Comparison of Clinical Outcomes for Glycopeptides and Beta-Lactams in Methicillin-Susceptible Staphylococcus Aureus Bloodstream Infections.

PURPOSE: This study aimed to provide compelling evidence of anti-staphylococcal beta-lactam use for methicillin-susceptible Staphylococcus aureus bloodstream infection (MSSA BSI). MATERIALS AND METHODS: We retrospectively collected data on patients with MSSA BSI who were admitted to two academic tertiary-care hospitals from 2010 to 2018. Only patients who received nafcillin, cefazolin, vancomycin, or teicoplanin as definitive therapy were included. The primary outcome was 28-day mortality. To perform unbiased comparisons between both treatments, we used inverse probability of treatment weighting (IPTW) analysis. RESULTS: A total of 359 patients were divided into two groups based on the definitive therapy used: beta-lactams (n=203), including nafcillin or cefazolin; and glycopeptides (n=156), including vancomycin or teicoplanin. In the IPTW analysis, glycopeptides were associated with significantly increased odds of 28-day mortality (adjusted odds ratio, 3.37; 95% confidence interval, 1.71-6.61; p<0.001). The rate of primary outcome in prespecified subgroups was largely consistent with the main analysis. CONCLUSION: Definitive therapy with beta-lactams in patients with MSSA BSI was associated with lower 28-day mortality compared to definitive therapy with glycopeptides.

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.

Disproportionality Analysis of Safety with Nafcillin and Oxacillin with the FDA Adverse Event Reporting System (FAERS).

Antistaphylococcal penicillins such as nafcillin and oxacillin are among the first choices of treatment for severe invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections, although there has been limited safety evaluations between individual agents. Using the FDA Adverse Event Reports System (FAERS), oxacillin was observed to have a lower proportion of reports of acute renal failure (reporting odds ratio [ROR], 5.3 [95% confidence interval {CI}, 3.1 to 9.3] versus 21.3 [95% CI, 15.8 to 28.6], respectively) and hypokalemia (ROR, 0.7 [95% CI, 0.1 to 4.8] versus 11.4 [95% CI, 7.1 to 18.3], respectively) than nafcillin.

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia.

BACKGROUND: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. METHODS: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. RESULTS: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval -5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p=0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR)=1.2; 95% CI, 0.3-4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR)=5.4; 95% CI, 1.1-26.8). CONCLUSION: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections.

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.

Patient Variables Associated with Nafcillin Plasma Concentrations and Toxicity.

PRIMARY OBJECTIVE: To retrospectively review nafcillin plasma concentrations (CNAF ) and determine nafcillin clearance (CLNAF ) in a diverse sample of patients treated with nafcillin administered as a continuous infusion. SECONDARY OBJECTIVE: To identify clinical variables associated with CLNAF and nafcillin-related adverse drug reactions (ADRs). METHODS: Retrospective chart review of patients receiving nafcillin via continuous infusion at University of Utah Health Care from 2006 to 2013 who had at least one steady-state CNAF measured. CLNAF was determined by dividing the nafcillin rate of infusion by CNAF . Adverse drug reactions (ADRs) were defined using the National Institutes of Health, Division of Microbiology and Infectious Diseases criteria and scored for probability of association with nafcillin by using Naranjo criteria. Multivariate models were constructed to identify independent variables associated with CLNAF and ADRs. MAIN RESULTS: Seventy-six CNAF from 54 patients were included. Median CLNAF was 13.9 L/hour (range ≤ 4.2 to 36.9 L/hr). Congestive heart failure (p=0.007), hyperbilirubinemia (p<0.0001), and serum creatinine (p<0.0001) were associated with reduced CLNAF , and Hispanic race (p=0.002) was associated with increased CLNAF by multivariate analysis. Twenty patients (37.0%) experienced an ADR. CNAF were significantly higher between patients that experienced an ADR and those that did not (66.0 vs 25.5 mg/L, p<0.001). Individual ADRs associated with CNAF included hepatotoxicity (62.8 vs 27.0 mg/L, p=0.001), nausea/vomiting (80.0 vs 28.5 mg/L, p=0.01), and diarrhea (66.5 vs 26.5 mg/L, p<0.001). Multivariate analysis identified CNAF as being independently associated with ADRs. A putative toxicity relationship between CNAF and predicted probability of ADR was established. CONCLUSIONS: Several patient variables were associated with impaired CLNAF , and elevated CNAF were associated with ADRs. Additional studies assessing the utility of nafcillin therapeutic drug monitoring to minimize toxicity are warranted.

Adverse Events Lead to Drug Discontinuation More Commonly among Patients Who Receive Nafcillin than among Those Who Receive Oxacillin.

Nafcillin and oxacillin are used interchangeably in clinical practice, yet few studies have evaluated the safety of these two agents. Our objective was to compare the differential tolerabilities of nafcillin and oxacillin among hospitalized patients. We conducted a retrospective cohort study of all patients who received 12 g/day of nafcillin or oxacillin for at least 24 h. Two hundred twenty-four patients were included. Baseline characteristics and comorbidities were similar among patients receiving nafcillin (n = 160) and those receiving oxacillin (n = 64). Hypokalemia, defined as a potassium level of ≤3.3 mmol/liter or ≤2.9 mmol/liter or as a ≥0.5-mmol/liter decrease from the baseline level, occurred more frequently among patients who received nafcillin (51%, 20%, and 56%, respectively) than among those who received oxacillin (17%, 3%, and 34%, respectively; P < 0.0001, P = 0.0008, and P = 0.005, respectively). By multivariate logistic regression analysis, receipt of nafcillin was an independent predictor of severe hypokalemia (odds ratio [OR] = 6.74; 95% confidence interval [CI], 1.46 to 31.2; P = 0.02). Rates of hepatotoxicity did not differ between groups; however, acute kidney injury occurred more commonly with nafcillin than with oxacillin (18% versus 6%; P = 0.03). Overall, 18% of patients who received nafcillin discontinued therapy prematurely due to adverse events, compared to 2% of patients who received oxacillin (P = 0.0004). Nafcillin treatment is associated with higher rates of adverse events and treatment discontinuation than oxacillin among hospitalized adult patients. These findings have important implications for patients in both inpatient and outpatient settings, particularly patients who require long-term therapy and cannot be monitored routinely. Future randomized controlled studies evaluating the efficacy, costs, and tolerability of nafcillin versus oxacillin are warranted.

Possible case of nafcillin-induced acute interstitial nephritis.

PURPOSE: To report a case of acute interstitial nephritis (AIN) secondary to nafcillin. SUMMARY: A 55-year-old Hispanic man (height, 63 in.; weight, 61.2 kg) with a history of deep vein thrombosis in the right lower extremity, hypertension, hyperlipidemia, and hepatitis C infection was admitted to the hospital with right-sided chest pain that radiated down his right arm and leg. The patient was diagnosed with methicillin-sensitive Staphylococcus aureus endocarditis. A renal ultrasound was performed on hospital day 9 after the patient developed acute renal failure and showed diffusely increasing echogenicity of the renal parenchymal bilaterally with an interpolar cyst in the left kidney. A urine analysis, serum chemistry panels, and complete blood counts were consistent with AIN. The patient received a total of seven days of nafcillin, and cefazolin was initiated. A renal ultrasound and renal biopsy were performed, which confirmed the diagnosis of AIN. The patient received short-term hemodialysis, after which his renal function slowly returned to baseline. He then underwent an aortic valve replacement and tricuspid valve repair. His antibiotics were changed to rifampin and vancomycin after methicillin-resistant S. aureus was found in an aortic valve culture on hospital day 26. Cefazolin was discontinued 3 days after rifampin and vancomycin were added. The patient received 18 more days of antibiotics and was discharged on the last day of therapy (hospital day 45). CONCLUSION: A 55-year-old, critically ill man developed a possible case of nafcillin-induced AIN after receiving a 7-day course of treatment with the drug.

Nafcillin-induced bullous skin eruption with granulocytopenia in a patient with end-stage renal disease.

Nafcillin is an antibiotic used for infections due to penicillin-resistant Staphylococcus aureus. In general, the adverse reactions to nafcillin have not been frequent and serious. We report here a new type of adverse reaction to nafcillin in a patient with end-stage renal disease in whom nafcillin caused the unexpected complication of bullous drug eruption and subseqent neutropenia. Three weeks after the start of intravenous nafcillin for the treatment of peritoneal dialysis peritonitis, the patient developed blisters on his right ankle. These became progressive and widespread, with bullae affecting most of the body surface. In addition, neutropenia developed three days after the appearance of bullous skin lesions. Spontaneous recovery of skin lesions and neutropenia was observed after the withdrawal of naficillin. When treating patients with chronic renal failure, physicians should be aware of these rare but potentially severe adverse reactions.

Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis.

OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 µg/mL and 0.52 µg/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted.

Interaction between warfarin and nafcillin: case report and review of the literature.

A 39-year-old man with a history of deep vein thrombosis and septic arthritis of the left knee was treated with warfarin and cefazolin. Therapeutic prothrombin times and international normalized ratios (INRs) were maintained with warfarin 32 mg/week for approximately 1 month. When the patient's antibiotic regimen was changed from cefazolin to nafcillin 2 g every 4 hours, his INR declined significantly. His warfarin dosage had to be increased to a maximum of 88 mg/week to achieve a therapeutic INR. After completion of antibiotic therapy with nafcillin, the patient's warfarin requirements slowly declined over several weeks. A maintenance dosage of warfarin 42-48 mg/week was necessary after nafcillin discontinuation. Hepatic cytochrome P450 isoenzyme induction by nafcillin is likely the mechanism of a warfarin-nafcillin interaction. The usual onset of effect is within 1 week after starting nafcillin, and the offset of the effect is usually evident within 4 weeks after nafcillin discontinuation. In patients taking warfarin who are prescribed nafcillin, a 2-4-fold increase in the warfarin dose may be necessary, and clinicians should closely monitor INRs.

Four cases of nafcillin-associated acute interstitial nephritis in one institution.

BACKGROUND: Over the course of 1 year, four patients in a single institution developed acute kidney injury most likely secondary to nafcillin-associated acute interstitial nephritis, indicating that this complication might not be as rare as is commonly believed. The main case presented here is that of a 73-year-old man with a history of chronic low back pain who presented with worsening back pain, as well as nausea, vomiting and volume depletion. Imaging studies revealed a soft tissue abscess in the left psoas major muscle. INVESTIGATIONS: Physical examination, complete urine analysis, blood and urine cultures, measurement of peripheral eosinophil and plasma creatinine levels, and renal ultrasound. DIAGNOSIS: Nafcillin-associated acute interstitial nephritis. MANAGEMENT: Discontinuation of nafcillin and provision of supportive care.

Evaluation of the efficacy and safety of outpatient parenteral antimicrobial therapy for infections with methicillin-sensitive Staphylococcus aureus.

OBJECTIVES: As increasing numbers of patients are being treated with outpatient parenteral antimicrobial therapy (OPAT), it becomes ever more important to ascertain the risks and benefits of such treatment for patients. METHODS: We conducted a retrospective analysis of 1,515 patients with methicillin-sensitive Staphylococcus aureus infections who were treated with outpatient parenteral antimicrobial monotherapy. All patients were included in the adverse drug reaction analysis; 1,252 were evaluable for purposes of evaluating treatment efficacy. RESULTS: The six antibiotics most frequently used in this study (ceftriaxone, cefazolin, vancomycin, oxacillin, nafcillin, and clindamycin) appeared to be equivalent in achieving the desired efficacy outcome. CONCLUSIONS: Vancomycin was associated with a significantly greater number of side effects than was ceftriaxone, cefazolin, or oxacillin, and nafcillin was associated with a significantly greater number of adverse events than ceftriaxone.

Drug-induced lupus erythematosus secondary to nafcillin: the first reported case.

With an estimated incidence of 15-30,000 cases per year in the United States, drug-induced lupus erythematosus (DIL) is an uncommon iatrogenic condition. The number of implicated medications increases each year. We report the first case of DIL secondary to nafcillin administration in a patient with a prosthetic aortic valve and methicillin-sensitive Staphylococcus aureus who developed a facial rash and lower back pain.

Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials.

This study compared adverse drug reactions (ADRs) to oxacillin with those to nafcillin and other antibiotics. We reviewed the medical records of 222 children receiving outpatient parenteral antimicrobial therapy (OPAT) from February 1995 through June 1999. The diagnosis, antibiotics used, ADRs, action taken, and patient demographics were recorded. The most common ADRs were neutropenia (9.8%), rash (8.5%), and hepatotoxicity (3.8%). ADRs occurred more frequently in the oxacillin group (58.5%) than in the nafcillin group (29.3%; P=.004), the clindamycin group (12.5%; P<.001) and the "other" antibiotics group (14.4%; P<.001). Hepatotoxicity and rash occurred more frequently in the oxacillin group (22% and 31.7%, respectively) than in the nafcillin group (0% [P<.001] and 10.3% [P=.008]), the clindamycin group (1.4% [P<.001] and 8.3% [P=.001]), and the other antibiotics group (1.4% [P<.001] and 1.4% [P<.001]). On the basis of this retrospective analysis, oxacillin use in children was associated with a higher incidence of hepatotoxicity and rash, compared with the use of nafcillin and other intravenous antimicrobials.

Possible role of cellular immunity: a case of cellulitis.

On the basis of the observation that there was a "skip" area in an otherwise diffuse drug eruption where cellulitis had previously occurred, it is theorized that both delayed hypersensitivity type of dermatologic drug reaction and cellulitis share pathogenic mechanisms.

Adverse drug reactions in home care patients receiving nafcillin or oxacillin.

Documented adverse reactions to anti-infective agents in patients of a home infusion company were studied to determine whether the prevalence of reactions was greater in patients receiving nafcillin or oxacillin than in those receiving other i.v. antiinfectives. Data on adverse drug reactions (ADRs) were obtained by reviewing the discharge summaries of all patients who received anti-infective therapy in 1990-1994 and the company's quarterly and annual ADR reports for that period. The occurrence of ADRs per total courses of therapy was calculated for groups of antiinfectives, as were intensity and causality. For ADRs to nafcillin and oxacillin, patient demographics and treatment information and outcomes were reviewed. A total of 2488 courses of anti-infective therapy were documented, and ADRs occurred in 10.9%. Nafcillin and oxacillin accounted for 105 courses, with an ADR rate of 31.4%; 99 patients received one of these drugs and 24 had ADRs, with rash and phlebitis the most common ADRs. Thirty-nine patients receiving nafcillin or oxacillin had documented infection with methicillin-sensitive Staphylococcus aureus. Seventy-five patients receiving nafcillin or oxacillin did not have an ADR; therapy was successful in 62 of these patients. Of the 24 patients with ADRs to nafcillin or oxacillin, 13 were switched to other i.v. anti-infectives, which were successful in 10 of them. Five patients were hospitalized because of ADRs to nafcillin or oxacillin. Most nafcillin or oxacillin ADRs that resulted in a therapy change or hospitalization occurred in the second or third week of therapy. Home care patients who received nafcillin or oxacillin therapy had a disproportionately high number of ADRs, compared with patients who received other anti-infective agents.