Nafcillin Augmentation of Daptomycin and Cathelicidin LL-37 Killing of Methicillin-resistant Staphylococcus epidermidis: Foundations of Successful Therapy of Endocarditis.

Methicillin-resistant Staphylococcus epidermidis (MRSE) endocarditis failing conventional therapy has been successfully treated with nafcillin plus daptomycin in the clinic. In vitro studies showed that nafcillin enhanced daptomycin killing of MRSE in both planktonic cells and biofilm. Nafcillin exposure also sensitized MRSE to killing by human neutrophils and cathelicidin antimicrobial peptide LL-37. Fluorescent microscopy showed increased daptomycin and LL-37 binding to the MRSE bacterial surface upon nafcillin treatment. Ceftaroline also increased MRSE killing by daptomycin in planktonic cultures and biofilms, as well as daptomycin and LL-37 binding on the bacterial surface. Nafcillin, ceftaroline, and possibly other ß-lactams, may serve an important role in the therapy of MRSE endocarditis through augmentation of cationic peptide, the innate immune system, and daptomycin killing. Clinical studies will be needed to determine how early these regimens should be deployed to optimize clinical outcome.

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis.

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A ß-lactamase (ßla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its ßla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 µg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the ßla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.

Acupuncture and postpartum pyogenic sacroiliitis: a case report.

INTRODUCTION: Pyogenic sacroiliitis, a rare form of septic arthritis, occurs in patients following trauma, intravenous drug use, genitourinary infections and pregnancy. Here we report a rare case where both acupuncture and pregnancy served as predisposing risk factors to the development of this infection. CASE PRESENTATION: A 33-year-old white woman received several sessions of acupuncture treatment during her gestation at the site of her sacroiliac joint for sciatica; she developed biopsy-confirmed sacroiliitis with methicillin-sensitive Staphylococcus aureus during the immediate postpartum period. The diagnosis, medical management and treatment course are described. CONCLUSIONS: Low back and pelvic pain are common conditions during pregnancy and postpartum. Acupuncture is a common modality of medication-free treatment used by many patients. Recognition of the potential complications of such therapies can lead to early diagnosis, accurate treatment, decreased morbidity and increased chances for a successful outcome.

Is cefazolin inferior to nafcillin for treatment of methicillin-susceptible Staphylococcus aureus bacteremia?

About 20% of methicillin-susceptible Staphylococcus aureus (MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case-control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n = 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n = 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P > 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P > 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%; P = 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia.

Community-acquired methicillin-resistant Staphylococcus aureus prostatic abscess.

We present a 43-year-old man with a history of intravenous drug abuse who presented to the emergency department with a 5-week history of lower urinary tract symptoms. On digital rectal examination, a firm prostate with exquisite tenderness was noted. Computed tomography scan of the pelvis with contrast demonstrated a 4.4 by 2.7-cm prostatic abscess in the right lobe. Suppurative fluid was expressed from the right prostatic lobe during transurethral resection of the prostate. Cultures of blood and suppurative prostatic fluid grew methicillin-resistant Staphylococcus aureus.

Microbiological tolerance in orthopaedic infections: delayed response of septic arthritis and osteomyelitis of the hip due to infection with tolerant Staphylococcus aureus.

A 14-year-old boy presented to another hospital with a clinical picture of septic arthritis. After aspiration of purulent material from the joint, empiric antibiotic treatment was initiated and an arthrotomy was performed. Antibiotic treatment was then modified to nafcillin according to microbiological sensitivity results of the isolated Staphylococcus aureus as determined by minimal inhibitory concentration testing. One week later purulent drainage recurred and open drainage had to be repeated; an abscess anterior to the joint was noted. Once again the infection failed to resolve, and the patient was transferred to our institution where a third arthrotomy had to be performed. The organism isolated at the first aspiration was reexamined and found to have a minimal bactericidal concentration to minimal inhibitory concentration ratio of 32, implying a tolerant organism. The antibiotic treatment was modified to an antibiotic not subject to the tolerance phenomenon, and the infection resolved without additional surgical intervention.

Oral ciprofloxacin compared with standard parenteral antibiotic therapy for chronic osteomyelitis in adults.

A group of fourteen patients who had chronic osteomyelitis and were treated with oral ciprofloxacin was compared with a group of twelve patients of similar age who had chronic osteomyelitis and received standard parenteral antibiotic therapy consisting of nafcillin, clindamycin, and gentamicin, singly or in combination. The osteomyelitis was arrested at the end of therapy and on follow-up examination of eleven patients in the first group and ten in the second group. The average duration of antibiotic therapy (thirty-eight days) and follow-up (approximately thirty months) were about the same for both groups. Oral administration of ciprofloxacin was as effective and safe as parenteral therapy for the treatment of osteomyelitis in these adults.

Antimicrobial prophylaxis of experimental endocarditis caused by Staphylococcus epidermidis.

Using two different strains of Staphylococcus epidermidis in a rat model of experimental endocarditis, we examined the prophylactic efficacy of cefamandole (200 mg/kg/dose), cefazolin (200 mg/kg/dose), nafcillin (200 mg/kg/dose), and vancomycin (20 mg/kg/dose). In vitro susceptibility testing demonstrated that both test strains were resistant to methicillin and cefazolin and susceptible to cefamandole and vancomycin. A 10(6) cfu inoculum was used for both strains, an inoculum which produced endocardial infections in greater than 90% of rats. Initial doses of each antibiotic were given 45 min to 1 h prior to bacterial challenge and were followed by six additional doses of each antibiotic administered subcutaneously every 6 h. The efficacy rates of cefamandole (84.0%) and cefazolin (70.8%) were exactly the same for rats infected with either S. epidermidis strain. Similar efficacy rates were seen in rats infected with either strain and treated with vancomycin (94.4% and 86.7%). Unlike the other three drugs, the efficacy of nafcillin was quite different in rats challenged with the two strains (62.5% and 38.5%, p = 0.19). It appears that cefamandole and cefazolin may have considerable prophylactic efficacy against certain infecting strains of methicillin-resistant, coagulase-negative staphylococci when relatively large doses of cephalosporins are administered subcutaneously in this animal model.

Ciprofloxacin therapy of experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus.

Ciprofloxacin was more effective (P less than 0.01) than either imipenem or nafcillin therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis in rabbits after 2 or 3 days of treatment. There was no significant difference between results of treatment of methicillin-susceptible S. aureus experimental endocarditis with ciprofloxacin and results with the combination of nafcillin and gentamicin. Ciprofloxacin was more effective (P less than 0.01) than vancomycin therapy of experimental methicillin-resistant S. aureus endocarditis after 3 days of treatment. After 5 days of treatment, there was no significant difference between the results of treatment of experimental methicillin-resistant S. aureus endocarditis with ciprofloxacin and results with vancomycin.

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Comparative evaluation of A-56619, A-56620, and nafcillin in the treatment of experimental Staphylococcus aureus osteomyelitis.

A rabbit model for Staphylococcus aureus osteomyelitis was used to compare the results of treatment with A-56619 and A-56620, two new aryl-fluoroquinolones, and nafcillin. A-56619 (15 mg/kg) and A-56620 (20 mg/kg), both used for 28 days of treatment, were injected subcutaneously every 12 h, and nafcillin (40 mg/kg) was injected every 6 h. After treatment, S. aureus was found on bone marrow cultures from 19 of 20 control rabbits, 6 of 20 treated with A-56619, 14 of 20 treated with A-56620, and 8 of 20 treated with nafcillin. Drug concentrations in serum and uninfected and infected bone were measured 1 h after A-56619 and A-56620 injection and 30 min after nafcillin injection in a group of rabbits that had been infected for 3 to 4 weeks. The concentrations in infected bone were similar for all three drugs and were significantly higher than in uninfected bone. The results of this study showed that A-56619 had a high rate of eradication of S. aureus from infected bone and compared favorably to nafcillin.

Relationship of staphylococcal tolerance, teichoic acid antibody, and serum bactericidal activity to therapeutic outcome in Staphylococcus aureus bacteremia.

A randomized cooperative study of therapy for Staphylococcus aureus bacteremia was conducted in which nafcillin was given for four or six weeks to patients with clinical endocarditis and for two or four weeks to those without evidence of endocarditis. Eighty-four patients were enrolled, and 32 completed treatment, all of whom had bacteriologic cures. Three patients, treated for two weeks, had complications that were undetectable by assay of serum teichoic acid antibody. Data were insufficient to allow conclusions regarding the optimal duration of therapy for patients with or without endocarditis. However, the results suggest that neither clinical nor immunologic methods can reliably detect complications in patients treated for two weeks only. In addition, patients infected with tolerant organisms remained febrile longer than those infected with nontolerant strains but did not require additional antibiotics for cure. Peak serum bactericidal activity at a dilution of 1:8 or greater was present in all patients. Serum bactericidal activity of 1:8 prior to an antibiotic dose was not necessary for cure.

Imipenem therapy of experimental Staphylococcus epidermidis endocarditis.

Imipenem was evaluated for its activity against Staphylococcus epidermidis in vitro and in a rabbit model of endocarditis. The MBC for imipenem of 55 methicillin-resistant S. epidermidis isolates from patients with prosthetic valve endocarditis increased by eightfold or greater with increasing inoculum size; there was no inoculum-associated increase in the imipenem MBC for 20 methicillin-susceptible S. epidermidis isolates. Endocarditis was produced in rabbits with either a methicillin-susceptible or a methicillin-resistant S. epidermidis isolate to investigate the correlation in vivo of the in vitro inoculum effect for imipenem. Six days of imipenem treatment eradicated methicillin-susceptible S. epidermidis from vegetations of infected rabbits significantly better than no therapy but was less effective against methicillin-resistant S. epidermidis in this regard. Among methicillin-resistant S. epidermidis-infected rabbits, 6 days of imipenem therapy (i) was not significantly better than that of the control and was significantly worse than that of vancomycin in eradicating bacteria from infected vegetations and (ii) increased the frequency of imipenem-resistant subpopulations in infected vegetations. Resistant subpopulations were not seen in vegetations from untreated or imipenem-treated, methicillin-susceptible S. epidermidis-infected rabbits. Imipenem may not be effective therapy for serious human methicillin-resistant S. epidermidis infections.

Acute interstitial nephritis associated with mezlocillin, nafcillin, and gentamicin treatment for Pseudomonas infection.

Two patients developed acute interstitial nephritis (AIN) following treatment with mezlocillin sodium. Diagnosis was made by renal biopsy. Gallium 67 citrate scanning was abnormal in both. All patients were receiving multiple-drug therapy, but AIN has either not been described with the other drugs, or the temporal relationship between the AIN and termination of other drug therapy makes a causative relationship unlikely. All were infected with Pseudomonas aeruginosa. A role for the infecting organism or drug synergism in contributing to the renal disease cannot be excluded.

Newer beta-lactam antibiotics in the treatment of experimental Staphylococcus aureus endocarditis.

Antistaphylococcal activity of three beta-lactam antibiotics, i.e. cefmenoxime, cefotaxime and latamoxef (moxalactam) was compared with that of nafcillin by studying cure rates of aortic valvular endocarditis caused by one of three clinical isolates of Staphylococcus aureus in New Zealand white male rabbits. The animals were randomly allocated to a control and four antibiotic treatment groups. Each animal except the controls received 60 mg/kg of one antibiotic intramuscularly twice daily for two weeks, beginning 24 h after induction of endocarditis. The aortic valve was sterilized in 11 of 15 (73%) animals treated with cefmenoxime, nine of 13 (69%) treated with cefotaxime, 11 of 13 (85%) treated with latamoxef and 12 of 15 (80%) treated with nafcillin. All nine animals in the control group developed aortic valvular vegetations with an average of 2.4 X 10(9) cfu/g. The differences in sterility rates resulting from treatment with the four antibiotics were not statistically significant (P greater than 0.70).

Teicoplanin versus nafcillin and vancomycin in the treatment of experimental endocarditis caused by methicillin-susceptible or -resistant Staphylococcus aureus.

In rabbits with experimentally induced endocarditis, the efficacy of teicoplanin compared favorably both with that of nafcillin for infection by a methicillin-susceptible strain of Staphylococcus aureus and with that of vancomycin for infection by a methicillin-resistant strain of S. aureus. In a 4-day treatment regimen, teicoplanin was as effective as either nafcillin or vancomycin in eliminating organisms from aortic valve vegetations in the respective infection. In a 10-day regimen for methicillin-resistant S. aureus endocarditis, both teicoplanin and vancomycin sterilized the vegetations of some rabbits, but the relapse rate was high for both. These results justify further investigation into the role of teicoplanin for the treatment of serious infections caused by S. aureus.

Laboratory tests for defining bactericidal activity as predictors of antibiotic efficacy in the treatment of endocarditis due to Staphylococcus aureus in rabbits.

The validity of laboratory tests that define bactericidal activity to predict antimicrobial efficacy was studied in rabbits with endocarditis due to Staphylococcus aureus, both nafcillin-nontolerant (NT) and nafcillin-tolerant (T). Infected rabbits were treated with nafcillin, clindamycin, chloramphenicol, or no drug (control) for up to 11 days; dosage was designed so that peak antibiotic serum concentration/minimal inhibitory concentration ratios were approximately 50. During treatment, peak and trough serum concentration/minimal bactericidal concentration ratios and peak and trough titers of serum bactericidal antibacterial activity were determined. The rank order of efficacy, as defined by survival, eradication of bacteremia, and sterilization of cardiac vegetations, was nafcillin = clindamycin greater than chloramphenicol greater than control, both adjusted and unadjusted for the challenge strain of S. aureus. Bactericidal activity (observed only with nafcillin plus S. aureus NT) was associated with lower bacterial counts in vegetations at four days but was otherwise unrelated to therapeutic outcome.

Staphylococcal beta-lactamase and efficacy of beta-lactam antibiotics: in vitro and in vivo evaluation.

The susceptibility of five cephalosporins and nafcillin to changes in inoculum size of 26 isolates of Staphylococcus aureus was studied. The spectrum of antibiotic sensitivity to such changes was cefazolin = cephaloridine greater than cefamandole greater than cephalothin greater than cefoxitin = nafcillin. Half of the isolates resulted in large and half in minimal inoculum-induced changes in minimal inhibitory concentrations (MICs). These changes correlated with the amount of beta-lactamase produced by the isolates. The in vivo relevance of these findings was studied in a model of intraperitoneal infection in mice. The effect of beta-lactamase production on mortality was greatest among animals given cefazolin or cephaloridine, intermediate among those given cefamandole, and nonexistent among those given cefoxitin, cephalothin, or nafcillin. The number of organisms in the animals' spleens paralleled survival rates. An increase in the serum level of cefazolin increased the survival rate among mice given that drug. Hence, the survival of mice was influenced by (1) the ability of the infecting organism to increase the MIC of an antibiotic via inoculum increases, (2) the sensitivity of the antibiotic to beta-lactamase, and (3) the peak level of antibiotic attained in serum.

Management of infected cerebellar stimulation systems.

Over a 7-year period (February 1974 through February 1981), 318 patients underwent the implantation of cerebellar stimulation systems for the reduction of spasticity (98%) or epilepsy (2%). A total of 518 procedures were carried out to implant and maintain the equipment during this period. Fourteen patients developed infections in the tissue around their implanted systems, which represented 4.4% of the patients or 2.7% of the procedures performed. Staphylococcus aureus was the infectious agent in 7 cases (50%), the clinical features of which occurred usually within 1 month. Staphylococcus epidermidis infected 5 patients with features presenting late (more than 2 years) after the initial implantation. The management involved antibiotic therapy for 2 weeks in all 14 patients. In 12 patients, the entire system was removed, with 100% eradication of the infection. In the other 2 patients, the radio receiver and lead wires up to but not including the cerebellar electrode pads were removed. One of these 2 patients has been free of infection for 4 years. The other had S. aureus cultured from removed electrode pads after 6 weeks. Of the 14 cases, morbidity was severe in only 1 patient. Seven patients underwent reimplantation 6 weeks after the infection.

Penicillinase-resistant penicillin/gentamicin synergism. Effect in patients with Staphylococcus aureus bacteremia.

Gentamicin sulfate has been shown to enhance the effects of penicillinase-resistant penicillins against clinical isolates of Staphylococcus aureus in vitro, but the relevance of this observation to bacteremic patients is unclear. Therefore, serum samples from 14 patients with staphylococcal bacteremia were tested for growth inhibitory and bactericidal effects against the patients' own pathogen while they received a penicillinase-resistant penicillin alone, and again when gentamicin was added to the therapeutic regimen. Addition of gentamicin in vivo was associated with slight improvement in growth inhibitory activity but it caused profound increases in serum bactericidal activity. This effect could not be attributed to higher serum levels of penicillinase-resistant penicillin during gentamicin administration. Addition of gentamicin to penicillinase-resistant penicillin can lead to marked improvement in a patient's serum bactericidal activity against his own staphylococcal pathogen, and should be considered for any patient who does not respond to more conventional therapy.