A Broken Antibiotic Market: Review of Strategies to Incentivize Drug Development.

The threat posed by infections arising from antimicrobial-resistant bacteria is a global concern. Despite this trend, the future development of new antimicrobial agents is currently very uncertain. The lack of commercial success for newly launched antimicrobial agents provides little incentive to invest in the development of new agents. To address this crisis, a number of push and pull incentives have been constructed to support antimicrobial drug development. Push incentives, which are designed to lower the cost of developing new antimicrobial agents, include grants, contracts, public-private partnerships, tax credits, and clinical trial networks. Pull incentives, which are designed to facilitate higher financial returns for a newly launched antimicrobial agent, include those that decrease the time for a regulatory review, extend patent exclusivity, or provide premium pricing. Such incentives may also include direct, advanced, or milestone payments or they may be insurance-based whereby healthcare systems pay for the right to access an antimicrobial agent rather than the number of units administered. Another strategy involves the re-evaluation of interpretive criteria for in vitro susceptibility testing (susceptibility breakpoints) of old antimicrobial agents using the same standards applied to that of new agents, which will allow for an accurate determination of antimicrobial resistance. Although each of the above-described strategies will be important to ensure that antimicrobial agents are developed in the decades to come, the update of susceptibility breakpoints for old agents is a strategy that could be implemented quickly and one that could be the most effective for incentivizing drug developers and financiers to reconsider the development of antimicrobial agents.

ARGONAUT II Study of the In Vitro Activity of Plazomicin against Carbapenemase-Producing Klebsiella pneumoniae.

Plazomicin was tested against 697 recently acquired carbapenem-resistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of >32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate.

Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profiles of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

Pharmacodynamics of plazomicin and a comparator aminoglycoside, amikacin, studied in an in vitro pharmacokinetic model of infection.

The new aminoglycoside plazomicin shows in vitro potency against multidrug-resistant Enterobacteriales. The exposure-response relationship of plazomicin and the comparator aminoglycoside amikacin was determined for Escherichia coli, while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic model was used. Five E. coli strains (two meropenem-resistant) and five K. pneumoniae strains (two meropenem-resistant) with plazomicin MICs of 0.5-4 mg/L were used. Antibacterial effect was assessed by changes in bacterial load and bacterial population profile. The correlation between change in initial inoculum after 24 h of drug exposure and the AUC/MIC ratio was good (plazomicin R2 ≥ 0.8302; amikacin R2 ≥ 0.9520). Escherichia coli plazomicin AUC/MIC ratios for 24-h static, -1, -2 and -3 log drop were 36.1 ± 18.4, 39.3 ± 20.9, 41.2 ± 21.9 and 44.8 ± 24.3, respectively, and for amikacin were 49.5 ± 12.7, 55.7 ± 14.8, 64.1 ± 19.2 and 73.3 ± 25.3. Klebsiella pneumoniae plazomicin AUC/MIC ratios for 24-h static, -1, -2 and -3 log drop were 34.0 ± 15.2, 46.8 ± 27.8, 67.4 ± 46.5 and 144.3 ±129.8. Plazomicin AUC/MIC ratios >66 and amikacin AUC/MIC ratios >57.7 were associated with suppression of E. coli growth on 4 × or 8 × MIC recovery plates. The equivalent plazomicin AUC/MIC to suppress resistance emergence with K. pneumoniae was >132. The plazomicin AUC/MIC for 24-h static effect and -1 log reduction in E. coli and K. pneumoniae bacterial load was in the range 30-60. Plazomicin AUC/MIC targets aligned with those of amikacin for E. coli.

Plazomicin Is Active Against Metallo-ß-Lactamase-Producing Enterobacteriaceae.

Plazomicin is an aminoglycoside that was approved in June 2018 by the US Food and Drug Administration for the treatment of complicated urinary tract infections, including pyelonephritis, due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis. Plazomicin was engineered to overcome the most common aminoglycoside resistance mechanism, inactivation by aminoglycoside-modifying enzymes, but is not active against the less common 16S ribosomal RNA methyltransferases (16S-RMTase), which confer target site modification. As an aminoglycoside, plazomicin maintains activity against Enterobacteriaceae that express resistance mechanisms to other antibiotic classes, including metallo-ß-lactamases. Therefore, in the absence of a 16S-RMTase, plazomicin is active against metallo-ß-lactamase-producing Enterobacteriaceae.

Once-Daily Plazomicin for Complicated Urinary Tract Infections.

BACKGROUND: The increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae. METHODS: We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population. RESULTS: Plazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) 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 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum ß-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 µmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group. CONCLUSIONS: Once-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).

In vitro activity of Plazomicin against Enterobacteriaceae isolates carrying genes encoding aminoglycoside-modifying enzymes most common in US Census divisions.

Aminoglycoside-nonsusceptible isolates of Escherichia coli, Klebsiella, Proteus, and Enterobacter species (480/3675) from US hospitals collected during 2014-2015 were screened for 16S rRNA methyltransferase and aminoglycoside-modifying enzyme (AME) genes. Only 5 isolates had high aminoglycoside MICs and carried 16S rRNA methyltransferases. AME genes were observed among 89.7% (426/475) of isolates and the most common genes were aac(3)-IIa (n = 270) and aac(6')-Ib (n = 269). Among other genes, ant(2″)-Ia, aac(3)-Iva, and aph(3')-VIa were observed among 36, 23, and 3 isolates, respectively. Forty-nine (10.3%) isolates yielded negative results for the investigated AME genes. Plazomicin (MIC50/90, 0.5/1 µg/ml) inhibited 99.3% of the AME-carrying isolates at its susceptible breakpoint while amikacin, gentamicin, and tobramycin inhibited 90.1%, 20.9%, and 18.3%, respectively. Plazomicin was approved by the US Food and Drug Administration in June 2018 for the treatment of complicated urinary tract infections when limited treatment options are available. This agent displayed activity against isolates carrying AMEs that were resistance to other aminoglycosides and comparator agents.

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation.

Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally. Furthermore, aminoglycosides are recommended as part of combination therapy for empiric treatment of certain difficult-to-treat infections. The development of semisynthetic aminoglycosides designed to overcome common aminoglycoside resistance mechanisms, and the shift to once-daily dosing, has spurred renewed interest in the class. Plazomicin is the first new aminoglycoside to be approved by the FDA in nearly 40 years, marking the successful start of a new campaign to rejuvenate the class.

Activity of plazomicin compared with other aminoglycosides against isolates from European and adjacent countries, including Enterobacteriaceae molecularly characterized for aminoglycoside-modifying enzymes and other resistance mechanisms.

Background: Plazomicin is a next-generation aminoglycoside that was developed to overcome common aminoglycoside-resistance mechanisms. Objectives: We evaluated the activity of plazomicin and comparators against clinical isolates collected from 26 European and adjacent countries during 2014 and 2015 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends (ALERT) global surveillance programme. Methods: All 4680 isolates collected from 45 hospitals were tested for susceptibility to antimicrobials using the reference broth microdilution method. Selected isolates were screened for genes encoding carbapenemases, aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases. Results: Plazomicin (MIC50/90 0.5/2 mg/L) inhibited 95.8% of Enterobacteriaceae at ≤2 mg/L, including carbapenem-resistant Enterobacteriaceae (MIC50/90 0.25/128 mg/L). Plazomicin was more active compared with other aminoglycosides against isolates carrying blaKPC (MIC50/90 0.25/2 mg/L), isolates carrying blaOXA-48-like (MIC50/90 0.25/16 mg/L) and carbapenemase-negative isolates (MIC50/90 0.25/1 mg/L). Approximately 60% of the isolates harbouring blaVIM and blaNDM-1 carried 16S rRNA methyltransferases (mainly rmtB and armA). AME genes were detected among 728 isolates and 99.0% of these were inhibited by plazomicin at ≤2 mg/L. Plazomicin activity against Pseudomonas aeruginosa (MIC50/90 4/8 mg/L) was similar to amikacin activity (MIC50/90 2/16 mg/L). Plazomicin demonstrated activity against CoNS (MIC50/90 0.12/0.25 mg/L) and Staphylococcus aureus (MIC50/90 0.5/1 mg/L). Plazomicin activity was limited against Acinetobacter spp. (MIC50/90 8/>128 mg/L), Enterococcus spp. (MIC50/90 32/128 mg/L) and Streptococcus pneumoniae (MIC50/90 32/64 mg/L). Conclusions: Plazomicin demonstrated activity against Enterobacteriaceae isolates tested in this study, including isolates carrying AMEs and a high percentage of the carbapenem-non-susceptible isolates. Plazomicin displayed activity against staphylococci.

In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes.

Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/MIC90, 0.5/2 µg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 µg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, by applying CLSI breakpoints. The activities of plazomicin were similar among Enterobacteriaceae species, with MIC50 values ranging from 0.25 to 1 µg/ml, with the exception of Proteus mirabilis and indole-positive Proteeae that displayed MIC50 values of 2 µg/ml. For 97 carbapenem-resistant Enterobacteriaceae (CRE), which included 87 isolates carrying blaKPC, plazomicin inhibited all but 1 isolate at ≤2 µg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5 and 95.5% of the gentamicin-resistant isolates, 96.9 and 96.5% of the tobramycin-resistant isolates, and 64.3 and 90.0% of the amikacin-resistant isolates according to CLSI and EUCAST breakpoints, respectively. The activities of plazomicin against Pseudomonas aeruginosa (MIC50/MIC90, 4/16 µg/ml) and Acinetobacter species (MIC50/MIC90, 2/16 µg/ml) isolates were similar. Plazomicin was active against coagulase-negative staphylococci (MIC50/MIC90, 0.12/0.5 µg/ml) and Staphylococcus aureus (MIC50/MIC90, 0.5/0.5 µg/ml) but had limited activity against Enterococcus spp. (MIC50/MIC90, 16/64 µg/ml) and Streptococcus pneumoniae (MIC50/MIC90, 32/64 µg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying blaKPC from U.S. hospitals, supports the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.

Plazomicin is a novel aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem, and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem, or tigecycline human-equivalent doses alone or in combinations of plazomicin-meropenem and plazomicin-tigecycline. Treatments were initiated at 1 h postinfection and continued for 24 h. Efficacy was assessed by determination of mouse survival through 96 h. Compared with the survival of the controls, plazomicin monotherapy produced a significant improvement in survival for all mice infected with the isolates (P < 0.05) and resulted in overall survival rates of 86% (n = 50) and 53.3% (n = 30) for mice infected with isolates with plazomicin MICs of ≤4 and ≥8 mg/liter, respectively (P < 0.05). The survival of the meropenem and tigecycline groups correlated well with susceptibilities of their respective isolates, with incremental increases in survival being observed at lower MIC values. For mice infected with isolate Klebsiella pneumoniae 561 (plazomicin, meropenem, and tigecycline MICs, 8, >32, and 2 mg/liter, respectively), combination therapies showed a significant reduction in mortality compared with that achieved with any monotherapy (P < 0.05). Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably, for mice infected with isolates with plazomicin MICs of ≤4 mg/liter. As evidenced by our current data, coadministration of meropenem or tigecycline could potentially lead to a further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MICs of ≤4 mg/liter, including carbapenem-resistant isolates.

The Continued Value of Disk Diffusion for Assessing Antimicrobial Susceptibility in Clinical Laboratories: Report from the Clinical and Laboratory Standards Institute Methods Development and Standardization Working Group.

Expedited pathways to antimicrobial agent approval by the U.S. Food and Drug Administration (FDA) have led to increased delays between drug approval and the availability of FDA-cleared antimicrobial susceptibility testing (AST) devices. Antimicrobial disks for use with disk diffusion testing are among the first AST devices available to clinical laboratories. However, many laboratories are reluctant to implement disk diffusion testing for a variety of reasons, including dwindling proficiency with this method, interruptions of the laboratory workflow, uncertainty surrounding the quality and reliability of disk diffusion tests, and a perceived need to report MIC values to clinicians. This minireview provides a report from the Clinical and Laboratory Standards Institute Methods Development and Standardization Working Group on the current standards and clinical utility of disk diffusion testing.

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes.

Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compound was designed by chemical modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chemically alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one aminoglycoside resistance enzymes. Plazomicin retained antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying enzymes, aac(2')-Ia and aph(2″)-IVa, decreased plazomicin potency. On the other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. In vitro enzymatic assessment confirmed that AAC(2')-Ia and APH(2'')-IVa (aminoglycoside acetyltransferase, AAC; aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2')-Ia and APH(2'')-IVa are limited in their distribution to Providencia stuartii and Enterococci, respectively. These data demonstrate that plazomicin is not modified by a broad spectrum of common aminoglycoside modifying enzymes including those commonly found in Enterobacteriaceae. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs.

Efficacy of ceftazidime-avibactam in a rat intra-abdominal abscess model against a ceftazidime- and meropenem-resistant isolate of Klebsiella pneumoniae carrying blaKPC-2.

Efficacies of ceftazidime-avibactam (4:1 w/w) and ceftazidime were tested against ceftazidime-susceptible (blaKPC-2-negative), and meropenem- and ceftazidime-resistant (blaKPC-2-positive), Klebsiella pneumoniae in a 52-h, multiple dose, abdominal abscess model in the rat. Efficacies corresponded to minimum inhibitory concentrations (MICs) measured in vitro and were consistent with drug exposures modelled from pharmacokinetics in infected animals. The ceftazidime, ceftazidime-avibactam and meropenem control treatments were effective in the rat abscess model against the susceptible strain, whereas only ceftazidime-avibactam was effective against K. pneumoniae harbouring blaKPC-2.

Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates.

Objectives: Plazomicin, a novel aminoglycoside with in vitro activity against MDR Gram-negative organisms, is under development to treat patients with serious enterobacterial infections. We evaluated the activity of plazomicin and comparators against colistin-resistant enterobacterial isolates. Methods: Susceptibility to plazomicin and comparators was tested by broth microdilution for a collection of 95 colistin-resistant enterobacterial isolates collected from 29 hospitals in eight countries. Forty-two isolates (Klebsiella pneumoniae and Klebsiella oxytoca) possessed chromosomally encoded resistance mechanisms to colistin, 21 isolates (Escherichia coli and Salmonella enterica) expressed the mcr-1 gene, 8 isolates (Serratia, Proteus, Morganella and Hafnia) were intrinsically resistant to colistin and 24 isolates (K. pneumoniae, E. coli and Enterobacter spp.) had undefined, non-mcr-1 mechanisms. Susceptibility profiles were defined according to CLSI for aminoglycosides and to EUCAST for colistin and tigecycline. Results: Plazomicin inhibited 89.5% and 93.7% of the colistin-resistant enterobacterial isolates at ≤ 2 and ≤4 mg/L, respectively. MICs of plazomicin were ≤2 mg/L for all of the mcr-1 positive isolates and ≤4 mg/L for all the intrinsic colistin-resistant Enterobacteriaceae. Non-susceptibility to currently marketed aminoglycosides was common: amikacin, 16.8%; gentamicin, 47.4%; and tobramycin, 63.2%. Plazomicin was the most potent aminoglycoside tested with an MIC90 of 4 mg/L, compared with 32, >64 and 64 mg/L for amikacin, gentamicin and tobramycin, respectively. Conclusions: Plazomicin displayed potent activity against colistin-resistant clinical enterobacterial isolates, including those expressing the mcr-1 gene. Plazomicin was more active than other aminoglycosides against this collection of isolates. The further development of plazomicin for the treatment of infections due to MDR Enterobacteriaceae is warranted.

Fosfomycin and Comparator Activity Against Select Enterobacteriaceae, Pseudomonas, and Enterococcus Urinary Tract Infection Isolates from the United States in 2012.

INTRODUCTION: Fosfomycin is a broad-spectrum cell wall active agent that inhibits the MurA enzyme involved in peptidoglycan synthesis and is FDA-approved for treatment of uncomplicated urinary tract infections (UTIs) caused by Escherichia coli and Enterococcus faecalis in women. Data regarding the susceptibility of recent UTI isolates to fosfomycin are limited. METHODS: This study compared the fosfomycin susceptibility of 658 US UTI isolates with susceptibility to ciprofloxacin, levofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole (SXT). Isolates included E. coli (n = 257), Klebsiella spp. (n = 156), Enterobacter spp. (n = 79), Pseudomonas aeruginosa (n = 60), E. faecalis (n = 54), and Proteus spp. (n = 52). Extended-spectrum ß-lactamase (ESBL)-producing E. coli, Klebsiella spp., and Proteus mirabilis, ceftazidime-nonsusceptible P. aeruginosa and Enterobacter spp., and vancomycin-nonsusceptible E. faecalis were included. RESULTS: Overall, the minimum concentration inhibiting 50% of isolates (MIC50) and 90% of isolates (MIC90) for fosfomycin were 4 and 64 µg/mL, respectively. Of the 257 E. coli isolates, 99.6% were susceptible to fosfomycin. Ciprofloxacin, levofloxacin, SXT, and nitrofurantoin susceptibility rates were 65.4%, 65.8%, 59.9%, and 90.3%, respectively. The fosfomycin-susceptibility rate for E. faecalis (94.4%) was comparable with the nitrofurantoin-susceptibility rate (98.1%). Among the 144 ESBL-producing isolates, the fosfomycin MIC50 and MIC90 values were 2 and 32 µg/mL, respectively. Fosfomycin MIC50 and MIC90 values were 16 and 128 µg/mL for the 38 ceftazidime-nonsusceptible Enterobacter isolates and 64 and 128 µg/mL for the 15 ceftazidime-nonsusceptible P. aeruginosa isolates, respectively. CONCLUSION: These results demonstrate that fosfomycin has in vitro activity against many US UTI isolates, including drug-resistant isolates, and may provide another therapeutic option for treatment of UTIs caused by antibiotic-resistant pathogens.

Aminoglycosides: An Overview.

Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes. They were among the first antibiotics to be introduced for routine clinical use and several examples have been approved for use in humans. They found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones. Aminoglycosides synergize with a variety of other antibacterial classes, which, in combination with the continued increase in the rise of multidrug-resistant bacteria and the potential to improve the safety and efficacy of the class through optimized dosing regimens, has led to a renewed interest in these broad-spectrum and rapidly bactericidal antibacterials.