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.

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.

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.

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.

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.

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.

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.

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.

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.

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 reactions to methicillin and nafcillin during treatment of serious Staphylococcus aureaus infections.

Relative toxicities of methicillin and nafcillin were compared in 70 patients with serious infections caused by Staphylococcus aureus. Of the 29 patients treated with nafcillin, four had fever, rash, and leukopenia and 1 had absolute neutropenia. Of the 41 patients treated with methicillin, 16 experienced 27 reactions. In addition to fever and skin rash, neutropenia and urinary tract abnormalities were common. Methicillin and nafcillin are equally effective in treating S aureus infections, but methicillin was significantly and more frequently associated with adverse drug reaction that was nafcillin.

Hypoprothrombinemia associated with cefamandole use in a rural teaching hospital.

The incidence of hypoprothrombinemia (prothrombin time greater than or equal to 2 s above the highest control) associated with concurrent cefamandole nafate usage in our institution was determined. Of 77 patients receiving cefamandole for no less than 48 hours, serial prothrombin time was monitored in 31 (40.2%). Four (12.9%) of 31 in whom a baseline normal prothrombin time was obtained developed hypoprothrombinemia during cefamandole therapy. An additional three patients for whom baseline prothrombin time was not determined were noted to have hypoprothrombinemia during therapy with cefamandole. Two patients had clinically significant bleeding episodes. The prothrombin time normalized in six of seven patients following administration of fresh frozen plasma, phytonadione therapy, discontinuation of cefamandole, or a combination of the three. This study illustrated that the incidence of hypoprothrombinemia associated with concurrent cefamandole use is relatively high. Serial prothrombin time monitoring is indicated when patients receive cefamandole.

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.

Cefotaxime vs nafcillin and tobramycin for the treatment of serious infection. Comparative cost-effectiveness.

To evaluate the cost-effectiveness of cefotaxime sodium at a dosage of 12 g/day vs nafcillin sodium and tobramycin sulfate for the treatment of serious infection, the hospital and physician charges of patients enrolled in a prospective, randomized, clinical trial were analyzed. For 187 patients receiving therapy empirically, mean hospital charges for the interval in which the trial antibiotics were used were $3,550 +/- $1,740 for cefotaxime and $3,160 +/- $1,990 for nafcillin and tobramycin. After adjusting for cost-generating factors, charges for cefotaxime were greater than for nafcillin and tobramycin, but the difference was not significant. For 107 patients with clinically or bacteriologically documented infection, mean charges were $3,980 +/- $1,800 for cefotaxime and $4,170 +/- $1,780 for nafcillin and tobramycin. Adjusted charges did not differ. Incremental charges for cefotaxime per additional response were $1,630 in all patients and -$820 in patients with clinically or bacteriologically documented infections.

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.

Hemodynamic changes in human anaphylaxis.

Human anaphylactic reactions are usually unexpected and catastrophic. Therefore, opportunities to record the physiologic changes that occur are uncommon. A patient is described who experienced an anaphylactic reaction to a penicillin drug while being monitored in an intensive care unit for ischemic heart disease. Hemodynamic monitoring indicated that the decrease in cardiac output was most likely due to a decrease in venous return. In addition, this patient's previous reactions to other penicillins demonstrated that variations in the clinical manifestations of systemic anaphylaxis can occur within the same person.

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.

Nafcillin-induced neutropenia in children.

Neutropenia developed in three pediatric patients treated intravenously with nafcillin. This association has not been, to our knowledge, previously reported in children. One of the patients is the youngest reported who had neutropenia associated with any penicillin; another patient had a prolonged recovery. The literature pertaining to marrow suppression by all penicillins is reviewed. This usually occurs 10 to 25 days after the inception of high-dose intravenous therapy and resolves when the penicillin therapy is discontinued. An absolute neutrophil count of less than 1,000/ml is an indication to change to an antibiotic other than a penicillin. Children receiving intravenous penicillins should have WBC counts with differential analysis two to three times a week.