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Daptomycin for CNS infections
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Design
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Case studies |
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Case Series 11
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A case series presented 3 successful treatments of vancomycin-resistant Enterococcus faecium (VRE) meningitis using daptomycin and linezolid or gentamicin. The patients were males aged 58-78 years.
Patient 1 was initiated on intravenous (IV) daptomycin 12 mg/kg daily with synergistic gentamicin (peak 4 mg/L, trough < 0.5 mg/L) on hospital day 17. After 10 days of therapy, gentamicin was discontinued, and daptomycin was decreased to 10 mg/kg daily due to elevated serum creatinine kinase (CK; 783 units/L) to complete the 3-week course of therapy.
Patient 2 was initiated on IV daptomycin 9 mg/kg daily plus gentamicin 6.5 mg/kg daily on hospital day 10. On day 19, gentamicin was discontinued. After 15 days of high-dose daptomycin therapy, dose was decreased to 6 mg/kg every 48 hours on hospital day 25 due to acute renal injury. The renal injury was primarily thought to be due to gentamicin use as well as critical status of patient. Daptomycin was continued for 30 days.
Patient 3 was initiated on IV daptomycin 6 mg/kg daily and linezolid 600 mg every 12 hours on hospital day 15. The patient completed a 20-day course of both medications.
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Case Series 22
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Another case series focused on VRE faecium meningitis in a 55-year-old male patient with acute myeloid leukemia. Five days after his second transplantation, the patient developed VRE faecium bacteremia and was initiated on daptomycin 6 mg/kg IV. Eleven days into treatment, following a bacterial culture, daptomycin was discontinued, and patient was commenced on linezolid for two weeks. Following this treatment course, patient again presented with symptoms. Following additional blood cultures, the patient was again started on daptomycin 6 mg/kg IV every 24 hours in addition to quinupristin–dalfopristin (QD) 7.5 mg/kg IV every 8 hours. Although the patient's bacteremia cleared 3 weeks after treatment, the patient presented with sepsis and respiratory and renal failure, eventually passing away. Lumbar puncture and blood cultures were negative.
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Case Series 33
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A case series presented 4 cases of CNS infections due to gram-positive pathogens that were successfully treated with daptomycin combined with rifampin.
Patient 1 was a 73-year-old woman presenting with fever, chills, altered mental status, and purulent drainage from surgical wound site following an L3/L4 laminectomy with implanted hardware for spinal stenosis. Blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA), and the patient was initiated on vancomycin. Due to continuous deterioration and positive cerebrospinal fluid (CSF) culture for MRSA, after 6 days, the patient was switched to daptomycin 6 mg/kg daily plus rifampin 300 mg/daily orally. Daptomycin was continued for 4 weeks. Evidence of meningitis recurrence was not revealed at 6-week follow-up.
Patient 2 was a 37-year-old white woman presenting with serosanguineous drainage of pus from ventriculoperitoneal shunt place 3 weeks prior. Cerebrospinal fluid and blood cultures grew MRSA. Due to a previous vancomycin allergy, the patient was initiated on daptomycin 6 mg/kg daily and rifampin 600 mg/day. The patient's symptoms improved within 72 hours; she completed 4 weeks of antibiotic therapy, with a new shunt placed at the end of therapy.
Patient 3 was a 47-year-old woman with a recent history of vaginal hysterectomy presenting with a 5-day history of altered mental status, fever, headache, and progressive deterioration of mental status. The patient's CSF cultures grew E. faecalis, susceptible to vancomycin. Despite vancomycin treatment, patient continued to worsen neurologically. Vancomycin was discontinued on day 6, and daptomycin 6 mg/kg/day was initiated for 6 weeks, along with rifampin 300 mg/day orally. Within 4-5 days, the patient's mental status improved, and CSF cultures showed resolution.
Patient 4 was a 42-year-old woman with a CSF leak after craniotomy. The patient was treated with a ventricular shunt and discharged but readmitted 3 weeks later with fever, altered mental status, and headaches. CSF cultures grew multidrug-resistant Alcaligenes xylosoxidans and methicillin-resistant Staphylococcus epidermidis. When vancomycin and imipenem-cilastatin failed, patient was instead started on IV daptomycin 6 mg/kg daily, rifampin 600 mg/daily orally, and gentamicin 2 mg/kg every 8 hours. Patient was treated with daptomycin and rifampin for 14 days but passed away 3 weeks later with persisting A. xylosoxidans cultures in CSF.
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Case 44
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A 52-year-old female presented with spontaneous intraventricular hemorrhage, requiring an emergency bedside ventriculostomy, with CSF cultures revealing coagulase-negative staphylococcal (CoNS) species. Vancomycin 1 gram and rifampin 600 mg IV were administered every 12 hours. Cultures of CSF continued to show CoNS for the next three days despite the addition of daptomycin IV at 10 mg/kg (dosed at actual body weight) daily. Intraventricular daptomycin was added on day 18, 10 mg daily for the first two days, and then every other day. Culture of CSF became sterile on day 25 following 7 days of daptomycin intravenous and intraventricular therapy in addition to continued administration of intravenous vancomycin and rifampin. Intravenous daptomycin and vancomycin were discontinued on day 55 after 37 days of dual treatment.
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Case 55
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A 23-year-old male with a history of multiple ventriculoperitoneal shunt revisions associated with multidrug-resistant Staphylococcus epidermidis shunt infection presented with meningitis despite suppressive antibiotic therapy. The patient ultimately improved with daptomycin 750 mg IV every 24 hours in place of vancomycin. Intrathecal (IT) daptomycin was then added, dosed at 5 mg IT every 24 hours for 3 days, then every 72 hours thereafter. The patient received a total of 9 doses of IT daptomycin over 21 days. Daptomycin administered IV was continued empirically.
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Case 66
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An incidence of treatment failure of daptomycin was reported in a female adult patient with cervical spine osteomyelitis involving the skull base with evidence of infection. The patient was empirically treated with vancomycin and piperacillin/tazobactam. CSF studies were consistent with bacterial meningitis, and patient was recommended to start an 8-week course of vancomycin for hematogenous skull base osteomyelitis secondary to MRSA bacteremia. On day 14, patient was febrile and developed profound leucopenia, after which vancomycin was transitioned to daptomycin 8 mg/kg (500 mg) every 24 h combined with ceftriaxone 2 g every 24 h. Four weeks later, the patient was readmitted and increased daptomycin to 10 mg/kg (650 mg) every 24 hours and ceftriaxone to 2 g every 12 h due to concern of worsening bacterial meningitis/skull base osteomyelitis. Patient was ultimately switched to meropenem 2 g every 8 h and linezolid 600 mg every 12 h due to a lack of CNS penetration and clinical interpretation/application of minimum inhibitory concentration (MIC) breakpoints in CNS infection.
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Case 77
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A 60-year-old man presented with fever and multiple muscles and brain abscesses caused by Panton-Valentine leukocidin-negative community-associated MRSA. The patient was started on empiric antibiotic therapy with meropenem (1g IV three times daily), linezolid (600mg IV twice daily), and levofloxacin (500mg IV twice daily). The strains isolated were susceptible to rifampin, fluoroquinolones, gentamicin, tetracycline, and cotrimoxazole, as well as glycopeptides, linezolid, daptomycin, quinupristin/dalfopristin, and tigecycline. On day 12, the patient was switched to daptomycin 6 mg/kg daily in place of meropenem. On day 38, following a normal chest X-ray, daptomycin and levofloxacin were stopped, and patient was discharged. Linezolid 600 mg twice daily was continued for two additional weeks.
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Case series 88
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Patient 1 was a 30-year-old white male presenting with altered mental status, lethargy, and increasing fever. One of two blood cultures was positive for Staphylococcus. Given the history of IV drug abuse and clinically suspected meningitis, the patient initially received one dose each of gentamicin and ceftriaxone in the emergency department, later changed to vancomycin, ceftriaxone, and levofloxacin. The patient underwent a decompression lumbar laminectomy of L4–L5 with microscopic drainage of the epidural and subdural abscesses. Due to subtherapeutic vancomycin trough, patient was changed to rifampin 600 mg (IV to PO) and daptomycin 450 mg IV daily (8 mg/kg daily). Patient began to recover, and treatment continued for 6 weeks. Daptomycin was well tolerated, and no adverse events were reported during therapy.
Patient 2 was a 72-year-old man presenting with chest pain that radiated to his back. Blood cultures were positive for S. aureus and were subsequently identified as MRSA, sensitive to rifampin, tetracycline, cotrimoxazole, and vancomycin but resistant to levofloxacin, erythromycin, and oxacillin. Urinalysis and culture were positive for S. aureus, nitrites, and moderate leukocytes. Initial therapy with vancomycin, piperacillin/tazobactam, and cotrimoxazole was changed on day 3, partly due to concern for further renal impairment with vancomycin therapy. The patient was started on daptomycin 650 mg (6 mg/kg) IV and rifampin 600 mg orally, both once daily, for MRSA bacteremia. Patient was eventually discharged home with 35 additional days of daptomycin and 21 days of rifampin. For the final 12 days of therapy, daptomycin was dose adjusted to 6 mg/kg every 48 hours due to obstructive uropathy related to underlying prostate cancer.
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Case report 99
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A 54-year-old male presented with severe generalized weakness, decreased appetite, and nonproductive cough. He was empirically treated with IV vancomycin 1 g every 12 hours, levofloxacin 750 mg daily, and piperacillin/tazobactam 3.375 g every 8 hours for presumed healthcare-associated pneumonia with sepsis complicated by neutropenia. Urine and blood cultures were positive for MSSA, and vancomycin was changed to IV nafcillin 2 g every 4 hours on hospital day 4, which was initially effective; however, on hospital day 9, the patient developed relapsing MSSA bacteremia. Nafcillin was discontinued on hospital day 10 due to acute kidney injury, and treatment was initiated with once-daily IV daptomycin 800 mg (9 mg/kg/day). Blood cultures determined on hospital day 12 showed no growth at 5 days. Daptomycin therapy was continued until the patient died on hospital day 16 after the family withdrew ventilator support.
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Study Author Conclusions, abridged
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By extrapolating in vitro antimicrobiological data in 3 patients with VRE. CSF infections, the authors applied treatment strategies employing daptomycin 9-12 mg/kg with gentamicin or daptomycin 6 mg/kg with linezolid.1
The ideal antimicrobial drug for the treatment of VRE. faecium meningitis would be a bactericidal agent with high CNS penetration and low side effect profile. Such a drug does not currently exist. Linezolid, daptomycin, and QD have become available over the last decade and have been used for the treatment of VRE. faecium meningitis.2
The treatment of CNS shunt infections with and without meningitis is problematic. There are limited data, mainly clinical trial information, to aid in appropriate drug therapy choices. Daptomycin has activity against most gram-positive pathogens that cause CNS infections; however, limited data for these types of infections are available. These case reports suggest that daptomycin with rifampin can be an option for patients with gram-positive CNS shunt infections.3
The decision to add intraventricular administration of daptomycin was made due to continued neurosurgical need for the ventriculostomy and potentially limited CSF penetration of IV daptomycin. More clinical data are needed to delineate consistent daptomycin CSF penetration and role of intraventricular administration of daptomycin in CNS infections in conjunction with removal of involved prosthetic devices.4
Intrathecal daptomycin is an appropriate option for treating resistant Staphylococcal infections after traditional IV administration has failed. Administering daptomycin 5 mg IT every 24 hours for 3 days followed by every 72 hours for 18 days resulted in sterile CSF after the first 24 hours of therapy, which remained sterile thereafter without adverse sequelae.5
Further investigation is needed to evaluate the microbiological and clinical efficacy of newer antimicrobial agents in the treatment of CNS infections.6
Although the patient was given antimicrobials that were active against the isolated MRSA strain, namely levofloxacin, and linezolid, his clinical condition rapidly worsened. A likely explanation is the bacteriostatic effect of linezolid, the concentration-dependent activity of levofloxacin, and an aggressive virulence of the MRSA strain. In the presented case, the introduction of daptomycin in the antimicrobial schedule allowed fast improvement concerning skin, soft tissue, muscle lesions, and brain manifestations. Indeed, daptomycin has been shown to be effective in central nervous system infection in humans and animal models.7
On switching to high-dose daptomycin-based therapy, both patients stabilized, with subsequent clinical improvement. After 6 weeks of daptomycin-based therapy, complete recovery was achieved, followed by prolonged oral antibiotics. High-dose daptomycin was tolerated by both patients with no treatment-related adverse events. Results of follow-up cultures showed bacterial eradication.8
Daptomycin may be considered a therapeutic option for the treatment of invasive MSSA infections when traditional therapy is contraindicated due to a medication allergy, adverse drug reaction, or associated toxicity. In the treatment of meningitis, daptomycin represents a reasonable alternative given its bactericidal activity against common gram-positive pathogens and lack of cell lysis. Higher-than-recommended daptomycin doses (>6 mg/kg) may be considered for use in invasive infection with a CNS source.9
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