THE EMERGENCE OF multidrug-resistant pathogens is forcing physicians to use newer, sometimes untried, antibiotics to clear systemic infections. Treatment difficulties are compounded if the bacteria are present in sites not normally accessible to antibiotics, such as the central nervous system (CNS). Infections of the meninges may compromise the integrity of the blood-brain barrier, allowing antibiotics to penetrate the CNS. However, this does not occur when the infection originates in a CNS or ventriculoperitoneal shunt. Typically, these infections are caused by gram-positive bacteria, such as coagulase-negative staphylococci and enterococci. With the emergence of resistance of these bacteria, in particular vancomycin-resistant Enterococcus faecium (VREF), new antibiotics and routes of delivery must be explored.
Quinupristin/dalfopristin (Synercid, Aventis Pharmaceuticals) is a new injectable antibiotic composed of two streptogramin molecules, quinupristin and dalfopristin, which act synergistically against gram-positive pathogens, including VREF [1,2]. The mechanism of action is via inhibition of protein synthesis at the 50S ribosome: dalfopristin blocks an early stage of protein elongation, and quinupristin causes a premature detachment of incomplete polypeptide chains later in the protein synthesis process . Quinupristin/dalfopristin is bactericidal against many gram-positive pathogens. However, time-kill studies indicate that quinupristin/dalfopristin shows only bacteriostatic activity against clinical VREF strains that are erythromycin resistant .
In worldwide clinical trials and an emergency-use program, quinupristin/dalfopristin has been shown to be effective when administered intravenously (IV) to seriously ill patients infected with gram-positive organisms resistant to other drugs [4–6]. Preclinical animal studies show negligible distribution of IV-administered quinupristin/dalfopristin across noninflamed meninges , but greater penetration when inflammation is present ; however, no human data are available. Apart from case reports on two patients [9,10], there have been no data on the use of quinupristin/dalfopristin in the treatment of CNS infections. This report reviews the safety and efficacy of quinupristin/dalfopristin, administered IV and intrathecally (IT), in the treatment of six cases of CNS infection with VREF.
Patients were enrolled into one of three emergency-use, noncomparative, open-label, multicenter trials. Patients were enrolled if they met all of the following inclusion criteria: a positive culture for VREF; signs and symptoms of infection as per Infectious Diseases Society of America guidelines ; and the presence of a pathogen resistant to all clinically appropriate antibiotics, or documented failure of treatment using all clinically appropriate antibiotics, or patient intolerance of all clinically appropriate antibiotics.
Patients were to receive quinupristin/dalfopristin for a duration determined by the treating physician as appropriate for the indication. The test-of-cure assessment was performed 3–21 days after treatment or at end-of-treatment if the patient did not progress to follow-up. Only serious adverse events and those considered by the investigator to be related to treatment were recorded.
Each request for IT administration of quinupristin/dalfopristin was reviewed and authorized by both the Anti-Infective Drug Product Division of the U.S. Food and Drug Administration and the manufacturer (Rhône-Poulenc Rorer, Inc.). No data on IT administration of quinupristin/dalfopristin were available before the treatment of patient 1. For each subsequent case, the investigator was provided with information on the previous cases.
Clinical response was assessed as cure, improved, indeterminate, or failure by the investigator at test-of-cure (or end-of-treatment if the patient did not progress to test-of-cure). Bacteriologic response was assessed as eradicated, presumed eradicated, persistence, presumed persistence, or indeterminate for the primary infection site.
An 8-month-old, former 26-week gestation, female infant with a CNS shunt was admitted with hydrocephalus, fever, and lethargy after a recent long neonatal intensive care unit stay during which she had recurrent shunt infections. VREF was isolated from cultures of admission cerebrospinal fluid (CSF). The shunt was removed and an Ommaya reservoir placed. Treatment with IV chloramphenicol and IT and IV gentamicin failed to eradicate the VREF. Treatment with quinupristin/dalfopristin 7.5 mg/kg (37.5 mg) IV every 8 hours plus 1 mg IT per day was then started. Clinical signs and symptoms resolved and sterilization of the CSF was obtained after 28 days of IV and IT quinupristin/dalfopristin. The patient remains well with no relapse 4 years later .
A 3-year-old boy was diagnosed with a CNS tumor at admission, and underwent partial surgical excision and ventriculoperitoneal shunt placement. Infection of the shunt with coagulase-negative staphylococci was treated with IV vancomycin. VREF plus the original organism were isolated from subsequent CSF cultures, then VREF alone on two occasions. Treatment with quinupristin/dalfopristin was started at a dose of 7.5 mg/kg (135 mg) IV every 8 hours. The ventriculoperitoneal shunt was removed and a drain placed. One week later, a new ventriculoperitoneal shunt was placed and treatment with quinupristin/dalfopristin 1 mg IT per day was added when the CSF culture yielded gram-positive cocci, later identified as VREF. The ventriculoperitoneal shunt was replaced once more. After 16 days of IT quinupristin/dalfopristin and 27 days of IV quinupristin/dalfopristin, the patient’s signs and symptoms resolved, with sterilization of the CSF. The patient remained well at 2-month follow-up.
A 23-year-old man with spina bifida, paraplegia, and intraventricular shunt for hydrocephalus since childhood was admitted for abdominal distension and underwent abdominal surgery for lysis of adhesions, hernia repair, and ileal resection. His postoperative course was complicated by sepsis, intubation, and multiple replacements of the ventriculostomy. VREF sensitive to chloramphenicol was isolated from CSF cultures. Treatment with IV chloramphenicol failed, with repeat cultures yielding VREF 3 weeks later. Treatment with quinupristin/dalfopristin 7.5 mg/kg (560 mg) IV every 8 hours and 2 mg IT per day was started. On day 3, the ventriculostomy was replaced. IT administration of quinupristin/dalfopristin was suspended for 4 days, then resumed. On day 8, the patient developed a decrease in mental status accompanied by posturing, with a negative computed tomography scan. Symptoms persisted, with a repeat scan showing anterior-posterior bilateral stroke on day 10. Two days later, an electroencephalogram revealed no brain activity. The family elected to withdraw support and the patient died of stroke. This event was assigned as remotely related to IT quinupristin/dalfopristin because of the lack of any apparent cause for the stroke. CSF cultures were sterile at the end of the 10-day treatment course .
A 17-month-old, former 33-week gestation, female child with Down syndrome, hypothyroidism, and congenital hydrocephalus requiring ventriculoperitoneal shunt was admitted with respiratory syncytial virus infection. This infection resolved, but she remained unstable over the next 2 weeks, with frequent temperature spikes and hypoxic events. A computed tomography scan of the head and chemistry of the CSF suggested ventriculoperitoneal infection; treatment with vancomycin was therefore started, but with no subsequent improvement. Multiple neurosurgical interventions for replacement of the possibly infected shunt were performed. VREF was then isolated from a culture from the tip of the ventriculoperitoneal shunt. Treatment with quinupristin/dalfopristin was started at a dose of 1 mg IT per day injected into the ventriculoperitoneal shunt. No quinupristin/dalfopristin was given IV. After 21 days of IT quinupristin/dalfopristin therapy, there was resolution of signs and symptoms of CNS infection and sterilization of the CSF. One-month follow-up indicated no further shunt infections with VREF. Long-term follow-up at 2 years revealed multiple shunt revisions with intermittent CNS infection with other organisms.
A 14-month-old boy with a seventh nerve palsy was diagnosed with a CNS tumor during craniotomy. Postoperatively, the patient developed non-communicating hydrocephalus. A ventriculoperitoneal shunt was placed which subsequently became infected with several pathogens, including Enterobacter cloacae and E. faecalis. Chemotherapy with cyclophosphamide was started for the tumor, and an Ommaya reservoir was placed for CNS access. Upon its removal, one colony of VREF was isolated from its tip. At this time, the patient was also rectally colonized with VREF. He was lethargic, unable to tolerate feedings, and febrile to 101°F. Treatment with quinupristin/dalfopristin at a dose of 7.5 mg/kg (67 mg) IV every 8 hours was started, but the patient then developed small focal seizures, fevers, and alteration in mentation. A ventriculostomy was inserted, and the CSF culture was positive for VREF the next day. Treatment with quinupristin/dalfopristin 1 mg IT per day was started 2 days later and continued for 28 days, then for a further 5 days at 2 mg IT per day. His symptoms of meningitis improved and the CSF became sterile. He gradually deteriorated neurologically over the next 2 months because of the CNS tumor, and died from progression of his tumor, gram-negative sepsis, and neutropenia.
A 46-year-old woman recently diagnosed with an intracranial hemorrhage underwent craniotomy for a mass thought to be a metastatic tumor. She was subsequently treated with chemotherapy and radiation. She then developed a postoperative wound infection with a CNS abscess, which was drained. She improved over the next month but then relapsed with fever, neck stiffness, and persistent wound drainage with clear CSF. The wound was debrided and a lumbar drain placed. VREF was isolated from a CSF culture, and quinupristin/dalfopristin at a dose of 7.5 mg/kg (500 mg) IV every 8 hours was started. The patient began to improve, with clearing of the CSF, and the lumbar drain was discontinued. One week later, the patient became febrile again and VREF was cultured from the CSF. Treatment with quinupristin/dalfopristin 2 mg IT per day was started after placement of a new lumbar drain. Quinupristin/dalfopristin was given IT for 6 days. The patient became clinically stable, with negative repeat CSF cultures. At her 1-month follow-up, the patient remained well with no relapse.
The characteristics of these six patients and their treatment are summarized in Table 1. None of the patients was bacteremic.
Five of the six patients were administered quinupristin/dalfopristin both IV and IT. One patient received IT therapy only. IT quinupristin/dalfopristin doses were either 1 mg or 2 mg per day for a total of 5 to 33 days. Total duration of IV quinupristin/dalfopristin ranged from 10 to 74 days.
Antibiotic susceptibility of baseline isolates.
The baseline isolates of VREF from each patient were tested for susceptibility to quinupristin/dalfopristin and other antibiotics (Table 2). In all five cases in which susceptibility to quinupristin/dalfopristin was tested, the VREF isolate was susceptible to quinupristin/dalfopristin. National Committee for Clinical Laboratory Standards–approved breakpoints for quinupristin/dalfopristin are ≤1 μg/mL, sensitive; 2 μg/mL, moderately susceptible; and ≥4 μg/mL, resistant . All of the isolates were resistant to ampicillin, but the four isolates tested were susceptible to chloramphenicol.
All six patients received one or more concomitant antibiotics; the most common were chloramphenicol, vancomycin, and gentamicin (Table 1). In two cases, vancomycin and gentamicin were delivered by the IT route.
Efficacy of quinupristin/dalfopristin.
Clinical cure or improvement was documented in all five of the patients who could be assessed, and bacteriologic eradication or presumed eradication was achieved in all six patients. In the five patients fitted with a ventriculoperitoneal shunt, the indwelling device was removed or replaced before or during treatment with quinupristin/dalfopristin.
Safety of quinupristin/dalfopristin.
None of the patients had an adverse event judged to be possibly or probably related to quinupristin/dalfopristin. Two of the six patients died while on treatment. Patient 3 died of a stroke for which no apparent cause could be found; it was therefore judged to be remotely related to quinupristin/dalfopristin. Patient 5 died of worsening of his underlying brain tumor, gram-negative sepsis, and neutropenia; none of these was judged to be related to quinupristin/dalfopristin.
The emergence of multidrug-resistant pathogens is driving a requirement for new antibiotics for clinical practice. Treatment options are particularly limited for patients who are in the hospital for a prolonged period, have received multiple courses of antibiotics, have a foreign body (shunt) in place, and then acquire an infection of the CNS because of an organism with multiple resistance.
Data are available for the use of IT gentamicin [13–16], vancomycin [17–19], and teicoplanin  in the treatment of CNS infections. Physicians have resorted to the IT route of administration of these antibiotics because of difficulty in achieving sufficient CSF levels via the IV route of administration. As in the cases reported herein, most published reports regarding the use of IT antibiotics involve small series of patients or anecdotal case reports. Gentamicin has been used in doses ranging from 100 μg  to 160 mg  IT per day. In some case series, vancomycin has been used in doses ranging from 10 mg IT (in pediatric patients) to 20 mg IT (in adults), whereas other centers have used 0.075–20 mg depending on the age and status of the patient [17,18]. Teicoplanin has been used at a dose of 10 mg IT daily . In addition to these antibiotics’ reported successes in eradicating infections, there have also been a significant number of failures of sterilization of the CSF reported with their use. Concerns have also been raised about neurotoxicity, fevers, and the need for a mechanism that would allow daily instillation into the ventricular fluid.
Quinupristin/dalfopristin is a new injectable antibiotic composed of two streptogramin molecules, quinupristin and dalfopristin, which act synergistically against gram-positive pathogens including VREF, Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and methicillin-resistant S. epidermidis, but not E. faecalis [1,2]. Animal studies have indicated that quinupristin/dalfopristin, like most antibiotics, does not cross the blood-brain barrier in sufficient quantities to treat CNS infection in the absence of meningeal inflammation. IV infusion of radiolabeled quinupristin/dalfopristin 10 mg/kg in healthy male cynomolgus monkeys revealed low or negligible diffusion into the CNS . In a rabbit model of experimental S. pneumoniae meningitis, IV bolus injection of quinupristin/dalfopristin 50 mg/kg had no effect on the growth of bacteria if administered before CNS inflammation occurred. However, the same dose was bactericidal against this strain if given at or after the time of inflammation . Data previously available on the use of quinupristin/dalfopristin in the treatment of human CNS infections were restricted to case reports on two patients, which are included in this review for completeness [9,10].
CSF levels of quinupristin/dalfopristin were not measured in the patients included in the present study. However, in a recent report of a case of VREF shunt infection successfully treated with quinupristin/dalfopristin , CSF concentrations were measured after 1-mg and 2-mg IT administrations of quinupristin/dalfopristin. After the 1-mg IT administration, the summed concentration of quinupristin, dalfopristin, and their active metabolites in CSF was approximately 7.5 μg/mL at 1.7 hours after administration, and remained >1 μg/mL for 5 hours. For the 2-mg IT dose, the corresponding CSF concentration was approximately 16 μg/mL after 2.2 hours, and it remained >1 μg/mL for at least 8 hours .
All of the patients in this study received one or more concomitant antibiotics, in some cases via the IT route. However, in each case, there was evidence that these antibiotics would not be successful against the main causative pathogen.
In the present study, there were no events of probable or possible toxicities reported with the use of IT quinupristin/dalfopristin. In one patient who developed a stroke, the event was judged to be remotely related to the IT therapy.
With the lack of other clinically appropriate therapeutic options for device-associated VREF meningitis, these few case reports are encouraging. They indicate that quinupristin/dalfopristin administered IT may be a therapeutic option for patients with VREF infection of the CNS. Further studies are required to determine fully the efficacy and safety of IT quinupristin/dalfopristin and its optimal dosing regimen.
The effort of the following study group investigators and their study coordinators are gratefully acknowledged: Drs. Lenny Krilov, Amy Phillips, Suresh Antony, and Esklid Peterson.
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