NEJM: Oral drug for complicated urinary tract infection, efficacy is non-inferior to intravenous drip expert review

Urinary tract infection (UTI) is a common clinical infectious disease, and its incidence is second only to upper respiratory tract infection, ranking second in community infections [1]
.

Complicated urinary tract infection refers to a urinary tract infection that is accompanied by a risk of acquiring infection or treatment failure, such as structural or functional abnormalities of the genitourinary tract, or other underlying diseases [2]
.

In the United States, more than 8 million people visit a doctor for urinary tract infection every year, and about 3 million of them are complicated urinary tract infection, which is the main cause of nosocomial infection and bacteremia in the United States
.

Patients with complicated urinary tract infection or acute pyelonephritis account for approximately 35% to 45% of nosocomial infections and often require hospitalization for intravenous antibiotics [3,4]
.

Multidrug-resistant bacteria represented by gram-negative bacteria in complicated urinary tract infections are common and important pathogens, and they have shown a rapid upward trend in recent years.
Their treatment is difficult, and there is a lack of effective oral drugs, which often brings great difficulties to the lives of patients.
It has a great impact and brings great challenges to clinical anti-infective treatment [5]
.

The characteristics of complicated UTIs in China are the increased proportion of strains producing extended-spectrum β-lactamase (ESBL).
The application of antibiotics treatment leads to the production of multi-drug resistant bacteria, which brings a heavy burden to the society and economy, and seriously affects the physical and mental health of patients [6]
.

Tebipenem pivoxil hydrobromide (tebipenem pivoxil hydrobromide) is a novel orally bioavailable oral carbapenem antibiotic, which is rapidly transformed into active components in intestinal epithelial cells, with broad-spectrum antibacterial activity, in vitro and in animals The level showed good antibacterial effect against multi-drug resistant Gram-negative bacteria, including fluoroquinolone-resistant and ESBL-producing Enterobacteriaceae
.

The ADAPT-PO study, published in the New England Journal of Medicine (NEJM) on April 7, 2022, is an international multicenter, double-blind, double-dummy, non-inferiority, randomized controlled trial [7]
.

This phase 3 clinical trial, conducted in 95 hospitals worldwide, aims to demonstrate that tipipenem hydrobromide is noninferior to ertapenem in the treatment of complex UTIs, including acute pyelonephritis, with a non-inferiority margin The value of 12.
5%, that is, the overall treatment response rate of tipipenem hydrobromide in the treatment of complicated urinary tract infection and acute pyelonephritis in patients with intravenous ertapenem was less than or equal to 12.
5% ​​was defined as "non-inferiority"
.

The study included 1372 hospitalized patients in Europe, South Africa, and the United States and tested the noninferiority hypothesis
.

The main inclusion criteria for the ADAPT-PO study were patients over 18 years old with a confirmed diagnosis of complicated urinary tract infection or acute pyelonephritis, and the main exclusion criteria included infection with suspected or carbapenem-resistant pathogens, creatinine clearance rate Less than 30 ml per minute, received short-acting antibiotics within 72 hours before randomization, and septic shock
.

According to the ratio of 1:1, 1372 patients with complicated UTI (including acute pyelonephritis) were randomly divided into two groups to receive: Group 1) Tipipenem hydrobromide (600 mg each time, once every 8 hours) ) and intravenous ertapenem mimetic injection once every 24 hours; or group 2) ertapenem (1 g, intravenous infusion over 30 minutes) and oral tipipenem hydrobromide mimetic once every 8 hours
.

Both groups were treated continuously for 7 to 10 days, which could be extended to 14 days for patients with persistent bacteriuria; for patients with moderately reduced renal function (baseline creatinine clearance 30 to 50 ml/min), oral tibipe hydrobromide was given.
The dose of acetaminophen was halved (300 mg every 8 hours), and no dose adjustment was made for ertapenem
.

The primary efficacy indicator was the composite cure rate (clinical cure and good microbiological response) of patients in the microbiologic intention-to-treat population during the test-of-cure visit (19 days ± 2 days).
); clinical cure refers to complete or clinically significant remission of signs and symptoms of complex UTI or acute pyelonephritis with no new symptoms and no need for further antimicrobial therapy
.

A good microbiological response was defined as a reduction in urine pathogen levels from baseline to less than 103 CFU per milliliter in urine cultures after baseline and, for patients with positive blood cultures at baseline, requiring retesting as negative
.

The ADAPT-PO study had very good regimen compliance, with 99.
6% in the tipipenem hydrobromide group and 99.
1% in the ertapenem group
.

Complex UTI was diagnosed in 50.
8% of the enrolled patients and acute pyelonephritis in 49.
2%
.

ESBL-positive patients accounted for 24.
3%, fluoroquinolone insensitivity accounted for 39%, trimethoprim-sulfamethoxazole (TMP-SMX) resistance accounted for 43%, and 11.
5% of patients had bacteremia
.

Of note, the study included a high proportion of patients with complex disease at baseline and a high proportion of patients infected with drug-resistant pathogens
.

The results of the study showed that at the end of treatment (7-10 days), in the microbiological ITT population, the composite cure rates of the tipipenem hydrobromide group and the ertapenem group were 97.
3% (437%), respectively.
/449) and 94.
5% (396/419), the weighted difference between the two groups was 2.
8% (95% CI, 0.
1% to 5.
7%)
.

During the cure verification visit (19 days ± 2 days), the composite cure rates of the tipipenem hydrobromide group and the ertapenem group were 58.
8% (264/449) and 61.
6% (258/419), respectively.
, the weighted difference between the two groups was -3.
3% (95% CI, -9.
7% to 3.
2%), and the lower limit of the 95% CI of 9.
7% was less than the non-inferiority margin of 12.
5%, so the non-inferiority hypothesis was validated
.

During the cure-verification visit, clinical cure was observed in 93.
1% of patients treated with tipipenem hydrobromide and 93.
6% of patients treated with ertapenem (group weighted difference -0.
6%; 95% CI , -4.
0% to 2.
8%), the majority of patients with microbial response failure were asymptomatic patients with recurrent bacteriuria
.

Results were consistent in subgroup analyses based on age, sex, baseline diagnosis, renal function level, presence or absence of bacteremia, and prior antibiotic use
.

In addition, this study also observed the adverse reactions of the drug in the safety population
.

Adverse events were observed in 25.
7% and 25.
6% of patients treated with tipipenem hydrobromide and ertapenem, respectively; the most common adverse events were mild diarrhea and headache
.

No increased risk of C.
difficile infection associated with oral carbapenems was observed in this trial
.

In this trial, oral tipipenem hydrobromide was noninferior to intravenous ertapenem in the treatment of patients with complicated urinary tract infection or acute pyelonephritis
.

Results were consistent across trial populations and subpopulations, infection types and pathogens
.

Clinical cure was observed in 90% or more of patients in both treatment groups at end of treatment and cure trials, and efficacy persisted through late follow-up (25 days)
.

At the end of treatment, at least 96% of patients in both treatment groups had a favorable microbiological response to the pathogenic bacteria, and responses in both treatment groups declined proportionally at subsequent visits
.

This post-treatment discordance between clinical and microbiological responses may be the result of bacterial occult foci in patients with complex UTIs who have underlying functional or anatomical abnormalities, including urinary tract devices, which may lead to continuation of pathogens after cessation of antimicrobial therapy reproduce without causing clinical symptoms
.

This result is consistent with published trials involving complicated urinary tract infection or acute pyelonephritis [8]
.

Potential limitations of the trial include: 1) mandatory hospitalization of patients for 7 to 10 days of antibiotic therapy (up to 14 days in patients with bacteremia); 2) exclusion of immune abnormalities, severe renal impairment, confirmed or suspected carbapenem infection Studies on the efficacy of treatment of non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, fungi or mycobacteria in patients with drug-resistant bacteria Still lacking; 3) Most subjects were white
.

Although the pathophysiology and major pathogens of complicated urinary tract infection or acute pyelonephritis are largely consistent around the world, the specific strains and resistance mechanisms observed in this trial may differ from other regions; 4) The patients did not have a (definite) infection Pathogen type was then randomized, so we saw that in each group randomized, more than 200 patients had negative urine and blood bacterial cultures and were excluded from analysis
.

Tipipenem hydrobromide addresses the clinical need for an oral antibiotic with activity against drug-resistant Gram-negative pathogens, including ESBL- and fluoroquinolone-resistant strains, in the clinical treatment of complex UTIs
.

Efficacy and safety have been demonstrated in patients with complicated urinary tract infections or acute pyelonephritis
.

References 1.
Tandogdu Z, Wagenlehner FM.
Global epidemiology of urinary tract infections.
Curr Opin Infect Dis 2016;29:73-9.
‍2.
Guidelines on Urological Infections.
European Association of Urology 2014.
[EB/OL] http:/ / Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM.
Infectious Diseases Society of American guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
Clin Infect Dis 2005;40:643-54.
4.
Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP.
Nosocomial bloodstream infections in United States hospitals: a three-year analysis.
Clin Infect Dis 1999;29:239-44.
5.
Critchley IA, Cotroneo N, Pucci MJ, Mendes R.
The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017.
PLoS One 2019;14:e0220265.
6.
Qiao LD, Chen S, Yang Y, et al.
Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study.
BMJ Open 2013;3 :e004152.
7.
Eckburg PB, Muir L, Critchley IA, et al.
Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection.
N Engl J Med 2022;386:1327-38.
8.
Wagenlehner FME, Cloutier DJ, Komirenko AS, et al .
Once-Daily plazomicin for complicated urinary tract Infections.
N Engl J Med 2019;380:729-40.
About the authors Li Ping, Deputy Chief Physician, Associate Professor, Department of Nephrology, First Medical Center, PLA General Hospital, Doctor of Medicine, Master Supervisor , Master of Clinical Research, Harvard Medical Schoolet al.
Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection.
N Engl J Med 2022;386:1327-38.
8.
Wagenlehner FME, Cloutier DJ, Komirenko AS, et al.
Once-Daily plazomicin for complicated urinary tract Infections.
N Engl J Med 2019;380:729-40.
The author introduces Li Ping, Deputy Chief Physician, Associate Professor, Department of Nephrology, First Medical Center, PLA General Hospital, MD, Master Supervisor, Master of Clinical Research, Harvard Medical School, USAet al.
Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection.
N Engl J Med 2022;386:1327-38.
8.
Wagenlehner FME, Cloutier DJ, Komirenko AS, et al.
Once-Daily plazomicin for complicated urinary tract Infections.
N Engl J Med 2019;380:729-40.
The author introduces Li Ping, Deputy Chief Physician, Associate Professor, Department of Nephrology, First Medical Center, PLA General Hospital, MD, Master Supervisor, Master of Clinical Research, Harvard Medical School, USA
.

Beijing Science and Technology Rising Star, undertakes scientific research projects such as the National Natural Science Foundation of China and Beijing Project
.

Won the first prize of China Medical Science and Technology Progress Award
.

As the first author, he has published many SCI papers in CJASN, AJKD and other journals, participated in the compilation of 8 monographs, and participated in the compilation of 5 clinical guidelines
.

He is a young member of the Nephrology Branch of the Chinese Medical Doctor Association, a young member of the Nephrology Branch of the Beijing Medical Association, and the secretary of the Renal Disease Professional Committee of the Chinese Association of Integrative Medicine
.

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