Safety and Efficacy of Prolonged Use of Dalbavancin in Bone and Joint Infections.

Dalbavancin is a lipoglycopeptide with potent activity against Gram-positive microorganisms, a long half-life, a favorable safety profile, and a high concentration in bone, which makes it an interesting alternative for treatment of osteoarticular infections. We performed a multicentric retrospective study of all patients with an osteoarticular infection (septic arthritis, spondylodiscitis, osteomyelitis, or orthopedic implant-related infection) treated with at least one dose of dalbavancin between 2016 and 2017 in 30 institutions in Spain. In order to evaluate the response, patients with or without an orthopedic implant were separated. A total of 64 patients were included. Staphylococcus epidermidis and Staphylococcus aureus were the most frequent microorganisms. The reasons for switching to dalbavancin were simplification (53.1%), adverse events (25%), or failure (21.9%). There were 7 adverse events, and no patient had to discontinue dalbavancin. In 45 cases, infection was related to an orthopedic implant. The implant material was retained in 23 cases, including that in 15 (65.2%) patients that were classified as cured and 8 (34.8%) that presented improvement. In 21 cases, the implants were removed, including those in 16 (76.2%) cases that were considered successes, 4 (19%) cases were considered improved, and 1 (4.8%) case that was considered a failure. Among the 19 cases without implants, 14 (73.7%) were considered cured, 3 (15.8%) were considered improved, and 2 (10.5%) were considered failures. The results show that dalbavancin is a well-tolerated antibiotic, even when >2 doses are administered, and is associated with a high cure rate. These are preliminary data with a short follow-up; therefore, it is necessary to gain more experience and, in the future, to establish the most appropriate dose and frequency.

Staphylococcus aureus meningitis in adults: A comparative cohort study of infections caused by meticillin-resistant and meticillin-susceptible strains.

BACKGROUND: Staphylococcus aureus meningitis is an uncommon nosocomial infection usually associated with neurosurgical procedures, but spontaneous infections may occasionally appear. AIMS: To compare the features of meningitis caused by meticillin-resistant (MRSA) and meticillin-susceptible (MSSA) S. aureus and examine the prognostic factors for mortality, including MRSA infection and combined antimicrobial therapy. METHODS: Retrospective cohort study of 350 adults with S. aureus meningitis admitted to 11 hospitals in Spain (1981-2015). Logistic regression and propensity score matching were used to analyse prognostic factors. RESULTS: There were 118 patients (34%) with MRSA and 232 (66%) with MSSA. Postoperative infection (91% vs 73%) and nosocomial acquisition (93% vs 74%) were significantly more frequent in MRSA than in MSSA meningitis (P < 0.001). Combined therapy was given to 118 (34%) patients. Overall 30-day mortality rate was 23%. On multivariate analysis, mortality was associated with severe sepsis or shock (odds ratio (OR) 9.9, 95% confidence interval (CI) 4.5-22.0, P < 0.001), spontaneous meningitis (OR 4.2, 95% CI 1.9-9.1, P < 0.001), McCabe-Jackson score rapidly or ultimately fatal (OR 2.8, 95% CI 1.4-5.4, P = 0.002), MRSA infection (OR 2.6, 95% CI 1.3-5.3, P = 0.006), and coma (OR 2.6, 95% CI 1.1-6.1, P < 0.029). In postoperative cases, mortality was related to retention of cerebrospinal devices (OR 7.9, 95% CI 3.1-20.3, P < 0.001). CONCLUSIONS: Clinical and epidemiological differences between MRSA and MSSA meningitis may be explained by the different pathogenesis of postoperative and spontaneous infection. In addition to the severity of meningitis and underlying diseases, MRSA infection was associated with increased mortality. Combined antimicrobial therapy was not associated with increased survival.

Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study.

BACKGROUND: Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment. METHODS: To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid. RESULTS: A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179. CONCLUSIONS: SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources.

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models.

Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 µg/ml versus 3 µg/ml [P < 0.05] and 2 µg/ml versus 3.4 µg/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

IFNL4 ss469415590 polymorphism is associated with unfavourable clinical and immunological status in HIV-infected individuals.

The IFNL4 ss469415590 polymorphism, in high linkage disequilibrium with the IL28B rs12979860 variant, has been associated with hepatitis C virus clearance. We evaluated whether ss469415590 is associated with clinical and immunovirological parameters in human immunodeficiency virus-infected subjects. We found an independent association of the IFNL4 ss469415590 polymorphism with higher prevalence of AIDS-defining illnesses and lower CD4 T cell numbers. These results suggest the existence of common host defence mechanisms against different viral infections.

Efficacy of rifampin, in monotherapy and in combinations, in an experimental murine pneumonia model caused by panresistant Acinetobacter baumannii strains.

The objective of this work was to evaluate the efficacy of rifampin, and its combinations with imipenem or sulbactam, in an experimental pneumonia model caused by two panresistant Acinetobacter baumannii strains (HUVR99 and HUVR113). Minimum inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) (µg/ml) of the strains were rifampin 128/>128 for both strains, imipenem 128/>256 and 256/>256 for HUVR99 and HUVR113, respectively, and sulbactam >256/>256 for both strains. In time-kill studies, at MICs, rifampin was bactericidal for both strains and sulbactam against the HUVR99 strain. Rifampin plus imipenem or sulbactam, at the MIC or mice C (max), were synergistic. In vivo, against HUVR99 and HUVR113, rifampin (73% and 40%) and its combinations improved the survival with respect to the control group (20% and 0%, p < 0.05), respectively. Rifampin (87% and 46%) and its combinations improved the sterilization of blood cultures with respect to the control groups (0%, p < 0.05). In regard to the bacterial clearance from lungs, rifampin (2.57 ± 2.47 and 5.35 ± 3.03 log(10) cfu/g) and its combinations with imipenem or sulbactam diminished the bacterial lung concentration with respect to the control group (10.89 ± 3.00 and 11.86 ± 0.49, p < 0.05) with both strains. In conclusion, rifampin alone or associated to imipenem or sulbactam were effective for the treatment of murine pneumonia caused by selected panresistant A. baumannii strains.

Superinfection during treatment of nosocomial infections with tigecycline.

We performed a retrospective and observational study of 51 patients treated with tigecycline, as the treatment for nosocomial infections due to multidrug-resistant microorganisms, to evaluate the superinfection rate and their etiologies. Superinfections were diagnosed in 12 (23.5%) patients (seven due to Pseudomonas aeruginosa, 13.7%) and one patient had P. aeruginosa colonization. Five patients with superinfection died (41.6%), three due to superinfections and two to underlying diseases. The superinfection rate observed during tigecycline treatment is higher than that previously reported. Pseudomonas aeruginosa is the most frequent agent, being the cause of 58.5% of all superinfections.

Efficacy of tigecycline vs. imipenem in the treatment of experimental Acinetobacter baumannii murine pneumonia.

The in vivo activity of tigecycline was evaluated in an experimental pneumonia model (C57BL/6 mice) by Acinetobacter baumannii. Two clinical strains were used: minimum inhibitory concentrations (MICs) of imipenem and tigecycline 1 and 2 microg/mL (imipenem-susceptible, IPM-S), and 8 and 2 microg/mL (imipenem-intermediate, IPM-I), respectively. For imipenem (30 mg/Kg), T/CMI (h) were 1.04 and 0.51 for IPM-S and IPM-I, respectively. For tigecycline (5 mg/Kg), the area under the concentration-time curve (AUC)/MIC(0-24 h) (serum and lung) were 9.24 and 4.37 (for the two strains), respectively. In the efficacy experiments with the IPM-S, imipenem (log CFU/g 3.59 +/- 0.78, p = 0.006) and tigecycline (2.82 +/- 1.2, p = 0.054) decreased the bacterial counts in lungs with respect to its controls; with the IPM-I, both imipenem (1.21 +/- 0.52, p = 0.002) and tigecycline (3.21 +/- 0.28, p = 0.035) decreased the bacterial counts with respect to the controls. In the survival experiments, with the IPM-S, the mortality was the same in the control (67%) and in the tigecycline (77%) groups, and imipenem reduced it (21%, p = 0.025); with the IPM-I, the mortality was the same in the control (87%) and in the tigecycline (85%) groups, and imipenem (0%) reduced it (p < 0.001). In summary, the present study shows that tigecycline is less efficacious than imipenem in the treatment of experimental A. baumannii pneumonia caused by IPM-S and IPM-I strains.

Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia.

A guinea-pig pneumonia model involving imipenem-susceptible and imipenem-resistant strains of Acinetobacter baumannii was developed to assess the in-vitro and in-vivo activities of imipenem, alone or in combination with amikacin, and the pharmacokinetic and pharmacodynamic parameters. Serum levels were measured by bioassay (imipenem) or immunoassay (amikacin), followed by calculation of pharmacokinetic and pharmacodynamic parameters (Cmax, AUC, t1/2, Cmax/MIC, AUC/MIC, and Deltat/MIC). In-vivo efficacy was evaluated by comparing bacterial counts in the lungs of treatment groups with end-of-therapy controls by anova and post-hoc tests. Decreases in the Cmax (13.4%), AUC (13%), t1/2 (25%) and Deltat/MIC (11.8-32.2%) of imipenem were observed when it was administered with amikacin, compared with administration of imipenem alone. Similarly, decreases in the Cmax (34.5%), AUC (11.6%), Cmax/MIC (34.5%) and AUC/MIC (11.7%) of amikacin were observed when it was administered with imipenem. Bacterial counts in lungs were reduced by imipenem (p 0.004) with the imipenem-susceptible strain, and by amikacin (p 0.001) with the imipenem-resistant strain. The combination of imipenem plus amikacin was inferior to imipenem alone with the imipenem-susceptible strain (p 0.01), despite their in-vitro synergy, and was inferior to amikacin alone with the imipenem-resistant strain (p < 0.0001). In summary, combined use of imipenem with amikacin was less efficacious than monotherapy, probably because of a drug-drug interaction that resulted in decreased pharmacokinetic and pharmacodynamic parameters for both antimicrobial agents.

Activity of cefepime and carbapenems in experimental pneumonia caused by porin-deficient Klebsiella pneumoniae producing FOX-5 beta-lactamase.

The in-vivo activities of cefepime, imipenem and meropenem against the porin-deficient strain Klebsiella pneumoniae C2 and its derivative K. pneumoniae C2(pMG252) coding for the AmpC-type beta-lactamase FOX-5 were determined. Bactericidal activities were determined with the kill-curve method. A pneumonia model in guinea-pigs was developed, and Cmax, t(1/2) and DeltaT/MIC were calculated for the three agents tested. Animals were treated for 72 h with sterile saline (control group) or with cefepime, imipenem or meropenem (240 mg/kg/day, intramuscularly, three times daily). Bacterial counts in lungs (log10 CFU/g tissue) were determined by serial dilution. MICs (mg/L) of cefepime, imipenem and meropenem against K. pneumoniae C2/K. pneumoniae C2(pMG252), determined by macrodilution, were: 0.5/4, 0.5/0.5 and 0.25/0.5, respectively. Bacterial counts in the lungs of animals infected with K. pneumoniae C2 and treated with antimicrobial agents were always lower than in the control group (cefepime, 4.4 +/- 0.5; imipenem, 4.6 +/- 0.4; meropenem, 4.7 +/- 0.5; control group, 5.6 +/- 0.8; p <0.01). No significant differences were observed among the groups receiving therapy (p >0.05). Bacterial lung clearance was higher in treated animals than in control animals following infection with K. pneumoniae C2(pMG252) (cefepime, 4.5 +/- 0.4; imipenem, 4.0 +/- 0.3; meropenem, 4.6 +/- 0.4; control group, 6.1 +/- 0.6; p <0.01), with imipenem producing better clearance than either cefepime or meropenem (p <0.05). Thus, in the guinea-pig pneumonia model, cefepime, imipenem and meropenem were each effective against the porin-deficient K. pneumoniae strain C2 and its derivative expressing the plasmid-mediated AmpC type beta-lactamase FOX-5.

Morphological changes induced by imipenem and meropenem at sub-inhibitory concentrations in Acinetobacter baumannii.

Abstract Sub-inhibitory concentrations of imipenem and meropenem were evaluated for their ability to induce morphological changes with six strains of Acinetobacter baumannii isolated from patients with nosocomial pneumonia. Three strains were susceptible and three were resistant to carbapenems. The strains were grown in the presence of 0 (controls), 0.25x, 0.5x and 1x the MIC of both carbapenems for 4 h, and then examined after Gram's stain. Cells > or = 3 microm in size (spheroplasts) were considered to be altered. Both carbapenems induced significant numbers of spheroplasts compared to controls. Imipenem had more effect against susceptible strains, while meropenem had a greater effect against resistant strains.

Colistin efficacy in an experimental model of Acinetobacter baumannii endocarditis.

The in-vivo activity of colistin was evaluated in an experimental rabbit model of Acinetobacter baumannii endocarditis with a strain susceptible to colistin and intermediate to imipenem. Compared to a control group, colistin was effective (p < 0.05) in bacterial clearance from blood and in the sterilisation of blood cultures, but was not effective in clearing A. baumannii from vegetations. Thus, although colistin may be effective in treating bacteraemia caused by susceptible strains of A. baumannii, it may not be a suitable treatment for endocarditis, perhaps because of poor penetration into vegetations and a low C(max)/MIC ratio in tissue.

Tuberculous vertebral osteomyelitis in the new millennium: still a diagnostic and therapeutic challenge.

In order to determine the clinical features and current prognosis of tuberculous vertebral osteomyelitis, the charts of all patients diagnosed with definite or probable tuberculous vertebral osteomyelitis from January 1983 to June 2002 ( n=78) were reviewed. The mean delay to diagnosis was 6.1 months. Sixty-five (83.3%) patients had inflammatory spinal pain, 35 (44.9%) had some neurological deficit, and only 27 (34.6%) had fever. Paravertebral, epidural, and psoas abscesses were detected in 73.1, 65.4, and 24.4% of the cases, respectively. Culture was positive in 48% of the percutaneous biopsies and in 61.7% of the open biopsies. After histological findings were included, the diagnostic yield of percutaneous biopsies was 68%. Fifty-five (70.5%) patients required surgical treatment at some stage of the disease. Although no deaths were directly attributable to tuberculous vertebral osteomyelitis and only 5.1% of patients relapsed, the mean overall hospital stay was 69.1+/-36.9 days, and 30 (38.5%) patients had severe functional sequelae. In conclusion, diagnosis of tuberculous vertebral osteomyelitis requires a high degree of suspicion. Percutaneous biopsy should be undertaken as soon as possible in any patient with compatible symptoms or radiological images in order to initiate suitable therapy.

Cerebrospinal fluid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis.

Described here is a case of meningitis caused by multidrug-resistant Acinetobacter baumannii susceptible only to colistin, which was treated successfully with intravenous colistin sulfomethate sodium (5 mg/kg/day). The levels of colistin in serum and cerebrospinal fluid and the pharmacokinetic/pharmacodynamic parameters of colistin were determined. In this case, intravenously administered colistin penetrated cerebrospinal fluid (25% of serum levels) at levels sustaining bactericidal concentrations.

Aspergillus fumigatus cranial infection after accidental traumatism.

Described here is a case of Aspergillus fumigatus cranial infection secondary to accidental cranial traumatism that occurred in an immunocompetent patient and the questions that arose concerning treatment. No reports of post-traumatic cranial osteomyelitis caused by Aspergillus spp. and the ideal treatment to be followed have yet been described in the literature. In the present case, surgical debridement of the wound followed by treatment with 1 mg/kg/iv/day of amphotericin B for 21 days and then 200 mg/vo/12 h of itraconazole for 6 months obtained good results.

Sulbactam efficacy in experimental models caused by susceptible and intermediate Acinetobacter baumannii strains.

Sulbactam and imipenem were compared in an experimental pneumonia model in immunocompetent mice, using a susceptible strain of Acinetobacter baumannii, and in an experimental endocarditis model in rabbits, using an intermediately susceptible strain. In the former, sulbactam was as efficacious as imipenem in terms of survival, sterility of lungs and in the bacterial clearance from lungs and blood, provided that the t > MIC for sulbactam (1.84 h) was similar to that for imipenem (2.01 h). In the endocarditis model, imipenem (t > MIC, 2.12 h) was more efficacious than sulbactam (t > MIC, 1.17 h) in bacterial clearance from vegetations. These results show the efficacy of sulbactam in infections caused by susceptible strains of A. baumannii, with an MIC up to 4 mg/L, provided that doses reach a t > MIC similar to that of imipenem. The activity of sulbactam was time dependent.