy for obstructive hydrocephalus and developed XDR A. baumannii following the resection of an SOL with EVD in situ. To the best of our knowledge, reports of this treatment have previously been published in other countries but not in Bangladesh. By injecting a medication directly into the ventricle through the EVD, a technique known as the IVT route enables the medicine to enter the CSF by crossing the bloodbrain barrier (BBB) and quickly reaching its effective concentration. According to the published guidelines, IVT/ITH antibiotics should be taken into consideration, particularly for multidrug-resistant bacteria, if there is no response to IV antibiotics or if the concentrations of CSF do not approach their respective MICs [6]. The patient's intracranial infection in our study, however, was quite critical. IVT antibiotics must be added because IV antibiotics also do not work. Drug-resistant bacteria are more likely to arise in situations involving long-term mechanical ventilation, the use of broad-spectrum antibiotics, and long-term ventricular drainage following the excision of an SOL with EVD in situ because of obstructive hydrocephalus.
Carbapenems are typically the firstline treatment for intracranial infections caused by gram-negative bacilli. In regions where the prevalence of carbapenem-resistant A. baumannii is high, carbapenems might not be the treatment of choice due to their yearly increase in resistance [7]. The amount of XDR bacteria is increasing, making treatment more difficult. In many instances, the sole antimicrobial drug that is effective against meningitis pathogens is polymyxin-B [8].
CSF samples were collected multiple times after admission for our investigation, although no organism growth was observed at the beginning of the study. After a few days of mechanical breathing, the patient's GCS score did not improve, and the patient exhibited infection-related symptoms. For these reasons, we sent a tracheal aspirate C/S, which revealed moderately growing XDR Acinetobacter, and a chest X-ray revealed pneumonia. After the antibiotic regimen was changed to strengthen its anti-infective properties, the pneumonia considerably improved. Although the patient's level of consciousness did not improve to a tolerable degree and a repeat CT scan revealed ventriculomegaly, the neurosurgeon performed a revision of the EVD and sent CSF for C/S, which revealed profuse growth of Acinetobacter, which is carbapenem resistant.
Since the 1950s, polymyxin has been used widely, but its widespread use has been restricted because of its extreme nephrotoxicity and neurotoxicity, which can cause seizures, chemical meningitis, and ventriculitis. Since there were no other antibiotics available when carbapenem-resistant gram-negative bacteria first emerged and proliferated in the 1990s, polymyxin had to be reintroduced into clinical practice [9]. To better understand the pharmacokinetics (PK), pharmacodynamics (PD), and clinical characteristics of colistin [10], researchers and clinicians have recently found that polymyxin is active against a range of aerobic gram-negative bacteria, particularly strains that are resistant to multiple drugs, such as A. baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and that it possesses CNS permeability [11]. Next, we discussed the results of simultaneous IVT polymyxin-B 50,000 IU once daily and TGC 5 mg susceptibility tests with the patient's attendant. Tigecycline and polymyxin B clearly state in their official instructions that they can be used for IVT and ITH.
Patients receive polymyxin-B in its sulfate salt form, which is the active antibacterial agent given directly to them. The primary mode of elimination of polymyxin B is nonrenal clearance, which lowers the risk of nephrotoxicity [12]. When therapy is stopped, polymyxin-induced neurotoxicity is typically reversible. Our study included IVT polymyxin B (50,000 IU) once daily for 15 days. The patient's renal function was thoroughly monitored during this process, and no adverse effects that could be considered nephrotoxic or neurotoxic were noted.
Nevertheless, research has indicated that polymyxin has low permeability to the blood‒brain barrier [13, 14]. In patients receiving only intravenous (IV) treatment for cerebral infections, the CSF contains only 5–10% polymyxin. ITH administration can increase the amount of drug needed to kill bacteria, in CSF [14]. According to the 2019 International Consensus Guidelines for the Optimal Use of Polymyxins, a daily dose of 50,000 IU (5 mg) of polymyxin-B supplied by ITH/IVT for a mean of 18 days is recommended. According to the 2017 Infectious Diseases Society of America (IDSA) proposal, intracranial infections caused by aerobic gram-negative bacteria should be treated for 21 days, but this should be customized based on the patient's clinical response and should continue for at least three consecutive CSF cultures that yield negative results on different days [6]. The trial involved the administration of IV polymyxin 50000 units per day and IVT tigecycline 5 mg per day. The treatment was administered for a total of 15 days, during which three consecutive negative CSF cultures were obtained. The therapeutic result was deemed satisfactory.
There is currently little experience with ITH/ITV polymyxin B. According to Pan et al., the ITH/ITV polymyxin B had a good therapeutic effect on cerebral XDR A. baumannii infections, with a death rate of only 8.70%. Among the trial participants, there were no cases of acute renal injury or neurotoxicity [15]. It is evident from this that polymyxin B is reasonably safe.
The average CSF sterilization time in the literature was 4 days, which was significantly less (range 1–18 days) than the 15 days (range 8–48 days) that we found. This discrepancy can be attributed to how most published cases and our definitions of CSF sterilization criteria differ. Treatment was further complicated by the patient's XDR bacterial infection in our study. A viable option for treating cerebral infections is IVT polymyxin B, a gram-negative bacterium that is resistant to many drugs. However, information about the PK of polymyxin B (such as inhalation, ITH/IVT) and other methods outside IV injection is currently lacking. A glycylcycline-based antibiotic is called tigecycline. Tests conducted both in vitro and in vivo have verified that TGC typically demonstrates strong antibacterial activity against gram-positive and gram-negative bacteria that are resistant to drugs. The penetration rate of tigecycline in the CSF is only 11% as a result of its lack of penetration into the CNS, and patients with intracranial infection do not significantly benefit from IV injection. Consequently, patients are not advised to receive traditional IV tigecycline therapy [16].
As a result, we mixed IV TGC with IVT, which could be a possible course of treatment for patients. For the first time, XDR A. baumannii cerebral infection was successfully treated with IVT tigecycline in 2016 [5]. In our research, IV tigecycline was continued, and the IVT dosage was 5 mg/day. The course of antibiotic treatment was stopped after 15 days of treatment when the patient's CSF cultures became negative three times in a row.
IVT-tigecycline appeared to be a safe course of therapy. Our study was supported by prior studies that revealed successful patient application of IVT and the ITH tigecycline [17].
To treat XDR bacteria, tigecycline can be used in conjunction with colistin or polymyxin B. According to in vitro antibiotic investigations, tigecycline and polymyxin B may work synergistically to treat carbapenem-resistant A. baumannii, with up to 70% of these strains exhibiting such synergistic effects [18]. However, antibacterial activity in vitro does not always translate into in vivo activity. The effectiveness of TGC and polymyxin in clinical settings has been questioned, and additional clinical research is required to support the management of XDR A. baumannii [19].