Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, ؊4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, ؊8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n ‫؍‬ 17) of the ceftobiprole-treated patients and 6% (n ‫؍‬ 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.Complicated skin and skin structure infections (cSSSIs) in hospitalized patients are often caused by gram-positive bacteria (28). Because Staphylococcus aureus and Streptococcus pyogenes are the leading causes of cSSSIs, guidelines for the treatment of cSSSIs consistently recommend empirical antimicrobial therapy that provides activity against these bacteria.Over the last 20 years, the prevalence of methicillin-resistant S. aureus (MRSA) as a cause of cSSSIs has been increasing worldwide (15,18,19). Recent experience suggests that MRSA is now responsible for nearly 60% of purulent skin and soft tissue infections in patients presenting to emergency rooms in the United States (23). Community-origin MRSA with apparently enhanced virulence has emerged as the leading cause of serious skin infections arising in the community (23). The increasing importance of MRSA as a cause of cSSSIs has driven the need for the development of new agents with reliable activity against this pathogen. In particular, the development of a cephalosporin with a broad spectrum of activity that includes MRSA and that can be used to treat a range of serious polymicrobial infections began several years ago and has progressed to the point where one such agent, ceftobiprole, is now in late-stage clinical trials.Ceftobiprole, ...

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.

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). Monte Carlo simulation was performed with the ADAPT II program to estimate the PTA at which the free drug concentrations exceed the MIC for 30 to 60% of the dosing interval (30 to 60% fT > MIC). For ceftobiprole at 500 mg i.v. q12h, the probabilities of achieving 30% and 50% fT > MIC exceeded 90% for MICs <2 mg/liter and <1 mg/liter, respectively, For ceftobiprole at 500 mg i.v. q8h, the probabilities of achieving 40 and 60% fT > MIC exceeded 90% for MICs <4 mg/liter and <2 mg/liter, respectively. For ceftobiprole at both 500 mg i.v. q12h and 500 mg i.v. q8h, the probability of achieving a nearly bactericidal effect (50% fT > MIC) exceeded 90% for methicillin-susceptible S. aureus and MRSA. For gram-negative pathogens, the PTA for achieving a nearly maximal bactericidal effect (60% fT > MIC) for ceftobiprole at 500 mg i.v. q8h exceeded 90% for non-AmpCproducing gram-negative organisms. Ceftobiprole at 500 mg i.v. q12h, for patients who had a creatinine clearance rate of <50 ml/min, was identified as the most appropriate treatment regimen for patients who require renal dose adjustment for mild to moderate renal impairment.Methicillin-resistant Staphylococcus aureus (MRSA) has recently emerged as a serious problem in the community (13,18,21,23,(25)(26)(27), and it already represents 40 to 50% of staphylococcal isolates in many health care institutions (2). Given the magnitude of the problem, new agents with activity against MRSA are a welcome addition to the physician's therapeutic armamentarium. While new agents such as linezolid, new glycopeptides, and daptomycin have become available (5, 31), clinicians have long experience and trust in ␤-lactam antibiotics as therapeutic agents for life-threatening infections, and these drugs also have a broad margin of safety.MRSA isolates are endowed with a mecA cassette that allows the strain to express a new penicillin-binding protein (PBP 2a or PBP 2Ј). This protein has a markedly diminished affinity for acylating most ␤-lactam drugs, which is the genesis of its clinical resistance to such agents (17). Ceftobiprole, an investigational cephalosporin currently in phase III trials for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP), represents a major advance among the ␤-lactam antibiotics, in that its structure allows it to bind to PBP 2a and thus kill MRSA (4). Indeed, a considerable amount of preclinical data demonstrate that ceftobiprole acts in a bactericidal fashion in preclinical infection models, both in vitro and in vivo (3,6,9,10,12,15,16,19,33,34). The drug possesses excellent activity against MRSA and other resistant gram-positive pathogens, such as penicillin-resistant Streptococcus pneumoniae (3,6,9,12,16,19). Ceftobiprole also possesses activity against the common gram-negative pathogens often seen in the health care setting, making it a unique broadspectrum agent with potential for early, empirical use (3,9,15,34). Data from the laboratory of Andes and Craig demonstrated that pharmacodynamics of ceftobiprole are simila...

In a randomized, open-label, controlled, multicentre study, the clinical and bacteriological efficacy, safety and tolerability of oral gemifloxacin (320 mg once daily, 5 days) was compared with sequential intravenous (i.v.) ceftriaxone (1 g once daily, maximum 3 days) followed by oral cefuroxime axetil (500 mg twice daily, maximum 7 days) in adult hospitalized patients with acute exacerbations of chronic bronchitis (AECB) (n = 274). The clinical success rates at follow-up (21-28 days post-therapy) in the clinical per-protocol population (the primary endpoint) were 86.8% (105/121) for gemifloxacin vs. 81.3% (91/112) for ceftriaxone/cefuroxime (treatment difference = 5.5,95% CI -3.9,14.9). The corresponding clinical results in the clinical intention-to-treat (ITT) population were 82.6% (114/138) vs. 72.1% (98/136), respectively (treatment difference = 10.5,95% CI 0.7, 20.4).Thus, gemifloxacin had significantly higher clinical success rates than ceftriaxone/cefuroxime. The median time to discharge was 9 days in the gemifloxacin group vs. 11 days in the ceftriaxone/cefuroxime group (P = 0.04, Wilcoxon test). At follow-up, 120/138 (87.0%) gemifloxacin-treated patients had been discharged from hospital, compared with 111/136 (81.6%) ceftriaxone/cefuroxime-treated patients in the clinical ITT population. Both treatments were generally well tolerated and there was no significant difference between the treatment groups in the incidence or type of adverse events reported. A 5-day course of oral gemifloxacin was shown by this study to be at least equivalent to sequential i.v. ceftriaxone/cefuroxime axetil (for up to 10 days) in patients with AECB who require hospital treatment.

BackgroundThe recommended adult dose of ceftaroline fosamil is 600 mg q12h by 1 h intravenous (iv) infusion for 5–14 days in complicated skin and soft tissue infection (cSSTI) and 5–7 days in community-acquired pneumonia (CAP). A dosage of 600 mg q8h by 2 h iv infusion is approved in some regions for cSSTI patients with Staphylococcus aureus infection where the ceftaroline MIC is 2 or 4 mg/L. This analysis compares the safety profiles of the q8h and q12h regimens.MethodsSafety data from six Phase III, randomized, double-blind clinical trials were collated into the q8h cSSTI pool (ceftaroline fosamil n = 506; NCT01499277) and the q12h pool {ceftaroline fosamil n = 1686; comprising five studies [two cSSTI (NCT00424190 and NCT00423657) and three CAP (NCT01371838, NCT00621504 and NCT00509106)]}.ResultsThe pattern and incidence of adverse events were similar between the q8h and q12h ceftaroline fosamil pools. Most were gastrointestinal and of mild or moderate intensity. Overall, rash intensity was similar between the q8h pool and the q12h pool. For the q8h regimen, there was a higher frequency of rash in some Asian study sites, associated with longer duration of therapy (≥7 days); most cases were mild and resolved following treatment discontinuation. No dose-related vital sign or ECG abnormalities were detected with either regimen.ConclusionsThe q8h regimen in cSSTI was generally well tolerated; the observed safety profile was consistent with the known safety profile of ceftaroline fosamil, reflective of the cephalosporin class and qualitatively consistent with the q12h regimen.

Background Nirmatrelvir with ritonavir (nirmatrelvir/r) is an oral antiviral COVID-19 treatment. We report its efficacy to shorten time to sustained alleviation and resolution of COVID-19 signs/symptoms in nonhospitalized adults with COVID-19 at high risk of severe disease as of primary completion data cut (11 Dec 2021). Methods In this phase 2/3 double-blind study, eligible adults with confirmed SARS-CoV-2 and ≤ 5 days (d) of symptoms were randomized 1:1 to nirmatrelvir/r 300 mg/100 mg or placebo (PBO) every 12 hrs for 5 d. Pts logged presence and severity (on 3- or 4-point scales) of prespecified COVID-19 signs/symptoms daily Day 1 (pre-dose) through 28. Times to sustained alleviation and resolution of all targeted signs/symptoms were assessed, summarized with Kaplan-Meier curves, and compared by treatment by log-rank test. Individual signs/symptoms were compared with descriptive analyses. Results From Jul–Dec 2021, 2246 pts enrolled; 2085 pts (nirmatrelvir/r, n=1039; PBO, n=1046) met criteria for the mITT1 population (≤ 5 d of symptom onset, did not/not expected to receive an mAb). More pts achieved sustained alleviation or sustained resolution with nirmatrelvir/r. Shorter median times to sustained alleviation/resolution were observed with nirmatrelvir/r (13/16 d) vs PBO (15/19 d; Fig 1 & 2). Also, a shorter median time to sustained alleviation was seen in pts treated ≤ 3 d of symptoms with nirmatrelvir/r (12 d) vs PBO (15 d). The most common symptoms were cough, muscle/body aches, and headache in both groups. The median time to sustained alleviation of cough and headache was 2 d less with nirmatrelvir/r vs PBO. The median time to sustained resolution of muscle aches and shortness of breath was 3 d and 4 d less with nirmatrelvir/r. The proportion of pts with severe signs/symptoms in the nirmatrelvir/r vs PBO group was significantly higher at baseline, but significantly lower after treatment, showing nirmatrelvir/r significantly reduced symptom severity through Day 28 (Fig 3). Pts who were seronegative vs seropositive or had high vs low viral load at baseline achieved faster times to sustained alleviation with nirmatrelvir/r vs PBO. Conclusion Nirmatrelvir/r treatment reduced duration and severity of COVID-19 symptoms vs PBO in pts at high risk of progressing to severe disease. NCT04960202. Disclosures Jennifer Hammond, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Heidi Leister-Tebbe, BSN, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Annie Gardner, MPH, MSPT, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Paula Abreu, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Weihang Bao, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wayne Wisemandle, MA, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wajeeha Ansari, MPH, Pfizer Inc.: Stocks/Bonds Magdalena Alicja Harrington, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jesus Abraham Simón Campos, MD, AstraZeneca: Board Member|AstraZeneca: Speaker|Eli Lilly: Board Member|Pfizer: Board Member|Roche: Board Member|Roche: Speaker Kara W. Chew, M.D., M.S., Merck Sharp & Dohme: Grant/Research Support Rienk Pypstra, MD, MBA, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James M Rusnak, MD, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds.