Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
- Intravenous Fosfomycin for Complicated Urinary Tract Infections
- Plazomicin for Complicated Urinary Tract Infections: A Once-Daily Option
Did you miss the previous edition of Journal Club? You can find it and other past installments in the IDSA News archives. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, M.D., FIDSA, in each issue of Clinical Infectious Diseases.
Intravenous Fosfomycin for Complicated Urinary Tract Infections
Reviewed by Milana Bogorodskaya, M.D.
Fosfomycin is an epoxide antibiotic whose mechanism of action inhibits an early step in the synthesis of peptidoglycans. Oral fosfomycin is useful in treating uncomplicated urinary tract infections (UTIs) with multidrug-resistant pathogens. However, oral fosfomycin use for complicated UTI (cUTI) or pyelonephritis is limited due to the low bioavailability and dose-dependent gastrointestinal side effects of the drug. Recently reported in Clinical Infectious Diseases, a phase 2/3 multicenter, double-blinded, randomized, controlled trial assessed the efficacy, safety, tolerability, and pharmacokinetics of IV fosfomycin compared to piperacillin-tazobactam (PTZ) in this context.
Adults admitted with a cUTI or acute pyelonephritis who had not received any systemic antibiotics against typical Gram-negative uropathogens in 72 hours prior to randomization received 7-14 days of IV fosfomycin or IV PTZ with no allowance to step down oral therapy. Patients with abscesses, CrCL < 20 mL/min, non-renal source of infection, immunosuppression, or presence of severe sepsis/septic shock were excluded. The primary outcome was a composite of clinical and microbiological cure in a microbiologic modified intent-to-treat analysis at day 19-21.
In total, 465 participants were enrolled, 54% with acute pyelonephritis and 46% with cUTI. Seven to 10% in each arm had bacteremia. E. coli was the most common bacteria isolated, followed by K. pneumoniae. Overall success occurred in 64.7% in the fosfomycin group and 54.5% in the PTZ group (treatment difference 10.2%, 95% confidence interval [CI] -0.4, 20.8). Clinical cure was 90.8% in the fosfomycin group and 91.6% in the PTZ group (treatment difference -0.8%, 95% CI -7.2, 5.6). Microbiological cure was 70.1% in fosfomycin group and 60.1% in the PTZ group (treatment difference 10.5%, 95% CI 0.2, 20.8). Similar clinical cure rates were seen in multidrug-resistant, extended-spectrum β-lactamase, and carbapenem-resistant Enterobacteriaceae isolates between fosfomycin and PTZ. Gastrointestinal side effects (10.7%), transaminitis (8.6%), and hypokalemia (6.4%) were the most common adverse events in the IV fosfomycin group.
This study showed non-inferiority of IV fosfomycin compared to PTZ for cUTI and acute pyelonephritis with Enterobacteriaceae. While IV fosfomycin had more adverse effects, the study demonstrates that IV fosfomycin is a suitable choice to treat these infections when β-lactam antibiotics are not an ideal option.
(Kaye et al. Clin Infect Dis. 2019;69(12):2045–2056.)
Plazomicin for Complicated Urinary Tract Infections: A Once-Daily Option
Reviewed by Daniel Mendoza, M.D., Ph.D.
Multidrug resistance is an increasing problem among bacteria that commonly cause urinary tract infections, and new treatments are needed. Plazomicin is a new aminoglycoside available in intravenous and oral formulations, with activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae.
In a study in the New England Journal of Medicine, the authors randomly assigned 609 patients with complicated urinary tract infections (cUTIs), including pyelonephritis, to receive intravenous plazomicin or meropenem, with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. Twenty-six percent and 29% of patients who received plazomicin and meropenem had strains with extended-spectrum β-lactamase resistance, respectively. The primary objective was the non-inferiority of plazomicin to meropenem in the treatment of cUTI, including pyelonephritis. The non-inferiority margin was 15 percentage points. Composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit, 15 to 19 days after therapy began, were the primary end points.
At day 5, composite cure was observed in 88.0% of the patients (168 of 191) in the plazomicin group and in 91.4% (180 of 197) in the meropenem group (difference, –3.4 percentage points; 95% confidence interval [CI], –10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191) and 70.1% (138 of 197), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At this visit, a higher percentage of patients in the plazomicin group were also found to have microbiologic eradication: 89.5% vs. 74.6%, difference of 14.9 (7.0 to 22.7). In 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group, increases in serum creatinine of 0.5 mg or more per deciliter were observed.
Plazomicin was non-inferior to meropenem for the treatment of cUTI caused by Enterobacteriaceae. These results suggest that plazomicin can be an effective option to treat cUTI due to multidrug-resistant strains that has a low risk for kidney toxicity.
(Wagenlehner et al. N Engl J Med. 2019;380:729-740.)