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.

Tolerability of Cefazolin in Nafcillin-Intolerant Patients for the Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

BACKGROUND: Non-immunoglobulin E (IgE)-mediated hypersensitivity reactions (HSRs) to nafcillin are commonly reported, but scarce data are available to guide appropriate antibiotic change following these reactions. Although cefazolin is an attractive therapeutic alternative in methicillin-susceptible Staphylococcus aureus (MSSA) infections when patients experience an HSR to nafcillin, more data are needed to evaluate the tolerability of cefazolin after switching from nafcillin. The purpose of this study was to describe the tolerability of cefazolin in patients who develop a suspected non-IgE-mediated HSR to nafcillin. METHODS: This was a retrospective, descriptive case series of patients who received nafcillin for an MSSA infection, experienced a suspected non-IgE-mediated HSR, and were switched to cefazolin between October 2015 and November 2019 at a single academic medical center. The primary objective was to identify the percentage of patients who completed cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin. RESULTS: There were 80 patients with 87 prespecified non-IgE-mediated HSRs during the study period. Seventy-one (89%) patients completed cefazolin, with 53 (75%) of these patients completing at least 2 weeks of therapy. One patient was ultimately switched from cefazolin to daptomycin due to concern for treatment failure. Eight patients (10%) did not tolerate cefazolin after switching from nafcillin. Of these, 3 patients experienced an unrelated HSR, whereas 5 patients experienced the same non-IgE-mediated HSR that was attributed to nafcillin and discontinued cefazolin within 7 days. The most common HSR cited was immune-mediated nephritis; however, the majority were clinically presumed but did not meet objective diagnostic criteria. CONCLUSIONS: Treatment with cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin appears to be safe, even for patients requiring a prolonged duration of cefazolin.

Comparison of Nafcillin and Cefazolin for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia.

BACKGROUND: Traditionally, the antibiotic of choice for Methicillin-susceptible Staphylococcus aureus related blood stream infections (MSSA-BSI) are the antistaphylococcal penicillins. Cefazolin is considered an alternative agent, with recent evidence showing similar clinical efficacy. This study further evaluates the utility of nafcillin versus cefazolin in MSSA bacteremia including high disease burden sources of infection and its impact on treatment failure. METHODS: This retrospective study included patients admitted to Methodist LeBonheur Healthcare adult hospitals from 2011 to 2016. Patients were included if they received at least 3 days of either nafcillin or cefazolin and had a positive blood culture for MSSA. The primary objective was to evaluate rates of treatment failure between groups. Secondary outcomes included clinical and microbiological cure, MSSA-BSI associated readmissions, identification of risk factors for treatment failure including disease burden, in-hospital and 90 day mortality. RESULTS: A total of 277 patients were included (nafcillin n = 126; cefazolin n = 151). Treatment failure and microbiologic cure were similar between nafcillin and cefazolin (20.6% vs. 16.6%; 91.2% vs. 87.2%, respectively). Clinical cure was significantly higher in the cefazolin treatment arm (93.4 vs. 83.3%; P = 0.012). However, the total number of patients with high disease burden was greater in the nafcillin group (54.8% vs. 39.1%; P = 0.011). Higher rates of in-hospital mortality were observed in the nafcillin group (15.1% vs. 6%; P = 0.016). CONCLUSIONS: Our study observed significantly higher rates of clinical cure and reduced in-hospital mortality in patients who received cefazolin. Further analysis is warranted to evaluate the effectiveness of these agents and identifying predictors of treatment failure.

Retrospective Analysis of Adverse Drug Events Between Nafcillin Versus Cefazolin for Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

Background: Nafcillin or cefazolin are drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Prior studies indicate a higher incidence of acute kidney injury (AKI) with nafcillin, although AKI classification and time to occurrence is not well described. Objective: To characterize the incidence and time to adverse drug events for nafcillin versus cefazolin in the inpatient setting. Methods: A retrospective cohort study evaluated hospitalized, adult patients receiving intravenous nafcillin or cefazolin for treatment of MSSA infection. Incidence and time to AKI based on RIFLE criteria were measured. Secondary end points included antibiotic discontinuation and incidence of neutropenia, thrombocytopenia, elevated transaminases, and Clostridioides difficile infection (CDI). Results: Of 324 patients who received nafcillin (n = 119) or cefazolin (n = 205), higher rates of AKI were found for nafcillin versus cefazolin (19% vs 2%, respectively; P < 0.0001). Median time to AKI with nafcillin was 6.5 days (range, 3-14 days). The majority of patients were classified as RIFLE "Risk" stratum. Nafcillin treatment discontinuations were more frequent than for cefazolin (17.6% vs 0.9%, respectively; P < 0.0001). Nafcillin was an independent predictor of AKI (odds ratio = 12.4; 95% CI = 4.14-47.60, P < 0.0001). No differences in neutropenia, thrombocytopenia, elevated transaminases, or CDI were observed. Conclusion and Relevance: Nafcillin displayed higher rates of AKI at a median of 1 week of therapy, which provides a framework for clinician monitoring and consideration of antibiotic modification. Most patients developed "Risk" class AKI (RIFLE classification), which may be reversible with prompt intervention.

A comparison of safety and outcomes with cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bloodstream infections.

BACKGROUND: Methicillin-susceptible Staphylococcus aureus (MSSA) is a frequent cause of bloodstream infections (BSI). Treatment with nafcillin (NAF) has been preferred to cefazolin (CFZ). However, comparable outcomes have been found with CFZ with possibly lower risk for side-effects. This study compared safety and effectiveness of NAF versus CFZ for MSSA BSI. METHODS: This single center retrospective study evaluated adults admitted with MSSA BSI who received NAF or CFZ. Patients receiving ≥24 h of antibiotics were included for safety analyses. Patients receiving NAF or CFZ for ≥75% of a 14 day minimum treatment course were assessed for clinical effectiveness. The primary safety outcome was incidence of renal toxicity with multiple secondary safety endpoints. Clinical success was defined as symptom resolution, repeat negative cultures, lack of additional therapy for presumed failure, and lack of recurrence within 30 days. RESULTS: A total of 130 patients receiving NAF (n = 79) or CFZ (n = 51) were included for safety analysis. Of those, 90 met criteria for effectiveness assessment (NAF n = 40, CFZ n = 50). Baseline characteristics were well matched. NAF was associated with a higher incidence of nephrotoxicity compared to CFZ (25% vs. 2%, RR 1.31, 95% CI 1.15-1.5, p < 0.001), allergic reactions (p = 0.01) and a trend for hepatotoxicity (p = 0.08). Clinical success was achieved in 82% NAF and 94% CFZ treated patients (p = 0.1). CONCLUSION: CFZ was associated with less nephrotoxicity and no difference in clinical success compared to NAF for MSSA BSI. A prospective study comparing NAF to CFZ for MSSA BSI should be conducted to elucidate differences in therapies.

Septic arthritis of native hip joint by Staphylococcus lugdunensis: a case report.

Staphylococcus lugdunensis is a rare virulent coagulase-negative staphylococcus (CoNS) that behaves similarly to Staphylococcus aureus in causing deep abscesses, skin and soft tissue infections, and central nervous system infections. Additionally, there can be certain blood stream infections including sepsis, septic shock, toxic shock syndrome, and endocarditis complicated by embolic events. Reports of septic arthritis of a native joint associated with this organism have been infrequent, justifying the presentation and discussion of this case.

Septic arthritis of native hip joint by Staphylococcus lugdunensis: a case report

Abstract Staphylococcus lugdunensis is a rare virulent coagulase-negative staphylococcus (CoNS) that behaves similarly to Staphylococcus aureus in causing deep abscesses, skin and soft tissue infections, and central nervous system infections. Additionally, there can be certain blood stream infections including sepsis, septic shock, toxic shock syndrome, and endocarditis complicated by embolic events. Reports of septic arthritis of a native joint associated with this organism have been infrequent, justifying the presentation and discussion of this case.

Comparison of the efficacy of nafcillin and glycopeptides as definitive therapy for patients with methicillin-susceptible Staphylococcus aureus bacteremia: a retrospective cohort study.

BACKGROUND: Studies have shown that the prognosis of the treatment of methicillin-susceptible S. aureus (MSSA) with glycopeptides is inferior compared to treatment with ß-lactam. However, there are only few studies comparing treatment with antistaphylococcal penicillin alone to glycopeptide treatment. The aim of this study was to compare the efficacy of nafcillin, an antistaphylococcal penicillin, with that of glycopeptides as a definitive therapy for MSSA bacteremia. METHODS: Patients with MSSA bacteremia recruited from a tertiary referral hospital were enrolled in this retrospective cohort study. Demographic characteristics, laboratory data, and clinical outcome of the treatment were compared between a group receiving nafcillin and a group receiving glycopeptides. RESULTS: A total of 188 patients with MSSA bacteremia were included in this study. The glycopeptide group had a higher rate of malignancy (28.6 vs. 60.8%, p < 0.001) and proportion of healthcare-associated infections (47.3 vs. 72.2%, p < 0.001) compared to the nafcillin group. The ratio of skin and soft tissue infections (30.0 vs. 16.7%, p = 0.037) and bone and joint infections (17.8 vs. 6.3%, p = 0.022), as well as levels of C-reactive protein (139.60 vs. 107.61 mg/dL, p = 0.022) were higher in the nafcillin group. All-cause 28-day mortality was significantly high in the glycopeptide group (7.7 vs. 20.6%, p = 0.013). CONCLUSION: In patients with MSSA bacteremia, all-cause 28-day mortality rate was higher in a group treated with glycopeptides than in a group treated with nafcillin. Therefore, the use of nafcillin should be considered as a definitive therapy for MSSA bacteremia.

Does the Beta-Lactam Matter? Nafcillin versus Cefazolin for Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections.

BACKGROUND: Antistaphylococcal penicillins have historically been regarded as the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI). However, recent outcomes data compared to cefazolin treatment are conflicting. OBJECTIVE: This study compared treatment failure and adverse effects associated with nafcillin and cefazolin for MSSA BSI. METHODS: Adult inpatients with MSSA BSI between January 1, 2009 and August 31, 2015 were included in this retrospective cohort study if they received ≥72 h of nafcillin or cefazolin as directed therapy after no more than 72 h of any empiric therapy. The primary composite endpoint was treatment failure defined by clinician documentation, 30-day recurrence of infection, all-cause 30-day in-hospital mortality, or loss to follow-up. Secondary outcomes included antibiotic-related acute kidney injury (AKI), acute interstitial nephritis (AIN), hepatotoxicity, and rash. RESULTS: Among 157 patients, 116 (73.9%) received nafcillin and 41 (26.1%) received cefazolin. The baseline characteristics were similar except cefazolin-treated patients had higher APACHE II scores and more frequent renal dysfunction. No difference in the composite treatment failure outcome (28.4 vs. 31.7%; p = 0.69) was detected between the nafcillin and cefazolin groups, respectively. In a sensitivity analysis excluding patients without known follow-up, there was no significant difference of treatment failure. AKI, AIN, hepatotoxicity, and rash were all numerically more frequent among nafcillin-treated patients. CONCLUSIONS: Among nafcillin- or cefazolin-treated patients with MSSA BSI, there was no significant difference in treatment failure. Observing more frequent presumptive adverse effects associated with nafcillin receipt, future prospective studies evaluating cefazolin appear warranted.

Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea.

OBJECTIVES: No randomized controlled trials have evaluated the comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. METHODS: A prospective observational cohort study including all S. aureus bacteraemia was conducted at 10 hospitals. Patients (≥15 years) with MSSA bacteraemia who received cefazolin or nafcillin as definitive antibiotics were included. The rates of treatment failure (premature discontinuation of antibiotics because of adverse effects, switching of antibiotics because of clinical failure, all-cause mortality within 1 month, or recurrence) were compared between the cefazolin and nafcillin groups. Propensity score matching analyses were performed to balance the factors influencing the selection of antibiotics. RESULTS: Among the 242 included cases, the bones and joints (36.8%) were the most common sites of infection and 60.7% of the patients had sepsis. The overall treatment failure rate was 43.8% (106/242). All-cause mortality within 1 month was 6.2% (15/242). After propensity score matching, the treatment failure rate of cefazolin was lower than that of nafcillin (30.4% (24/79) vs. 49.4% (39/79), p 0.015) because of a higher rate of discontinuation caused by adverse events. When the data were limited to patients with sepsis, the treatment failure rates of both groups were not significantly different. Approximately 22% (24/110) of MSSA isolates exhibited a cefazolin-inoculum effect (CIE) that had significant impact on the failure rate and mortality of the cefazolin group. CONCLUSIONS: Cefazolin might be recommended as an adequate and better-tolerated treatment for MSSA bacteraemia in the absence of CIE.

Disseminated methicillin-susceptible Staphylococcus aureus infection.

INTRODUCTION: When clinicians think about Staphylococcus aureus bacteria, what comes to the mind of most is the dreaded methicillin-resistant form. However, clinicians should not forget the methicillin-susceptible type, which is just as virulent. CASE PRESENTATION: The authors present the case of a 20-year-old woman who was admitted with septic shock and multi-organ failure and was found to have disseminated methicillin-susceptible Staphylococcus aureus (MSSA) infection. The patient had persistent blood cultures positive for MSSA. A transesophageal echocardiogram showed a 1.1 cm vegetation in the mitral valve, and the patient had bilateral pleural effusions that grew MSSA. An MRI of the brain showed multiple areas consistent with infarctions thought to be secondary to septic emboli. The patient underwent a mitral valve replacement and was treated with a prolonged course of parenteral nafcillin. DISCUSSION: This case illustrates a severe clinical presentation and management of MSSA infections.

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.

Tacrolimus interaction with nafcillin resulting in significant decreases in tacrolimus concentrations: A case report.

Tacrolimus (TAC) is subject to many drug interactions as a result of its metabolism primarily via CYP450 isoenzyme 3A4. Numerous case reports of TAC and CYP3A4 inducers and inhibitors have been described including antimicrobials, calcium channel antagonists, and antiepileptic drugs. We present the case of a 13-year-old patient with cystic fibrosis and a history of liver transplantation, where subtherapeutic TAC concentrations were suspected to be a result of concomitant TAC and nafcillin (NAF) therapy. The observed drug interaction occurred on two separate hospital admissions, during both of which the patient exhibited therapeutic TAC concentrations prior to exposure to NAF, a CYP3A4 inducer. Upon discontinuation of NAF, TAC concentrations recovered in both instances. This case represents a drug-drug interaction between TAC and NAF that has not previously been reported to our knowledge. Despite the lack of existing reports of interaction between these two agents, this case highlights the importance of therapeutic drug monitoring and assessing for any potential drug-drug or drug-food interactions in patients receiving TAC therapy.

Cefazolin versus Nafcillin for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infection in a California Tertiary Medical Center.

Recent observational studies have suggested possible reductions in mortality in patients receiving cefazolin versus antistaphylococcal penicillins. We examined 90-day mortality in patients receiving cefazolin compared to nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection (BSI). We identified persons with MSSA BSI admitted to San Francisco General Hospital from January 2008 to July 2013 through a hospital-wide infection surveillance system and confirmed 90-day mortality using U.S. national vital registries. We included persons receiving cefazolin or nafcillin as the predominant intravenous antimicrobial agent; all participants received inpatient Infectious Diseases service consultation. We estimated the association between receipt of cefazolin and 90-day risk of death by multivariate logistic regression, including a propensity score for receiving cefazolin as the second predictor. Of 230 MSSA BSI cases, 30 received nafcillin and 70 received cefazolin as the predominant antimicrobial; 10 died within 90 days, 5 from each group. Unadjusted analysis showed substantial but not statistically significant reduced odds of death in those receiving cefazolin (odds ratio, 0.38; 95% confidence interval [CI], 0.10 to 1.44). Multivariate analysis with propensity scores found a similar adjusted odds ratio (0.40; 95% CI, 0.09 to 1.74; P = 0.22). We found a large reduction in 90-day mortality in those receiving cefazolin compared to nafcillin for MSSA BSI, but this finding was not statistically significant. The magnitude of effect seen in this and other studies justifies further study.

Reversion From Methicillin Susceptibility to Methicillin Resistance in Staphylococcus aureus During Treatment of Bacteremia.

Approximately 3% of Staphylococcus aureus strains that, according to results of conventional phenotypic methods, are highly susceptible to methicillin-like antibiotics also have polymerase chain reaction (PCR) results positive for mecA. The genetic nature of these mecA-positive methicillin-susceptible S. aureus (MSSA) strains has not been investigated. We report the first clearly defined case of reversion from methicillin susceptibility to methicillin resistance among mecA-positive MSSA within a patient during antibiotic therapy. We describe the mechanism of reversion for this strain and for a second clinical isolate that reverts at a similar frequency. The rates of reversion are of the same order of magnitude as spontaneous resistance to drugs like rifampicin. When mecA is detected by PCR in the clinical laboratory, current guidelines recommend that these strains be reported as resistant. Because combination therapy using both a ß-lactam and a second antibiotic suppressing the small revertant population may be superior to alternatives such as vancomycin, the benefits of distinguishing between mecA-positive MSSA and MRSA in clinical reports should be evaluated.

Rapidly Progressive Seeding of a Community Acquired Pathogen in an Immune-competent Host--End Organ Damage from Head to Bone.

This report describes a 64-years-old male patient that presented to our hospital with a chief complaint of acute worsening of his usual chronic lower back pain, progressive weakness in lower extremities and subjective fevers at home. Spine CT failed to demonstrate any infectious foci but showed partially visualized lung cavitary lesion and renal pole abnormalities. Blood cultures grew methicillin-sensitive Staphylococcus Aureus (MSSA). Transthoracic echocardiogram (TTE) showed no signs of infective endocarditis (IE). Later, the patient experienced an acute deterioration on clinical status and examination showed development of a new murmur. He also developed new hemiparesis with up-going babinski reflex. A head MRI showed multiple infarcts. MRI spine displayed osteomyelitis at T12-L1. Cerebro-spinal fluid was positive for meningitis. A transesophageal echocardiogram (TEE) was performed demonstrating new severe mitral and mild tricuspid regurgitations with a definitive 1.5 cm mobile vegetation on posterior mitral leaflet. We present is a very interesting case of a rapidly progressive MSSA infection. MSSA meningitis is a rare disease; there are only few reported cases in the literature to date. We describe a case of MSSA bacteremia, of questionable source, that resulted in MSSA endocarditis affecting right and left heart in a patient who did not have a history of intravenous drug use (IVDU) or immunosuppression. The case was complicated by septic emboli to systemic circulation involving the kidneys, vertebral spine (osteomyelitis), lungs and brain with consequent meningitis and stroke. Even when MSSA infections are well known, to our knowledge there are no previous case reports describing such an acute-simultaneous-manifestation of multi-end-organ failure, including meningitis and stroke. These latter are rarely reported, even individually.

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.