Cefepime hydrochloride

Treatment with the commonly used antibiotic piperacillin/tazobactam was associated with a 5 percent increase in 90-day mortality, more days on a ventilator, and more time with organ failure for patients with sepsis, finds a new study. In emergency rooms and intensive care units across the country, clinicians make split-second decisions about which antibiotics to give a patient when a life-threatening infection is suspected. A new U-M study reveals that these decisions may have unintended consequences for patient outcomes. Beginning in 2015, a 15-month national shortage of a commonly prescribed antibiotic, piperacillin/tazobactam, known by the brand name Zosyn, provided a unique opportunity to compare rates of death in hospitalized patients with sepsis who were administered two different types of antibiotics -- one that spares the gut microbiome and one that profoundly alters it. Piperacillin/tazobactam is a broad-spectrum antibiotic that is commonly administered for sepsis, a life-threatening complication from infection. In its absence, clinicians commonly instead use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on anaerobic gut bacteria. "We saw this Zosyn shortage as a one-of-a-kind opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes," said Robert Dickson, M.D. of the Department of Medicine's Division of Pulmonary & Critical Care Medicine and Deputy Director of the Weil Institute for Critical Care Research & Innovation. In health, the gut microbiome is largely populated by anaerobic bacteria that rarely cause disease. Prior work by the study team has revealed that even a single dose of piperacillin/tazobactam kills most of these anaerobic gut bacteria, which play important roles in the body's metabolism, immunity, and prevention of infections. Dickson, Rishi Chanderraj, M.D. of the Division of Infectious Disease, Michael Sjoding, M.D. of the Division of Pulmonary & Critical Care Medicine and their multidisciplinary team at U-M and the VA Ann Arbor used patient record data to look at outcomes in 7,569 patients. The team compared 4,523 patients who were treated were piperacillin/tazobactam with 3,046 patients who received cefepime. They found marked differences: treatment with piperacillin-tazobactam was associated with a 5 percent increase in 90-day mortality, more days on a ventilator, and more time with organ failure. "These are powerful antibiotics that are administered to patients every day in every hospital nationwide," said Chanderraj. "Clinicians use them because they are trying to treat every possible pathogen that might be causing their patients' illness. But our results suggest that their effects on the microbiome might also have important effects on patient outcomes." The study builds on previous work by the study team that suggested critically ill patients may do worse when given antibiotics that deplete the gut of anaerobes. They have also seen similar effects when studying animal models. "Our prior work suggested that there might be harm with piperacillin/tazobactam, but it was an observational study that had some limitations," said Sjoding, the study's senior author. "That's why the drug shortage was such an amazing opportunity. It created an almost perfect natural experiment that let us test the difference between these two drugs on patient outcomes in a very rigorous manner." A recent clinical trial pitted these two antibiotics against each other and compared side effects and mortality after two weeks. That trial did not find any differences in the short term -- a finding that the U-M team also observed in their analysis. "When we looked at two-week outcomes in our study, we didn't find differences either," said Chanderraj. "But the differences at three months were dramatic." Overall, the new findings suggest that treatment with piperacillin/tazobactam instead of cefepime may contribute to one additional death per every 20 septic patients treated. "A 5% mortality difference has enormous implications because sepsis is so common," said Dickson. "Every day, thousands of clinicians are deciding which of these drugs to use in septic patients." Physicians should give more thought about whether anti-anerobic antibiotics are warranted before prescribing them, added Chanderraj. "We need to think about antibiotics like chemotherapy. In the right context, treatment can be lifesaving, but in the wrong context, it can be quite harmful."

Nearly half of women will get a urinary tract infection in their lifetime. For the first time in more than 20 years the FDA has approved an antibiotic to treat the condition. For the first time in more than 20 years, the FDA has approved a treatment for uncomplicated urinary tract infections (uUTI). And the nod has come for an oral antibiotic that has been available in Europe for more than 40 years. It’s an odd set of circumstances and a dose of foresight by Utility Therapeutics that bring Pivya (pivmecillinam) to the market in the United States in the therapy’s golden years. The London-based company was formed specifically to develop and commercialize pivmecillinam in the U.S. where antimicrobial resistance is growing to standard of care antibiotics. The decreased “utility” of first-line antibiotics and the void the company is attempting to fill in the U.S. were the inspiration of the name of the company. And the void is significant as more than 30 million uUTIs are diagnosed every year in the U.S., with nearly half of all women contracting the infection at some point in their life. Outside of hospital setting, UTIs account for more antibiotic use than any other disorder. In 2018, Utility inked a licensing agreement with LEO Pharma, acquiring the U.S. rights to pivmecillinam and its subcutaneous formulation mecillinam, which the company has submitted for approval as a first-line therapy for complicated urinary tract infections (cUTI) in the hospital setting. The difference between cUTIs and uUTIs is that the former has reached the kidneys while the latter is limited to the bladder. “The FDA is committed to fostering new antibiotic availability when they prove to be safe and effective and Pivya will provide an additional treatment option for uncomplicated UTIs,” Peter Kim, M.D., the director of the Division of Anti-Infectives at the FDA’s Center for Drug Evaluation and Research, said in a release. The year that Utility acquired the rights to pivmecillinam and mecillinam, the FDA signed off on each as a Qualified Infectious Disease Product (QIDP). The status is extended to antibacterial and antifungal drug candidates intended to treat serious or life-threatening infections. When a QIDP treatment is approved, it gains an additional five years of market exclusivity. On the same day in January, when Utility revealed that the FDA had accepted the company’s new drug applications for pivmecillinam and mecillinam, it also announced it had received private funding from the AMR Action Fund. The global initiative—which was established by several prominent drugmakers including Amgen, Bayer, Eli Lilly, GSK, Novo Nordisk and Roche—invests in the development of new antimicrobial therapeutics. In addition to being a prodrug, which means that it is not pharmacologically active until it is digested and absorbed into the system, Pivya has a unique mechanism of action, targeting penicillin binding protein-2 in the cell wall of gram-negative bacteria. Pivya’s efficacy was assessed in separate trials versus placebo, an oral antibacterial and ibuprofen. The primary measure of efficacy in the studies was the composite response rate, which included clinical cure (resolution of the symptoms of the uUTI that were present in patients at trial entry and no new symptoms) and microbiological response (demonstration that the bacteria cultured from patients’ urine at trial entry was reduced). In the placebo trial, 62% of the participants who received Pivya achieved composite response compared to 10% of those on placebo. In the oral antibacterial trial, 72% of the subjects who received Pivya achieved composite response versus 76% of those on the comparator. In the third trial, 66% of the subjects who received Pivya achieved composite response compared to 22% of those on ibuprofen.  Commonly prescribed drugs for uUTIs in the U.S. are bactrim (sulphamethoxazole/trimethoprim), nitrofuranatoin and fluoroquinolones. But more than 1 in 5 who receive these are resistant, which can lead to progression of the disease, including life-threatening sepsis. Last month, Germany’s Allecra Therapeutics scored FDA approval for its antibiotic Exblifep, which is a combination of cephalosporin antibacterial cefepime and the beta-lactamase inhibitor enmetazobactam, to treat cUTI. The approval came days after the U.S. regulator rejected another combo therapy in the same indication from Venatorx Pharmaceuticals and Melinta Therapeutics.