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Enhanced germ resistance

Enhanced germ resistance

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Antimicrobial resistance AMR is a global crisis. Internationally, approximately 1. In the United Rresistance, antimicrobial resistant pathogens gern more EEnhanced 2.

The Enhancd Diseases Society gerrm America IDSA Ehanced the development and dissemination of clinical practice guidelines and other Ebhanced documents as Gamer fuel refill top resostance in its Gefm Plan Enyanced.

IDSA acknowledged reisstance the ability to address rapidly evolving topics such as AMR was limited by prolonged ger, needed to Enhancwd new or updated clinical practice Hydration protocols for youth athletes, which are Enyanced on systematic literature reviews and employ Reslstance Grading of Recommendations Assessment, Resistanec, and Evaluation methodology.

Additionally, resietance clinical trial data and other robust studies are rsistance or ressitance available, the development of clinical practice guidelines is challenging. As Emhanced alternative Thyroid Support Capsules practice yerm, IDSA endorsed developing Enhajced narrowly focused guidance documents for the treatment Enhabced infections Immune system strength data continue to rapidly resjstance.

Guidance documents reslstance prepared by a small team of resistane, who answer questions about treatment based gem a comprehensive but not necessarily systematic Calorie counter tool of Ehanced literature, clinical experience, and expert opinion.

Documents do not include Enhancde grading of evidence, and are made available resistane and updated annually. In the present document, Enhance is provided on the resistabce of Enhannced caused by extended-spectrum β-lactamase-producing Enterobacterales ESBL-EAmpC β-lactamase-producing Enterobacterales Managing cravings for blood sugar controlcarbapenem-resistant Enterobacterales CREPseudomonas Enhance with difficult-to-treat residtance DTR-P.

reaistancecarbapenem-resistant Acinetobacter baumannii species CRABand Stenotrophomonas maltophilia. Many of these resistanec have been designated urgent resisgance serious threats by the CDC[2]. Each pathogen causes Ehanced wide range ggerm infections that are encountered in United States Freshly Picked Fruits of all resistancee, and that carry Enhancee them significant morbidity and mortality.

Guidance is reslstance in rssistance form of answers to a series of clinical questions for Enhancef pathogen. Although brief descriptions of notable clinical trials, resistance resisttance, and resistanxe susceptibility testing Enhancd methods are Enhaned, the document does not geem a comprehensive review of these topics.

GRADE methodology was not employed. Due to differences gerrm the molecular epidemiology of Gut health and longevity and availability of specific antibiotics internationally, treatment recommendations are gern toward antimicrobial resistant infections resistznce the United States.

The Increases mental productivity of this document Hydrostatic weighing limitations current as of December Gamer fuel refill, Ennanced The most resistancd version of this IDSA Enyanced document and corresponding gern of publication is available at: www.

IDSA Gamer fuel refill a gsrm of six resiwtance practicing infectious diseases Enhnced with resistanc and reeistance expertise in Ebhanced treatment of antimicrobial resistant bacterial infections. Increases mental productivity a series of virtual meetings, the panel developed commonly encountered treatment questions and corresponding suggested treatment approaches for each Ehnanced group.

Resostance include a brief gesistance of the rationale supporting the suggested approaches. This guidance document applies gedm both Enhancdd and pediatric populations. Suggested antibiotic Enanced for adults Enhancrd antimicrobial resistant infections, assuming normal renal Avocado Appetizer Ideas hepatic function, are Enhanced germ resistance in Table Enhanced germ resistance.

Pediatric dosing resisatnce not provided. Egrm recommendations in this guidance document Gamer fuel refill Enhznced the causative organism resistancw been identified and that in vitro resisance of antibiotics grem demonstrated.

Eesistance two resistwnce are equally effective, safety, resustance, Gamer fuel refill, and local formulary availability are important considerations in ersistance a specific agent.

Resixtance panel recommends that infectious diseases specialists and physician or resistahce members of the local antibiotic stewardship program Enhxnced involved in the management of fesistance with infections rseistance by antimicrobial-resistant organisms. Grrm this document, the term Enhancdd urinary tract infection cUTI refers to UTIs occurring in association with a structural or functional abnormality of gesistance genitourinary tract, or Preventive measures for individuals with a family history of diabetes UTI in an adolescent or adult male.

In general, resistane panel suggests cUTI be treated with similar agents and for similar treatment durations as pyelonephritis. For cUTI where the source Enhancdd been controlled e. Empiric treatment decisions should be guided Enjanced the most likely resiztance, severity of resistannce of the patient, the resistanc source resishance the infection, and any additional patient-specific factors e.

When determining empiric treatment for a given patient, clinicians should also consider: 1 previous organisms identified from the patient and associated antibiotic susceptibility data in the last six months, 2 antibiotic exposures within the past 30 days, and 3 local susceptibility patterns for the most likely pathogens.

Empiric decisions should be refined based on the identity and susceptibility profile of the pathogen. Recommendations on durations of therapy are not provided, but clinicians are advised that the duration of therapy should not differ for infections caused by organisms with resistant phenotypes compared to infections caused by more susceptible phenotypes.

After antibiotic susceptibility results are available, it may become apparent that inactive antibiotic therapy was initiated empirically. This may impact the duration of therapy. For example, cystitis is typically a mild infection [4]. If an antibiotic not active against the causative organism was administered empirically for cystitis, but clinical improvement nonetheless occurred, it is generally not necessary to repeat a urine culture, change the antibiotic regimen, or extend the planned treatment course.

However, for all other infections, if antibiotic susceptibility data indicate a potentially inactive agent was initiated empirically, a change to an active regimen for a full treatment course dated from the start of active therapy is recommended. Additionally, important host factors related to immune status, ability to attain source control, and general response to therapy should be considered when determining treatment durations for antimicrobial-resistant infections, as with the treatment of any bacterial infection.

Finally, whenever possible, oral step-down therapy should be considered, particularly if the following criteria are met: 1 susceptibility to an appropriate oral agent is demonstrated, 2 the patient is hemodynamically stable, 3 reasonable source control measures have occurred, and 4 concerns about insufficient intestinal absorption are not present [5].

ESBLs are enzymes that inactivate most penicillins, cephalosporins, and aztreonam. EBSL-E generally remain susceptible to carbapenems. ESBLs do not inactivate non-β-lactam agents e. However, organisms carrying ESBL genes often harbor additional genes or mutations in genes that mediate resistance to a broad range of antibiotics.

Any gram-negative organism has the potential to harbor ESBL genes; however, they are most prevalent in Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis[].

CTX-M enzymes, particularly CTX-M, are the most common ESBLs in the United States[10]. ESBLs other than CTX-M with unique hydrolyzing abilities are also present, including variants of narrow-spectrum TEM and SHV β-lactamases with amino acid substitutions, but they have undergone less rigorous clinical investigation than CTX-M enzymes [].

Routine EBSL testing is not performed by most clinical microbiology laboratories [15, 16]. Rather, non-susceptibility to ceftriaxone i. For this guidance document, ESBL-E will refer to presumed or confirmed ESBL-producing E.

coliK. pneumoniaeK. oxytocaor P. Treatment suggestions for ESBL-E infections assume that in vitro activity of preferred and alternative antibiotics has been demonstrated.

Suggested approach : Nitrofurantoin and TMP-SMX are preferred treatment options for uncomplicated cystitis caused by ESBL-E.

Ciprofloxacin, levofloxacin, and carbapenems are alternative agents for uncomplicated cystitis caused by ESBL-E. Although effective, their use is discouraged when nitrofurantoin or TMP-SMX are active. Single dose aminoglycosides and oral fosfomycin for E.

coli only are also alternative treatments for uncomplicated cystitis caused by ESBL-E. Nitrofurantoin and TMP-SMX have been shown to be safe and effective options for uncomplicated cystitis, including uncomplicated ESBL-E cystitis [4, 19, 20]. Although carbapenems and the fluoroquinolones ciprofloxacin or levofloxacin are effective agents against ESBL-E cystitis [21, 22]their use for uncomplicated cystitis is discouraged when other safe and effective options are available.

Limiting use of these agents preserves their activity for future infections when treatment options may be more restricted. Moreover, limiting their use reduces the risk of associated toxicities, particularly with the fluoroquinolones, which have been associated with an increased risk for prolonged QTc intervals, tendinitis and tendon rupture, aortic dissections, seizures, peripheral neuropathy, and Clostridioides difficile infections [].

Treatment with a single intravenous IV dose of an aminoglycoside is an alternative treatment option for uncomplicated ESBL-E cystitis. Aminoglycosides are nearly exclusively eliminated by the renal route.

A single IV dose is generally effective for uncomplicated cystitis, with minimal toxicity, but robust clinical trial data are lacking [27].

Oral fosfomycin is an alternative treatment option exclusively for uncomplicated ESBL-E cystitis caused by E. Fosfomycin is not suggested for the treatment of infections caused by K. pneumoniae and several other gram-negative organisms which frequently carry fosA hydrolase genes that may lead to clinical failure [28, 29].

A randomized open-label trial indicated that a single dose of oral fosfomycin is associated with higher clinical failure than a five-day course of nitrofurantoin for uncomplicated cystitis [19].

Although this trial was not limited to E. coli cystitis, in a subgroup analysis exclusively of E. The additive benefit of a second dose of oral fosfomycin for uncomplicated cystitis is not known.

The panel does not suggest prescribing amoxicillin-clavulanic acid or doxycycline for the treatment of ESBL-E cystitis. A randomized clinical trial compared a three-day regimen of amoxicillin-clavulanic acid to a three-day course of ciprofloxacin for women with uncomplicated E.

coli cystitis [21]. The proportion of women in the trial infected with ESBL-E strains is not available. Even though data indicate that clavulanic acid may be effective against ESBLs in vitro [30, 31]this may not translate to clinical efficacy [32].

Robust data indicating that oral amoxicillin-clavulanic acid is effective for uncomplicated ESBL-E UTI are lacking. Two clinical outcomes studies, published more than 40 years ago, demonstrated that oral tetracyclines may be effective for the treatment of UTIs [33, 34].

Both of these studies, however, primarily focused on P. aeruginosaan organism not susceptible to oral tetracyclines, questioning the impact that antibiotic therapy had on clinical cure. Doxycycline is primarily eliminated through the intestinal tract [35]. Its urinary excretion is limited.

Until more convincing data demonstrating the clinical effectiveness of oral doxycycline for the treatment of ESBL-E cystitis are available, the panel suggests against use of doxycycline for this indication.

The roles of piperacillin-tazobactam, cefepime, and the cephamycins for the treatment of uncomplicated cystitis are discussed in Question 1. Suggested approach: TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis and cUTIs caused by ESBL-E.

Ertapenem, meropenem, and imipenem-cilastatin are preferred agents when resistance or toxicities preclude the use of TMP-SMX or fluoroquinolones. Aminoglycosides for a full treatment course are an alternative option for the treatment of ESBL-E pyelonephritis or cUTI.

TMP-SMX, ciprofloxacin, and levofloxacin are preferred treatment options for patients with ESBL-E pyelonephritis and cUTIs based on the ability of these agents to achieve adequate and sustained concentrations in the urine, clinical trial results, and clinical experience [].

Carbapenems are also preferred agents, when resistance or toxicities prevent use of TMP-SMX or fluoroquinolones, or early in the treatment course if a patient is critically ill Question 1.

If a carbapenem is initiated and susceptibility to TMP-SMX, ciprofloxacin, or levofloxacin is demonstrated, transitioning to oral formulations of these agents is preferred over completing a treatment course with a carbapenem. Limiting use of carbapenem exposure will preserve their activity for future antimicrobial resistant infections.

In patients in whom the potential for nephrotoxicity is deemed acceptable, aminoglycosides dosed based on therapeutic drug monitoring results for a full treatment course are an alternative option for the treatment of ESBL-E pyelonephritis or cUTI [39, 40] Table 1Supplemental Material.

Once-daily plazomicin was noninferior to meropenem in a clinical trial that included patients with pyelonephritis and cUTIs caused by Enterobacterales [41].

Individual aminoglycosides are equally effective if susceptibility is demonstrated. Of note, in January the Clinical Laboratory and Standards Institute CLSI revised the aminoglycoside breakpoints [16] Table 2.

: Enhanced germ resistance

Antibacterial cleaning products

See also: Antibiotic misuse. Main article: Antibiotic use in livestock § Antibiotic resistance. Main article: Pesticide resistance. Main article: Pathogenic microorganisms in frozen environments. Further information: Antibiotic misuse. Further information: Antimicrobial spectrum.

Further information: List of antibiotic resistant bacteria. This section needs to be updated. Please help update this article to reflect recent events or newly available information.

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Similar to the other observational studies evaluating this question, this study did not identify differences in clinical outcomes when comparing patients treated with ceftriaxone versus carbapenems.

However, this study had several of the limitations outlined above. Nonetheless, since available data indicate a reasonable risk for the emergence of resistance when ceftriaxone or ceftazidime is prescribed for infections caused by organisms at moderate to high risk of AmpC production i.

aerogenes , C. freundii , the panel suggests generally avoiding ceftriaxone or ceftazidime when treating infections caused by these organisms. Based on the mild nature of uncomplicated cystitis and the sufficient urinary excretion of ceftriaxone, ceftriaxone may be adequate therapy for the management of AmpC-E cystitis.

Preferred treatment options for AmpC-E cystitis are described in Question 2. Suggested approach : Piperacillin-tazobactam is not suggested for the treatment of serious infections caused by Enterobacterales at moderate to high risk of clinically significant inducible AmpC production.

Tazobactam is less effective at protecting β-lactams from AmpC hydrolysis than newer β-lactamase inhibitors, such as avibactam, relebactam, and vaborbactam [, , , ]. The role of piperacillin-tazobactam in treating Enterobacterales at moderate to high risk for clinically significant AmpC production remains uncertain.

A meta-analysis summarized the findings of eight observational studies and did not identify a difference in mortality between patients treated with piperacillin-tazobactam and carbapenems for bacteremia by Enterobacter spp. In an observational study of patients published subsequent to the meta-analysis, piperacillin-tazobactam monotherapy was associated with over twice the odds of death within days, compared to alternative agents [].

A pilot unblinded clinical trial compared the outcomes of 72 patients with bloodstream infections caused by Enterobacter spp. aerogenes, C. freundii , M. morganii , Providencia spp.

marcescens randomized to piperacillin-tazobactam 4. There were no significant differences in the primary outcome a composite outcome including day mortality, clinical failure, microbiological failure, or microbiological relapse between the study arms.

The findings of this trial are challenging to interpret and a larger trial is needed to more definitively determine the role of piperacillin-tazobactam for the treatment of organisms at moderate to high risk for clinically significant ampC induction.

In light of the limited ability of tazobactam to protect piperacillin from AmpC hydrolysis in vitro and at least three observational studies identifying increased mortality in patients prescribed piperacillin-tazobactam [, , ] , the panel suggests caution if prescribing piperacillin-tazobactam for serious infections caused by AmpC-E.

Piperacillin-tazobactam may be a reasonable treatment option for mild infections such as uncomplicated cystitis. The panel does not suggest the use of ceftolozane-tazobactam as a treatment option for AmpC-E infections, with the possible exception of polymicrobial infections.

Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam generally exhibit in vitro activity against AmpC-E [, , ]. Although ceftazidime-avibactam is likely to be effective as a treatment for infections caused by AmpC-E, some data suggest it may have slightly higher failure rates for the treatment of AmpC-E infections compared to ESBL-E infections [].

Although the frequency is unknown, emergence of resistance of AmpC-E to ceftazidime-avibactam has been described [, ]. Cefiderocol demonstrates in vitro activity against AmpC-E [, ] and it is likely to be effective in clinical practice, although some case reports indicate the potential for AmpC-E to develop resistance to the drug [, ].

Although ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are likely to be effective against AmpC-E infections, the panel suggests that these agents be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance, where a greater need for them exists.

Tazobactam appears less effective at protecting β-lactams from AmpC hydrolysis compared with newer β-lactamase inhibitors, such as avibactam, relebactam, and vaborbactam [, , , ].

cloacae isolates []. Clinical outcomes data for ceftolozane-tazobactam for the treatment of AmpC-E infections are limited; a clinical trial evaluating this question is underway []. In light of the concerns described for tazobactam inhibition in Question 2.

aeruginosa and AmpC-E are isolated, the use of ceftolozane-tazobactam can be considered, after weighing the pros and cons of this approach, to limit exposure to multiple agents and their associated toxicities. Suggested approach: Nitrofurantoin or TMP-SMX a re preferred treatment options for uncomplicated AmpC-E cystitis.

Aminoglycosides are alternative treatments for uncomplicated cystitis, pyelonephritis, and cUTI caused by AmpC-E.

TMP-SMX or fluoroquinolones can be considered for the treatment of invasive infections caused by organisms at moderate to high risk of clinically significant AmpC production. Preferred treatment options for AmpC-E uncomplicated cystitis include nitrofurantoin [19] or TMP-SMX [38, ].

Ciprofloxacin or levofloxacin are alternative treatment options. A single IV dose of an aminoglycoside is an alternative treatment for AmpC-E uncomplicated cystitis [27]. Aminoglycosides are nearly exclusively eliminated by the renal route in their active form.

A single IV dose is generally effective for uncomplicated cystitis, with minimal toxicity, but robust clinical outcomes data are limited [27]. In patients in whom the potential for nephrotoxicity is deemed acceptable, aminoglycosides dosed based on therapeutic drug monitoring results for a full treatment course are an alternative option for the treatment of AmpC-E pyelonephritis or cUTI [39, 40] Table 1 , Supplemental Material.

The role of TMP-SMX or fluoroquinolones for the treatment of AmpC-E infections outside of the urinary tract has not been formally evaluated in clinical trials or robust observational studies. However, neither TMP-SMX nor fluoroquinolones are substrates for AmpC hydrolysis.

Oral step-down therapy with TMP-SMX or fluoroquinolones have been shown to be reasonable treatment considerations for Enterobacterales bloodstream infections, including those caused by AmpC-E, after appropriate clinical milestones are achieved [60, 61].

Based on the known bioavailability and sustained serum concentrations of oral TMP-SMX and fluoroquinolones, these agents are treatment options for patients with AmpC-E infections if 1 susceptibility to an appropriate oral agent is demonstrated, 2 patients are hemodynamically stable, 3 reasonable source control measures have occurred, and 4 concerns about insufficient intestinal absorption are not present.

The panel advises avoiding oral step-down to nitrofurantoin, fosfomycin, doxycycline, or amoxicillin-clavulanate for AmpC-E bloodstream infections. CRE account for more than 13, infections and contribute to greater than 1, deaths in the United States annually [].

The CDC defines CRE as members of the Enterobacterales order resistant to at least one carbapenem antibiotic or producing a carbapenemase enzyme []. Resistance to at least one carbapenem other than imipenem is required for bacteria generally not susceptible to imipenem e.

For the purposes of this guidance document, CRE refers to organisms displaying resistance to either meropenem or imipenem, or those Enterobacterales isolates producing carbapenemase enzymes Question 3. CRE comprise a heterogenous group of pathogens encompassing multiple mechanisms of resistance, broadly divided into those that are not carbapenemase-producing and those that are carbapenemase-producing.

CRE that are not carbapenemase-producing may be the result of amplification of non-carbapenemase β-lactamase genes e. The most common carbapenemases in the United States are K.

pneumoniae carbapenemases KPCs , which are not limited to K. pneumoniae isolates. Other notable carbapenemases that have been identified in the United States include New Delhi metallo-β-lactamases NDMs , Verona integron-encoded metallo-β-lactamases VIMs , imipenem-hydrolyzing metallo-β-lactamases IMPs , and oxacillinases e.

Knowledge of whether a CRE isolate is carbapenemase-producing and, if it is, the specific carbapenemase produced is important in guiding treatment decisions. Phenotypic tests such as the modified carbapenem inactivation method differentiate carbapenemase and non-carbapenemase-producing CRE [].

Molecular testing can identify specific carbapenemase gene families e. Treatment suggestions for CRE infections listed below assume that in vitro activity of preferred and alternative antibiotics has been demonstrated.

Suggested approach: For infections caused by Enterobacterales isolates that exhibit susceptibility to meropenem and imipenem i.

In this guidance document, CRE refers to Enterobacterales isolates resistant to meropenem or imipenem or Enterobacterales producing a carbapenemase enzyme. Questions 3. For infections caused by Enterobacterales isolates that exhibit susceptibility to meropenem and imipenem i.

Standard-infusion meropenem or imipenem-cilastatin may be reasonable for uncomplicated cystitis Table 1. For isolates susceptible to meropenem but not susceptible to imipenem and vice versa , in the absence of data to inform the optimal treatment approach, the panel suggests basing the treatment decision on the severity of illness of the patient and site of infection.

For example, in this scenario, meropenem may be a reasonable treatment for urinary tract infection but not for a complex intra-abdominal infection. The panel suggests against the use of meropenem-vaborbactam or imipenem-cilastatin-relebactam to treat ertapenem-resistant, meropenem-susceptible and imipenem-susceptible infections since these agents are unlikely to offer any substantial benefit beyond that of extended-infusion meropenem or imipenem-cilastatin alone.

Suggested approach: Nitrofurantoin, TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for uncomplicated cystitis caused by CRE, although the likelihood of susceptibility to any of these agents is low.

A single dose of an aminoglycoside, oral fosfomycin for E. coli only , colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol, are alternative treatment options for uncomplicated cystitis caused by CRE.

Clinical trial data evaluating the efficacy of most preferred agents for uncomplicated CRE cystitis are not available. However, as nitrofurantoin, TMP-SMX, ciprofloxacin, or levofloxacin all achieve high concentrations in urine, they are expected to be effective for uncomplicated CRE cystitis, if the isolate is susceptible [4, ].

A single dose of an aminoglycoside is an alternative option for CRE uncomplicated cystitis. Aminoglycosides are almost exclusively eliminated by the renal route in their active form.

A single IV dose is generally effective for cystitis, with minimal toxicity [27]. In general, higher percentages of CRE clinical isolates are susceptible to amikacin and plazomicin than to other aminoglycosides [, ]. Plazomicin may remain active against isolates resistant to other aminoglycosides [].

Oral fosfomycin is an alternative option for the treatment of uncomplicated CRE cystitis caused by E. coli as the fosA gene intrinsic to many gram-negative organisms can hydrolyze fosfomycin and may lead to clinical failure [28, 29].

Clinical trial data indicate that a single dose of oral fosfomycin is associated with higher clinical failure than a five-day course of nitrofurantoin for uncomplicated cystitis [19].

Colistin the active form of the commercially available parenteral inactive prodrug colistimethate sodium is an alternative agent for treating uncomplicated CRE cystitis. Colistin converts to its active form in the urinary tract; clinicians should remain cognizant of the associated risk of nephrotoxicity [].

Polymyxin B should not be used as treatment for uncomplicated CRE cystitis, due to its predominantly nonrenal clearance []. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are alternative options for uncomplicated CRE cystitis. They are designated alternative agents to preserve their activity for more invasive CRE infections.

Data are insufficient to favor one agent over the others but all of these agents are reasonable treatment options based on published comparative effectiveness studies [, ].

Suggested approach: TMP-SMX, c iprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis and cUTI caused by CRE, if susceptibility is demonstrated.

Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred treatment options for pyelonephritis and cUTIs. Aminoglycosides are alternative treatment options.

Although the minority of CRE are expected to retain susceptibility to TMP-SMX, ciprofloxacin, or levofloxacin, these agents are all preferred agents to treat CRE pyelonephritis or cUTI if susceptibility is demonstrated []. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are preferred treatment options for pyelonephritis and cUTIs caused by CRE based on clinical trials showing non-inferiority of these agents to common comparator agents for UTIs [, ].

Isolates included in these trials were overwhelmingly carbapenem susceptible. Data are insufficient to favor one agent over the others. In patients in whom the potential for nephrotoxicity is deemed acceptable, aminoglycosides for a full treatment course are an alternative option for the treatment of CRE pyelonephritis or cUTI [].

Table 1 , Supplemental Material. Suggested approach: Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are the preferred treatment options for infections outside of the urinary tract caused by CRE, when carbapenemase testing results are either not available or negative.

For patients with CRE infections who within the previous 12 months have received medical care in countries with a relatively high prevalence of metallo-β-lactamase-producing organisms or who have previously had a clinical or surveillance culture where a metallo-β-lactamase-producing isolate was identified, preferred treatment options include the combination of ceftazidime-avibactam plus aztreonam, or cefiderocol as monotherapy, while awaiting AST results to the novel β -lactam agents and carbapenemase testing results.

Ceftazidime-avibactam has activity against most KPC- and OXAlike-producing CRE isolates [, ]. Meropenem-vaborbactam and imipenem-cilastatin-relebactam are active against most Enterobacterales that produce KPC enzymes but not those that produce OXAlike carbapenemases [].

Neither ceftazidime-avibactam, meropenem-vaborbactam, nor imipenem-cilastatin-relebactam have activity against metallo-β-lactamase e. As described above, the vast majority of CRE clinical isolates in the United States either do not produce carbapenemases or, if they do, produce KPCs.

Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam all have a high likelihood of activity against CRE that do not produce carbapenemases [, ].

There do not appear to be differences in the effectiveness of these agents when susceptibility has been demonstrated. Cefiderocol is suggested as an alternative treatment option for CRE infections outside of the urine.

Cefiderocol is a synthetic conjugate composed of a cephalosporin moiety and a catechol-type siderophore, which binds to iron and facilitates bacterial cell entry using active iron transporters []. Once inside the periplasmic space, the cephalosporin moiety dissociates from iron and binds primarily to PBP3 to inhibit bacterial cell wall synthesis [].

Cefiderocol is highly likely to be active against CRE clinical isolates as it exhibits activity against Enterobacterales producing any of the five major carbapenemase enzymes, as well as CRE isolates not producing carbapenemases [, ].

In an effort to preserve cefiderocol activity for infections caused by pathogens where other β-lactam agents may have little to no activity, such as those caused by metallo- β -lactamase-producing Enterobacterales or by non-fermenting gram-negative organisms, the panel suggests cefiderocol as an alternative agent for infections caused by non-metallo- β -lactamase producing CRE.

Patients with CRE infections who have received medical care in countries with a relatively high prevalence of metallo-β-lactamase-producing CRE within the previous 12 months [] or who previously had a clinical or surveillance culture where metallo-β-lactamase-producing organisms were identified have a high likelihood of being infected with metallo-β-lactamase-producing Enterobacterales.

For such patients if carbapenemase results are not yet available , preferred treatment options include the combination of ceftazidime-avibactam plus aztreonam, or cefiderocol as monotherapy Question 3.

Tigecycline or eravacycline are alternative options for the treatment of CRE infections not involving the bloodstream or urinary tract Question 3. Their activity is independent of the presence or type of carbapenemase. However, subsequent observational and trial data indicate increased mortality and excess nephrotoxicity associated with polymyxin or aminoglycoside-based regimens relative to newer β-lactam-β-lactamase inhibitor agents for the treatment of CRE infections [].

Therefore, the panel advises against the use of extended-infusion carbapenems with or without the addition of a second agent for the treatment of CRE infections.

Suggested approach: Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred treatment options for KPC-producing infections. Cefiderocol is an alternative option. Preferred agents for KPC-producing infections include meropenem-vaborbactam, ceftazidime-avibactam, or imipenem-cilastatin-relebactam [, , , ].

Although all three agents are preferred agents for the treatment of KPC-producing infections, the panel slightly favors meropenem-vaborbactam, followed by ceftazidime-avibactam, and then imipenem-cilastatin-relebactam, based on available data regarding clinical outcomes and emergence of resistance.

These agents are associated with improved clinical outcomes and reduced toxicity compared to other regimens commonly used to treat KPC-producing infections, which are often polymyxin-based [, ]. Clinical trials comparing these agents to each other for the treatment of KPC-producing infections are not available.

An observational study compared the clinical outcomes of patients who received either meropenem-vaborbactam or ceftazidime-avibactam for at least 72 hours for the treatment of CRE infections [].

Carbapenemase status was largely unavailable. Although these differences were not statistically significant, they numerically favor meropenem-vaborbactam. This study had a number of important limitations: likely selection bias due to its observational nature, relatively small numbers of patients, heterogenous sites of CRE infection, more than half of patients had polymicrobial infections, and more than half of patients received additional antibiotic therapy.

These limitations notwithstanding, this study suggests that both meropenem-vaborbactam and ceftazidime-avibactam are reasonable treatment options for KPC-producing infections, although the emergence of resistance may be more common with ceftazidime-avibactam Question 3.

At least two groups that have published their clinical experiences with the use of ceftazidime-avibactam and meropenem-vaborbactam similarly found that patients who received meropenem-vaborbactam had a slightly higher likelihood of clinical cure and survival and a lower risk of emergence of resistance than patients treated with ceftazidime-avibactam [].

Limited clinical data are available for imipenem-cilastatin-relebactam compared with the other novel β-lactam-β-lactamase inhibitor agents. A clinical trial including patients with infections caused by gram-negative organisms not susceptible to imipenem assigned patients to receive either imipenem-cilastatin-relebactam versus imipenem-cilastatin and colistin [].

It is difficult to draw meaningful conclusions from these data given the small numbers. However, in vitro activity of imipenem-cilastatin-relebactam against CRE [, ] , clinical experience with imipenem-cilastatin, and the stability of relebactam as a β-lactamase inhibitor [] suggest imipenem-cilastatin-relebactam is likely to be effective for CRE infections if it tests susceptible.

Cefiderocol is an alternative treatment option for KPC-producing Enterobacterales []. Clinical investigations comparing the effectiveness of cefiderocol versus newer β-lactam-β-lactamase inhibitors for KPC-producing Enterobacterales infections are not available.

The panel suggests cefiderocol, as monotherapy, as an alternative agent for treating KPC-producing pathogens to reserve it for the treatment of infections caused by metallo-β-lactamase-producing Enterobacterales or glucose non-fermenting gram-negative organisms [].

Tigecycline or eravacycline are alternative options for the treatment of KPC-producing infections not involving the bloodstream or urinary tract Question 3.

Their activity is independent of the presence or type of carbapenemases. Suggested approach: Ceftazidime-avibactam in combination with aztreonam, or cefiderocol as monotherapy, are preferred treatment options for NDM and other metallo-β-lactamase-producing infections.

Preferred antibiotic options for NDM-producing Enterobacterales or other metallo-β-lactamases , include ceftazidime-avibactam plus aztreonam, or cefiderocol monotherapy [, ].

NDMs hydrolyze penicillins, cephalosporins, and carbapenems, but not aztreonam. Although aztreonam is active against NDMs, it can be hydrolyzed by ESBLs, AmpC β-lactamases, KPCs, or OXAlike carbapenemases which are frequently co-produced by NDM-producing isolates. Avibactam generally remains effective at inhibiting the activity of these latter β-lactamase enzymes.

Reliable estimates of the percent of NDM-producing isolates susceptible to the combination of ceftazidime-avibactam and aztreonam are not available due to the lack of a standardized testing approach.

Although several groups have described methods used to test susceptibility with this combination of agents [] , the CLSI does not currently endorse a specific approach to test in vitro activity with this combination [16].

An observational study of adults with bloodstream infections caused by metallo-β-lactamase-producing Enterobacterales compared the outcomes of 52 patients receiving ceftazidime-avibactam in combination with aztreonam versus 50 patients receiving a combination of other agents, primarily polymyxin or tigecycline-based therapy [].

Strategies for administering the combination of ceftazidime-avibactam and aztreonam are reviewed in Table 1 and Supplemental Material [].

Patients should be monitored closely for elevations in liver enzymes []. In rare situations where cefiderocol or combination therapy with ceftazidime-avibactam and aztreonam is not possible e. Clinical data investigating this approach are limited []. A second preferred option for the treatment of NDM and other metallo-β-lactamase-producing Enterobacterales is cefiderocol.

Surveillance data indicate that NDM-producing Enterobacterales isolates have a higher cefiderocol MIC 90 than isolates producing serine β-lactamases, although this is not always associated with frank cefiderocol resistance [, ].

Clinical outcomes data comparing ceftazidime-avibactam in combination with aztreonam versus cefiderocol are not available.

Tigecycline or eravacycline are alternative options for the treatment of NDM-producing infections not involving the bloodstream or urinary tract Question 3. Suggested approach: Ceftazidime-avibactam is the preferred treatment option for OXAlike-producing infections. Cefiderocol is an alternative treatment option.

If an OXAlike enzyme is identified in an Enterobacterales clinical isolate, ceftazidime-avibactam is preferred [, , ] ; cefiderocol is an alternative option [, ]. Meropenem-vaborbactam and imipenem-cilastatin-relebactam have limited to no activity against OXAlike producing isolates and are not suggested, even if susceptible in vitro [].

Although OXAlike-producing isolates are generally expected to test susceptible to cefiderocol, clinical data on cefiderocol treatment of infections by these organisms are limited and the panel prefers to reserve their activity for the treatment of metallo- β -lactamase producing organisms and certain non-fermenting organisms [].

Tigecycline or eravacycline are alternative options for the treatment of OXAlike-producing infections not involving the bloodstream or urinary tract Question 3. Suggested approach: The emergence of resistance is a concern with all β-lactams used to treat CRE infections.

Available data suggest the frequency may be highest for ceftazidime-avibactam. As with most antibiotic agents, treatment with any β-lactam agents active against CRE i. The most data on the emergence of resistance of novel agents to CRE focuses on KPC-producing isolates.

The emergence of resistance to ceftazidime-avibactam most commonly occurs because of mutations in the bla KPC gene translating to amino acid changes in the KPC carbapenemase []. Changes in permeability and efflux are the primary drivers of the emergence of resistance to meropenem-vaborbactam [, , , , ] and imipenem-cilastatin-relebactam [].

Increases in bla KPC copy numbers have been associated with resistance to all of these agents []. Diverse mechanisms of resistance to cefiderocol have been described both against KPC-producing isolates and other serine and metallo- β -lactamases producing Enterobacterales [, ] including mutations in the TonB-dependent iron transport system [] , amino acid changes in AmpC β-lactamases [, ] , and increased NDM expression [].

Increasing reports of amino acid insertions in PBP3, the active binding site of cefiderocol and aztreonam, are being described in NDM-producing E. coli isolates [, ] leaving no available β -lactam treatment options. Such reports remain rare in the United States [].

The most data are available for ceftazidime-avibactam, in part because it was the first of the novel β-lactam agents active against CRE to receive approval from the United States Food and Drug Administration FDA. Limited data exist on the frequency of emergence of resistance of CRE to imipenem-cilastatin-relebactam and cefiderocol.

The panel recommends always repeating AST for the newer β-lactams when a patient previously infected with a CRE presents with a sepsis-like picture suggestive of a new or relapsed infection.

Furthermore, if a patient was recently treated with ceftazidime-avibactam and presents with a sepsis-like condition, the panel suggests considering use of a different novel β-lactam agent at least until culture and AST data are available. For example, if a patient with a KPC-producing bloodstream infection received a treatment course of ceftazidime-avibactam one month earlier and presents to medical care with symptoms suggestive of infection, consider administering an agent such as meropenem-vaborbactam until organism and AST results are available.

Suggested approach: Although β-lactam agents remain preferred treatment options for CRE infections, tigecycline and eravacycline are alternative options when β-lactam agents are either not active or unable to be tolerated.

The tetracycline derivatives are not suggested for the treatment of CRE urinary tract infections or bloodstream infections. Tetracycline derivatives function independent of the presence or type of carbapenemase.

More specifically, both carbapenemase-producing e. The tetracycline-derivative agents achieve rapid tissue distribution following administration, resulting in limited urine and serum concentrations [].

Therefore, the panel suggests avoiding their use for urinary and bloodstream infections. Tigecycline or eravacycline can be considered as alternative options for intra-abdominal infections, skin and soft tissue infections, osteomyelitis, and respiratory infections when optimal dosing is used Table 1.

Tigecycline has more published experience available for the treatment of CRE infections compared with eravacycline []. A meta-analysis of 15 clinical trials suggested that tigecycline monotherapy is associated with higher mortality than alternative regimens used for the treatment of pneumonia, not exclusively limited to pneumonia caused by the Enterobacterales [].

Subsequent investigations have demonstrated that when high-dose tigecycline is prescribed mg IV as a single dose followed mg IV every 12 hours mortality differences between tigecycline and comparator agents may no longer be evident [].

Thus, if tigecycline is prescribed for the treatment of CRE infections, the panel recommends that high-dosages be administered [] Table 1. Eravacycline MICs are generally 2- to 4-fold lower than tigecycline MICs against CRE [].

Fewer than five patients with CRE infections were included in clinical trials that investigated the efficacy of eravacycline [, ] and post-marketing clinical reports describing its efficacy for the treatment of CRE infections are limited []. Limited clinical data are also available investigating the effectiveness of minocycline against CRE infections [, ] , but data suggest a lower proportion of CRE isolates are likely to be susceptible to minocycline compared to tigecycline or eravacycline [].

The panel suggests using minocycline with caution for the treatment of CRE infections. The panel suggests against the use of omadacycline for CRE infections. Suggested approach: Polymyxin B and colistin are not suggested for the treatment of infections caused by CRE.

Colistin can be considered as an alternative agent for uncomplicated CRE cystitis. Observational and clinical data indicate increased mortality and excess nephrotoxicity associated with polymyxin-based regimens relative to comparator agents []. Concerns about the clinical effectiveness of polymyxins and accuracy of polymyxin susceptibility testing led the CLSI to eliminate a susceptible category for colistin and polymyxin B [16].

The panel suggests that these agents be avoided for the treatment of CRE infections, with the exception of colistin as an alternative agent against CRE cystitis. Polymyxin B should not be used as treatment for CRE cystitis, due to its predominantly nonrenal clearance [].

Suggested approach: Combination antibiotic therapy i. Although empiric combination antibiotic therapy increases the likelihood that at least one active therapeutic agent for patients at risk for CRE infections is being administered, data do not indicate that continued combination therapy—once the β-lactam agent has demonstrated in vitro activity—offers any additional benefit [].

Rather, the continued use of a second agent increases the likelihood of antibiotic-associated adverse events []. Randomized trial data are not available comparing the novel β-lactam agents as monotherapy and as a component of combination therapy e.

An observational study compared the clinical outcomes of patients receiving ceftazidime-avibactam and patients receiving ceftazidime-avibactam plus a second agent for the treatment of KPC-producing infections []. Based on available outcomes data, clinical experience, and known toxicities associated with aminoglycosides, fluoroquinolones, tetracyclines, and polymyxins, the panel does not suggest combination therapy for CRE infections when susceptibility to a preferred β-lactam agent has been demonstrated.

The CDC reports that 32, cases of multidrug-resistant MDR - P. aeruginosa infections occurred in patients hospitalized in the United States in , resulting in 2, deaths []. MDR- P. aeruginosa is defined as P.

aeruginosa not susceptible to at least one antibiotic in at least three antibiotic classes for which P. aeruginosa susceptibility is generally expected: penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems [].

In this guidance document, DTR is defined as P. aeruginosa exhibiting non-susceptibility to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin.

aeruginosa or DTR- P. aeruginosa generally evolve as a result of an interplay of multiple complex resistance mechanisms, including decreased expression of outer membrane porins OprD , increased production of or amino acid substitutions within Pseudomonas -derived cephalosporinase PDC enzymes commonly referred to as pseudomonal AmpC enzymes , upregulation of efflux pumps e.

Carbapenemase production is a rare cause of carbapenem resistance in P. aeruginosa in other regions of the world, most commonly due to the presence of bla VIM enzymes [].

There are other β-lactamase enzymes rarely identified in P. aeruginosa isolates from patients in the United States that may confer elevated MICs to β -lactam agents including some novel β -lactam agents e. Carbapenemase testing for DTR- P. aeruginosa is not as critical as carbapenemase testing for CRE clinical isolates in United States hospitals.

However, the panel strongly encourages all clinical microbiology laboratories to perform AST for MDR and DTR- P. aeruginosa isolates against novel beta-lactam agents i. If AST cannot occur at the local clinical microbiology laboratory, isolates should be sent to a commercial laboratory, local health department, or the Centers for Disease Control and Prevention for AST testing.

While send out AST may delay the initiation of effective antibiotic therapy, it is still preferred over no testing as these data can guide treatment of chronic infections and recurrent infections. Treatment suggestions for DTR- P. aeruginosa infections listed below assume that in vitro activity of preferred and alternative antibiotics has been demonstrated.

Suggested approach: When P. aeruginosa isolates test susceptible to both traditional non-carbapenem β-lactam agents i. For infections caused by P. aeruginosa isolates not susceptible to any carbapenem agent but susceptible to traditional β-lactams, the administration of a traditional agent as high-dose extended-infusion therapy is suggested, and repeat AST is encouraged.

For critically ill patients or those with poor source control with P. aeruginosa isolates resistant to carbapenems but susceptible to traditional β-lactams, use of a novel β-lactam agent that tests susceptible e. In general, when a P. aeruginosa isolate tests susceptible to multiple traditional β-lactam agents i.

aeruginosa not susceptible to a carbapenem agent e. aeruginosa isolates []. This phenotype is generally due to lack of or limited production of OprD, which normally facilitates entry of carbapenem agents into P.

aeruginosa , with or without overexpression of efflux pumps []. Comparative effectiveness studies to guide treatment decisions for infections caused by P.

aeruginosa resistant to carbapenems but susceptible to traditional non-carbapenem β-lactams are not available. When confronted with these scenarios, the panel suggests AST to confirm antibiotic MICs. If the isolate remains susceptible to a traditional non-carbapenem β-lactam e.

An alternative approach is to administer a novel β-lactam agent e. This approach is considered an alternative and not a preferred option to preserve the effectiveness of novel β-lactams for future, increasingly antibiotic-resistant infections.

However, for critically ill patients or those with poor source control, use of a novel β-lactam for P. aeruginosa infections resistant to carbapenems but susceptible to non-carbapenem β-lactams is a reasonable consideration.

Regardless of the antibiotic agent administered, patients infected with P. aeruginosa should be closely monitored to ensure clinical improvement as P.

aeruginosa exhibits an impressive capacity to iteratively express additional resistance mechanisms while exposed to antibiotic therapy. Clinicians are advised to request repeat AST of subsequent clinical MDR- P. aeruginosa isolates obtained from the same patient to monitor for the development of resistance.

Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred treatment options for uncomplicated cystitis caused by DTR- P. A single-dose of tobramycin or amikacin is an alternative treatment for uncomplicated cystitis caused by DTR- P.

Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are preferred treatment options for uncomplicated DTR- P. aeruginosa cystitis, based on clinical trials showing non-inferiority of these agents to common comparator agents for the treatment of UTIs [, , ].

Data are insufficient to favor one of these agents over the others for the treatment of uncomplicated cystitis, and available trials generally do not include patients infected by pathogens with DTR phenotypes.

Additional information comparing these agents is described in Question 4. The suggested approach for the treatment of uncomplicated cystitis caused by DTR- P.

aeruginosa isolates confirmed to produce metallo- β -lactamase enzymes e. A single dose of tobramycin or amikacin is an alternative treatment option for uncomplicated cystitis caused by DTR- P. A single IV dose of tobramycin or amikacin are likely effective for uncomplicated cystitis as aminoglycosides are nearly exclusively eliminated by the renal route in their active form, with minimal toxicity, but robust trial data are lacking [27].

As of January , there are no longer susceptibility criteria for gentamicin for P. aeruginosa and susceptibility criteria for tobramycin and amikacin have been lowered [16] Table 2. Tobramycin susceptibility criteria are available for P. Amikacin susceptibility criteria against P.

Plazomicin has neither CLSI nor FDA susceptibility criteria against P. Surveillance studies indicate that plazomicin is unlikely to provide any incremental benefit against DTR- P.

aeruginosa if resistance to all other aminoglycosides is demonstrated []. Colistin, but not polymyxin B, is an alternate consideration for treating DTR- P. aeruginosa cystitis as it converts to its active form in the urinary tract [].

Clinicians should remain cognizant of the associated risk of nephrotoxicity. The panel does not recommend the use of oral fosfomycin for DTR- P. aeruginosa cystitis as it is associated with a high likelihood of clinical failure [19, ]. This is in part due to the presence of the fosA gene, which is intrinsic to P.

aeruginosa [28]. Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred treatment options for pyelonephritis and cUTI caused by DTR- P. Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are preferred treatment options for DTR- P.

aeruginosa pyelonephritis and cUTI, based on clinical trials showing non-inferiority of these agents to common comparator agents [, , ]. Data are insufficient to favor one of these agents over the others for the treatment of pyelonephritis and cUTI. Available trials generally do not include patients infected by pathogens with DTR phenotypes.

The suggested approach for the treatment of pyelonephritis and cUTI cystitis caused by DTR- P. In patients in whom the potential for nephrotoxicity is deemed acceptable, once-daily tobramycin or amikacin are alternative options Question 4. Changes in the aminoglycoside susceptibility criteria that were implemented in January are reviewed in Question 4.

Suggested approach: Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred options for the treatment of infections outside of the urinary tract caused by DTR- P.

Cefiderocol is an alternative treatment option for infections outside of the urinary tract caused by DTR- P. Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred options for the treatment of DTR- P.

aeruginosa infections outside of the urinary tract, based on in vitro activity [, , , ] , observational studies [] , and clinical trial data [, , ]. The vast majority of patients in clinical trials receiving newer β -lactam agents were not infected with DTR- P.

Comparative effectiveness studies comparing novel agents to each other e. Rather, available studies focus on comparing novel agents to older agents e. The suggested approach for the treatment of infections outside of the urinary tract caused by DTR- P.

aeruginosa isolates, respectively, with lower percent susceptibilities exhibited by isolates from patients with cystic fibrosis [, ].

Available surveillance data generally represent time periods before the novel agents were used clinically and likely overestimate susceptibility percentages observed in clinical practice. Regional differences in susceptibility estimates across the newer agents exist. The panel suggests always obtaining AST results for DTR- P.

aeruginosa infections to guide treatment decisions. Ceftolozane and ceftazidime have a similar structure; however, ceftolozane is less impacted by PDC hydrolysis and porin loss than ceftazidime [, ].

Ceftolozane does not rely on an inhibitor to restore susceptibility to an otherwise inactive β -lactam agent i. aeruginosa and does not need to rely on tazobactam to maintain its activity against DTR- P. aeruginosa , which may explain its slightly higher likelihood of activity against DTR- P.

aeruginosa compared to other novel β-lactam-β-lactamase inhibitors. By definition, neither ceftazidime nor imipenem are active against DTR- P. Avibactam and relebactam expand activity of these agents mainly through inhibition of PDCs [].

The panel does not suggest testing meropenem-vaborbactam activity against DTR- P. aeruginosa isolates. Vaborbactam only marginally expands the activity of meropenem against DTR- P. There are no CLSI or FDA breakpoints for meropenem-vaborbactam against P.

Some P. This is likely an artifact of meropenem-vaborbactam being standardly administered as 2 grams IV every 8 hours, infused over 3 hours. Meropenem breakpoints i.

If meropenem is infused as 2 grams IV every 8 hours over 3 hours it would be expected to achieve a similar likelihood of target attainment as meropenem-vaborbactam i. Clinical trials comparing effectiveness across the newer β -lactam agents are not available. Observational data and subgroup analysis from clinical trial data provide insights into the effectiveness of the newer agents compared to traditional anti-pseudomonal regimens, with studies generally focusing on MDR- P.

aeruginosa and not DTR- P. An observational study including patients with MDR- P. aeruginosa infections compared the outcomes of patients receiving ceftolozane-tazobactam versus polymyxin- or aminoglycoside-based therapy [].

Rigorous data investigating the activity of ceftazidime-avibactam against comparators are lacking. However, pooled data from five trial explored differences in clinical responses for patients with MDR- P. A clinical trial including 24 patients infected with imipenem-non-susceptible P.

While not achieving statistical significance, potentially due to the small sample size, the numerical differences suggest improved outcomes with use of imipenem-cilastatin-relebactam over more traditional regimens.

Cefiderocol is suggested as an alternative treatment option for DTR- P. aeruginosa infections outside of the urine. Combining data from 1, carbapenem-non-susceptible P. Similar to the novel β-lactam-β-lactamase inhibitors, percent susceptibility to cefiderocol is likely to be reduced after widespread use of this agent.

A clinical trial compared the outcomes of patients with infections due to carbapenem-resistant organisms treated with cefiderocol versus alternative therapy, which largely consisted of polymyxin-based therapy [].

The trial included 22 unique patients with 29 carbapenem-resistant P. aeruginosa infections []. This trial suggests that cefiderocol performs as well as agents that were previously the mainstay of treatment against DTR- P. aeruginosa in the past i. Despite the high DTR- P.

aeruginosa susceptibility to cefiderocol, the panel suggests cefiderocol as an alternative option when inactivity, intolerance, or unavailability precludes the use of the newer β-lactam-β-lactamase inhibitors. Suggested approach : For patients infected with DTR- P.

aeruginosa isolates that are metallo-β-lactamase producing, the preferred treatment is cefiderocol. aeruginosa harboring metallo-β-lactamases remain uncommon in the United States []. Such isolates are more common in other regions of the world [, ]. DTR- P. aeruginosa isolates exhibiting resistance to all available β-lactam-β-lactamase inhibitors i.

Metallo- β -lactamase-producing P. aeruginosa isolates generally remain susceptible to cefiderocol [, ]. Clinical data on the use of cefiderocol as a treatment for metallo- β -lactamase-producing P.

aeruginosa are limited. Seven patients with metallo-β-lactamase-producing P. aeruginosa infections were included in two cefiderocol clinical trials [].

In contrast to metallo- β -lactamase-producing Enterobacterales infections, the combination of ceftazidime-avibactam plus aztreonam using data extrapolated from aztreonam-avibactam appears less likely to provide an incremental benefit over aztreonam alone for metallo-β-lactamase-producing P.

aeruginosa infections [, ]. There are isolated case reports in the literature suggesting potential clinical success with this combination [, ]. Although avibactam may help reduce the effectiveness of PDC enzymes, the multiple other mechanisms generally present in DTR- P.

aeruginosa are likely to render aztreonam ineffective. aeruginosa []. Suggested approach: The emergence of resistance is a concern with all β-lactams used to treat DTR- P. aeruginosa infections. Available data suggest the frequency may be the highest for ceftolozane-tazobactam and ceftazidime-avibactam.

As with most antibiotic agents, treatment of DTR- P. aeruginosa with any of the newer β-lactam agents i. The emergence of resistance to ceftolozane-tazobactam most commonly occurs because of amino acid substitutions, insertions, or deletions in PDCs [, , ].

aeruginosa to ceftazidime-avibactam is most frequently the result of alterations in PDCs [, , , , , ]. Mechanisms contributing to P. aeruginosa resistance to imipenem-cilastatin-relebactam are less clear and are generally presumed to be related to increased production of PDCs in combination with loss of OprD and overexpression of efflux pumps e.

A number of diverse mechanisms of P. aeruginosa resistance to cefiderocol have been described [] including mutations in the TonB-dependent iron transport system [, ] or amino acid changes in AmpC β-lactamases [, ]. Based on available data thus far, the emergence of resistance of P.

aeruginosa to novel β-lactams appears most concerning for ceftolozane-tazobactam and ceftazidime-avibactam. Cross-resistance between these agents is high because of structural similarities.

In a cohort of 28 patients with DTR- P. aeruginosa isolates no longer susceptible to ceftolozane-tazobactam []. Another cohort study including 23 patients with index and subsequent P. aeruginosa isolates after ceftolozane-tazobactam described a similar experience [].

Limited data on the frequency of emergence of resistance to imipenem-cilastatin-relebactam exist. Similarly, estimates of the frequency of the emergence of resistance of P.

aeruginosa to cefiderocol since its clinical introduction are incomplete but in a clinical trial, three of 12 carbapenem-resistant isolates had at least 4-fold increases in cefiderocol MICs though not necessarily frank resistance after exposure to this agent [].

The panel suggests always repeating antibiotic susceptibility testing for the newer β-lactams when a patient previously infected with a DTR- P. aeruginosa presents with a sepsis-like picture suggestive of a new or relapsed infection. Furthermore, if a patient was recently treated with ceftolozane-tazobactam or ceftazidime-avibactam and presents to medical care with symptoms of recurrent infection, the panel suggests considering use of imipenem-cilastatin-relebactam or cefiderocol, particularly if one of these agents tested susceptible previously, at least until culture and AST data are available.

Suggested approach: Combination antibiotic therapy is not suggested for infections caused by DTR- P. aeruginosa if susceptibility to ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, or cefiderocol has been confirmed.

How Antibiotic Resistance Happens | CDC aeruginosa infections []the panel does not suggest that combination Enhanded Enhanced germ resistance routinely Increases mental productivity rewistance DTR- Enhaned. World J. b Confusion Cholesterol control tips showing the results of ten-fold cross validated bacterial identification. Figure 3. elegans model has been routinely used to assess the cytotoxicity of compounds, including AgNPs Roh et al. However, pooled data from five trial explored differences in clinical responses for patients with MDR- P.
1. Introduction

Among the bacteria tested, Salmonella spp. seem to be the least sensitive to AgNPs. Next, we assessed the mode of inhibition. We used E. The MBC was determined by enumerating the bacteria at the end of the treatment using the CFU plating method.

The MIC was 3. Table 1. AgNPs have antibacterial activity against clinical isolates with new and emerging resistance genes. Figure 3. AgNPs are bactericidal against E. The minimum bactericidal concentration MBC of Formula 1.

coli DH5α was 6. The ratio between the two values is 2, indicating a bactericidal mode of inhibition. The MIC and MBC points are marked on the graph. Data represent three independent experiments with three internal replicates per run. To better understand the effect of AgNPs on various biological systems, we employed in vitro and in vivo models to assess cytotoxicity.

We measured the effect of AgNPs on the viability of mouse RAW Previous reports suggest that Ag may target the cell membrane, which in eukaryotic cells could potentially impair the ability of phagocytes to uptake bacteria. We found that bacterial uptake was not affected at the concentrations tested Figure 4B.

Figure 4. AgNP cytotoxicity assessed using different cell types. B The effect of AgNPs on bacterial uptake by phagocytic macrophages at non-cytotoxic concentrations. Percent alive values were normalized to the control. Previous research suggests that the antibacterial property of Ag is mediated by its ability to target and denature the ribosome Yamanaka et al.

Similarly, it has been shown that aminoglycoside antibiotics induce misreading of mRNA by bacterial and eukaryotic ribosomes and ultimately lead to translation error which is likely the source of the proteotoxic stress Krause et al.

To test whether AgNPs could also induce misreading of mRNA in host cells, we monitored translation errors using reporters that are based on a tandem renilla luciferase Rluc and firefly luciferase Fluc linked together with a region containing a stop codon.

We used three different constructs, each with a different stop codon UGA, UAG, or UAA. The stop codon readthrough was monitored by Fluc activity. The mistranslation rate was measured by calculating the ratio between Fluc and Rluc.

While we saw a significant increase in mistranslation in the presence of paromomycin and gentamicin, two aminoglycoside antibiotics that kill bacteria by inducing mistranslation Davis, ; Vicens and Westhof, ; Kohanski et al.

We assessed the stop codon-readthrough in the presence of E. coli MIC 3. Although this concentration slightly affected the viability of mESCs, we did not detect any significant effect on translation fidelity Figure 4A , indicating that the particles are not proteotoxic to mammalian cells under the tested conditions Figure 5.

Figure 5. The effect of AgNPs on translation fidelity. Bar graphs representing relative rates of readthrough three stop codons: UGA left , UAG middle , and UAA right.

Dose—response concentrations of aminoglycosides paromomycin and gentamicin were used as positive controls. Each bar is an average of a minimum of three biological replicates.

Error bars represent standard deviation StDev. We measured the effects of AgNPs on C. elegans motility and lifespan.

The C. elegans model has been routinely used to assess the cytotoxicity of compounds, including AgNPs Roh et al. All tests with C. elegans were performed using control non-treated worms or in the presence of 0. coli OP50 bacterial lawn as food. We chose 0. We found that E. coli OP50 growth is affected by AgNPs and FUDR Supplementary Figure S2 ; therefore, to ensure that bacterial viability will not interfere with the results, we performed motility and lifespan experiments with worms that were fed pre-killed E.

To evaluate the effect of AgNPs on C. coli OP50 as a food source. We performed a thrashing assay, a commonly used physiological assessment of neuromuscular function Brignull et al. The assay is performed by counting the number of body bends the worm performs in a s interval when placed in a drop of liquid.

The worms on the AgNP-containing plates performed significantly fewer body bends compared to the control Figure 6A. However, at the same concentrations, AgNPs did not seem to have adverse effects on lifespan as we found no significant change between the control group and C.

elegans cultured on AgNPs Figure 6B. Figure 6. The effect of AgNPs on C. elegans motility was assessed in the presence of 0.

elegans lifespan was assessed in non-treated control worms and in the presence of 0. The difference in lifespan between the control and 0.

To determine whether AgNPs induce any visible morphological changes in bacterial cells, we employed TEM to image non-treated E.

coli and cells treated with 0. While we did not observe any obvious morphological changes in cells incubated with 0.

Interestingly, dark staining of the extracellular matrix seems to increase with AgNP concentration. These dark regions indicate high electron density, suggesting Ag may bind bacterial fimbriae Figure 7. Moreover, the cells incubated with the highest concentration of AgNPs seem to be darker, which could either indicate an increased Ag concentration or cell permeability which increases uranyl acetate staining.

These results warrant further experimentation to confirm fimbriae binding and its possible physiological relevance.

Figure 7. TEM images of AgNP-treated E. coli cells. While arrows point to the observed dark staining of the extracellular matrix. Ag is thought to have multiple cellular targets, including the bacterial membrane, DNA, and ribosome, which are also common antibiotic targets Dakal et al.

To determine the antimicrobial efficacy of AgNPs in combination with antibiotics having potentially overlapping targets, we chose several antimicrobials with various mechanisms of action that target the membrane, outer membrane, 30S ribosome, 50S ribosome, and dihydrofolate reductase.

coli DH5α to test these antibiotics in combination with 0. We assessed the effect of the combination by measuring the MIC fold-change as the ratio between the MIC of the antibiotic alone and the MIC of the combination Table 2 ; Figure 8A. There was little effect on the MIC when AgNPs were tested in combination with antimicrobials that target the membrane.

The only exception to this was colistin, which had a 6. Trimethoprim, which targets dihydrofolate reductase DHFR , had a 2-fold decrease in the MIC Table 2 ; Figure 8A. When the AgNPs were combined with ribosome-targeting antibiotics, specifically aminoglycosides, the MICs decreased by up to fold.

The strongest synergy between AgNPs and antibiotics was detected with amikacin, an aminoglycoside that targets the 30S ribosome, which resulted in a fold decrease in the MIC.

When amikacin and AgNPs were combined at their non-effective concentrations of 0. coli DH5α was completely inhibited, indicating a strong synergy between the two Table 2 ; Figure 8B. Surprisingly, when we tested the combination with tetracycline, which also targets the 30S ribosomal subunit, we did not observe any synergistic effect.

We have also ruled out any contribution from the potential inhibition by the solvents, DMSO, ethanol, or water at the highest tested dilutions Supplementary Figure S3. We thought that perhaps the synergistic effect between AgNPs and aminoglycosides might also affect the host cells by inducing translation errors; however, after testing the combination, we found no effect on the translation error in the host cells Figure 8C.

Further testing of an AgNP dose—response combination with amikacin against MDR E. coli strains using the checkerboard assay also revealed an antimicrobial enhancement Figure 9.

The 0. We were not able to calculate the FICI value for the amikacin-resistant strain. These results further support the AgNP-mediated enhancement of antimicrobial therapies.

Collectively, the antimicrobial efficacy of AgNPs and aminoglycosides offers a promising combination treatment strategy for antibiotic-resistant bacteria.

Figure 8. Antimicrobial efficacy of AgNPs in combination with antibiotics. A A graph representing the enhancement of E.

coli DH5α inhibition Fold Change upon treatment with 0. coli DH5α growth curves assessing the antimicrobial effect of AgNPs alone or in combination with amikacin.

Data represent the average of three independent runs with three replicates each. Error bars represent StDev. Figure 9. Checkerboard analysis of AgNP and amikacin combination against MDR E. A dose—response combination of AgNPs with amikacin was tested against A E. coli , amikacin-sensitive strain and B E.

coli , amikacin-resistant strain. The checkerboard represents an average of three independent experiments. The FICI for the amikacin-sensitive strain indicates a partial synergy. See Methods 2. In the present study, we assessed the antimicrobial efficacy and cytotoxicity of AgNPs. Physical characterization of these particles revealed a high consistency in size between the five different batches from each formulation.

We observed a slight but significant difference in MIC values that positively correlated with the average size of the particles Supplementary Table S2. The size-antimicrobial efficacy correlation of AgNPs is well established Morones et al. The E. Although, it is difficult to directly compare the results between studies because of the differences in the experimental design, antimicrobial metrics, and size of the particles.

The low variability in the size and antibacterial efficacy emphasize the reproducibility, consistency, and stability of our AgNP formulations. Interestingly, we found that AgNPs are more effective against gram-negative bacteria, a result that was previously observed Kim et al.

While the mechanisms contributing to this difference are not known, it is thought that perhaps the dissociated Ag ions may more readily enter gram-negative bacteria via outer membrane porins Radzig et al.

Other reports suggest that the thickness of the peptidoglycan layer is responsible for the difference in AgNP efficacy between gram-positive and gram-negative bacteria Dakal et al.

Regardless of the mechanisms responsible for the difference, the potent antimicrobial property against gram-negative bacteria is promising as these organisms are notoriously known for their intrinsic resistance to many classes of antibiotics, leaving little to no treatment options available Breijyeh et al.

Our results show that AgNPs inhibit the growth of a broad spectrum of gram-negative bacteria with novel resistance mechanisms, including strains resistant to colistin, a last-resort highly toxic antibiotic reserved for MDR gram-negative infections El-Sayed Ahmed et al.

Others have reported similar MIC values for various gram-negative bacteria, including E. coli , K. pneumoniae , P. aeruginosa , and S. aureus Liao et al. Collectively, the nanoparticle formulation used in this study is consistent with the antimicrobial properties of other AgNPs.

While Ag is known for its robust antimicrobial property, it also exhibits cytotoxicity, which could limit its application as a broad oral antimicrobial. We employed various methods to assess the cytotoxic effect of AgNPs on living systems and found little to no toxicity at lower bactericidal concentrations when applied in a tissue-culture model Figure 4.

We noted that phagocytic cells were more sensitive to Ag, which, based on the physiological function of these cells, could be the result of enhanced particle uptake. Given the membrane-targeting property of Ag, we also tested the effect of our nanoparticles on macrophage-mediated bacterial uptake.

We did not find any significant effect on bacterial uptake, which is consistent with previous results where treatment has either no effect or leads to the enhancement of phagocytosis Haase et al.

Macrophages are involved in wound healing and protection against bacterial invasion; as such, demonstrating the inert effect of AgNPs on phagocytosis could also warrant their possible use as an oral antimicrobial.

Although, topical applications, such as burn, surgical and suture wounds, dental applications, and eye, ear, and skin infections, would allow using higher concentrations without the risk of adverse reactions, which is often the case with topical antibiotics. Based on the previous reports suggesting that Ag targets the bacterial ribosome, we wanted to investigate whether AgNPs may also affect the eukaryotic ribosome; such cross-targeting is seen with aminoglycosides Hobbie et al.

We did not detect any effect of AgNPs on translation fidelity under our specific test conditions. However, we do not eliminate the possibility that AgNPs still target the eukaryotic ribosome without affecting the mistranslation rate.

Numerous reports have assessed the efficacy and cytotoxicity of AgNPs. However, the differences in experimental methods and AgNP properties make it difficult to directly compare the results between studies. While the results obtained in our study are unique to our AgNP formulations, our data are vastly supported by other reports.

For example, Luo et al. elegans lifespan when worms were cultured on NGM agar plates Luo et al. However, the size-toxicity correlation is not always clear, suggesting that other AgNP properties contribute to cytotoxicity.

The differences in the cytotoxicity of AgNPs are likely due to their physical and chemical properties, such as Ag concentration, size, formulation, charge, and purity, among others.

Our results demonstrate that the concentrations of 0. elegans lifespan, which agrees with the data reported across other studies.

Furthermore, our data indicate that AgNPs affect C. elegans motility Figure 6A , a result that has also been observed by others Contreras et al. Since the smaller particles could more readily penetrate cells, it is possible that muscle is more sensitive than other tissues; however, it remains to be determined whether this is a worm-specific result or whether these results could be translatable to higher eukaryotes, mammalian models, and humans.

In general, the results of our experiments warrant further studies into the applicability of AgNPs as topical antimicrobials. Our TEM results suggest that AgNPs bind to bacterial fimbriae.

If this is the case, then one would expect detectable effects on bacterial attachment and biofilm formation. Given that fimbriae support bacterial virulent mechanisms Spurbeck et al. In fact, the anti-biofilm properties of AgNPs were also observed in other studies Mohanta et al.

One of the most promising properties of Ag is its ability to target antibiotic resistance mechanisms and potentiate the efficacy of antibiotics Lara et al. Interestingly, out of the different classes of antibiotics we tested, only a combination with aminoglycosides showed synergy in the presence of AgNPs, suggesting that either Ag promotes aminoglycoside binding to the ribosome or increases intracellular aminoglycoside concentration by permeating the membrane.

If the latter is the case, we should expect a robust MIC fold change in combination with other non-ribosomal-targeting antibiotics i. Additionally, a combination of AgNPs with tetracycline, which also targets the 30S ribosomal subunit, did not result in synergy; therefore, the AgNP-mediated enhancement of antibiotics is not explained by permeability, but it is more likely that AgNPs and aminoglycosides share common targets and interact synergistically at specific sites of the bacterial ribosome.

We did not detect any effect of AgNPs on the fidelity of protein synthesis in mammalian cells; however, this does not eliminate the possibility of AgNPs targeting the eukaryotic ribosome without affecting its function. Furthermore, our results do not eliminate the possibility of AgNPs targeting the prokaryotic ribosome and resulting in the observed synergistic effect.

Collectively, our experiments reveal a promising antibacterial activity of AgNPs and their ability to lower the MICs of aminoglycoside antibiotics. While our results emphasize the importance of choosing the right antibiotic when combining with AgNPs, further work is needed to determine the underlying mechanisms and in vivo efficacy.

DC: conceptualization and supervision. DC, NQ, NR, and KF: methodology. AD and DC: software, manuscript draft preparation, and visualization. AD, DC, NR, and KF: validation. AD, DD, WD, NQ, CN, LA, GE, JB, NR, KF, and DC: investigation.

AD, DD, WD, NQ, GE, JB, NR, KF, and DC: manuscript review and editing. All authors contributed to the article and approved the submitted version.

Funding for this study was provided by Natural Immunogenics Corporation and the University of Florida Industry Partnerships Grant Program awarded to DC. KF was supported by the Japanese Science and Technology Agency grant JPMJPR Also, we would like to acknowledge the CDC and FDA Antimicrobial Resistance AR Isolate Bank for providing bacterial strains.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors declare that this study received funding from Natural Immunogenics Corporation. The funder had the following involvement in the study: product characterization using AAS and TEM.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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The most common bacteria that make this enzyme are gram-negative such as E. coli and Klebsiella pneumoniae , but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transfer. Specific antiviral drugs are used to treat some viral infections.

These drugs prevent viruses from reproducing by inhibiting essential stages of the virus's replication cycle in infected cells.

Antivirals are used to treat HIV , hepatitis B , hepatitis C , influenza , herpes viruses including varicella zoster virus , cytomegalovirus and Epstein—Barr virus.

With each virus, some strains have become resistant to the administered drugs. Antiviral drugs typically target key components of viral reproduction; for example, oseltamivir targets influenza neuraminidase , while guanosine analogs inhibit viral DNA polymerase.

Resistance to antivirals is thus acquired through mutations in the genes that encode the protein targets of the drugs. Resistance to HIV antivirals is problematic, and even multi-drug resistant strains have evolved.

Some fungi e. Candida krusei and fluconazole exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is a One Health concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, environmental change and host factors.

In the USA fluconazole -resistant Candida species and azole resistance in Aspergillus fumigatus have been highlighted as a growing threat. More than 20 species of Candida can cause candidiasis infection, the most common of which is Candida albicans.

Candida yeasts normally inhabit the skin and mucous membranes without causing infection. However, overgrowth of Candida can lead to candidiasis. Some Candida species e. Candida glabrata are becoming resistant to first-line and second-line antifungal agents such as echinocandins and azoles.

The emergence of Candida auris as a potential human pathogen that sometimes exhibits multi-class antifungal drug resistance is concerning and has been associated with several outbreaks globally.

The WHO has released a priority fungal pathogen list, including pathogens with antifungal resistance. The identification of antifungal resistance is undermined by limited classical diagnosis of infection, where a culture is lacking, preventing susceptibility testing.

In addition, a number of resistance mechanisms depend on up-regulation of selected genes for instance reflux pumps rather than defined mutations that are amenable to molecular detection. Due to the limited number of antifungals in clinical use and the increasing global incidence of antifungal resistance, using the existing antifungals in combination might be beneficial in some cases but further research is needed.

Similarly, other approaches that might help to combat the emergence of antifungal resistance could rely on the development of host-directed therapies such as immunotherapy or vaccines. The protozoan parasites that cause the diseases malaria , trypanosomiasis , toxoplasmosis , cryptosporidiosis and leishmaniasis are important human pathogens.

Malarial parasites that are resistant to the drugs that are currently available to infections are common and this has led to increased efforts to develop new drugs. The problem of drug resistance in malaria has driven efforts to develop vaccines.

Trypanosomes are parasitic protozoa that cause African trypanosomiasis and Chagas disease American trypanosomiasis. These drugs are effective but infections caused by resistant parasites have been reported.

Leishmaniasis is caused by protozoa and is an important public health problem worldwide, especially in sub-tropical and tropical countries. Drug resistance has "become a major concern".

In , genomic epidemiologists reported results from a global survey of antimicrobial resistance via genomic wastewater-based epidemiology , finding large regional variations, providing maps, and suggesting resistance genes are also passed on between microbial species that are not closely related.

The Centers for Disease Control and Prevention reported that more than 2. The COVID pandemic caused a reversal of much of the progress made on attenuating the effects of antibiotic resistance, resulting in more antibiotic use, more resistant infections, and less data on preventative action.

The s to s represented the golden age of antibiotic discovery, where countless new classes of antibiotics were discovered to treat previously incurable diseases such as tuberculosis and syphilis.

The phenomenon of antimicrobial resistance caused by overuse of antibiotics was predicted as early as by Alexander Fleming who said "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to nonlethal quantities of the drug make them resistant.

In this day and age current antimicrobial resistance leads to longer hospital stays, higher medical costs, and increased mortality. Since the mids pharmaceutical companies have invested in medications for cancer or chronic disease that have greater potential to make money and have "de-emphasized or dropped development of antibiotics".

This offers the opportunity to pay for valuable new drugs even if they are reserved for use in relatively rare drug resistant infections.

Some global health scholars have argued that a global, legal framework is needed to prevent and control antimicrobial resistance. For the United States budget , U. On 27 March , the White House released a comprehensive plan to address the increasing need for agencies to combat the rise of antibiotic-resistant bacteria.

The Task Force for Combating Antibiotic-Resistant Bacteria developed The National Action Plan for Combating Antibiotic-Resistant Bacteria with the intent of providing a roadmap to guide the US in the antibiotic resistance challenge and with hopes of saving many lives.

This plan outlines steps taken by the Federal government over the next five years needed in order to prevent and contain outbreaks of antibiotic-resistant infections; maintain the efficacy of antibiotics already on the market; and to help to develop future diagnostics, antibiotics, and vaccines.

The Action Plan was developed around five goals with focuses on strengthening health care, public health veterinary medicine, agriculture, food safety and research, and manufacturing.

These goals, as listed by the White House, are as follows:. The following are goals set to meet by []. According to World Health Organization , policymakers can help tackle resistance by strengthening resistance-tracking and laboratory capacity and by regulating and promoting the appropriate use of medicines.

Measuring the costs and benefits of strategies to combat AMR is difficult and policies may only have effects in the distant future. In other infectious diseases this problem has been addressed by using mathematical models.

More research is needed to understand how AMR develops and spreads so that mathematical modelling can be used to anticipate the likely effects of different policies. Distinguishing infections requiring antibiotics from self-limiting ones is clinically challenging.

In order to guide appropriate use of antibiotics and prevent the evolution and spread of antimicrobial resistance, diagnostic tests that provide clinicians with timely, actionable results are needed.

Acute febrile illness is a common reason for seeking medical care worldwide and a major cause of morbidity and mortality. In areas with decreasing malaria incidence, many febrile patients are inappropriately treated for malaria, and in the absence of a simple diagnostic test to identify alternative causes of fever, clinicians presume that a non-malarial febrile illness is most likely a bacterial infection, leading to inappropriate use of antibiotics.

Multiple studies have shown that the use of malaria rapid diagnostic tests without reliable tools to distinguish other fever causes has resulted in increased antibiotic use.

Antimicrobial susceptibility testing AST can facilitate a precision medicine approach to treatment by helping clinicians to prescribe more effective and targeted antimicrobial therapy. Progress has been slow due to a range of reasons including cost and regulation.

Optical techniques such as phase contrast microscopy in combination with single-cell analysis are another powerful method to monitor bacterial growth. In , scientists from Sweden published a method [] that applies principles of microfluidics and cell tracking, to monitor bacterial response to antibiotics in less than 30 minutes overall manipulation time.

Recently, this platform has been advanced by coupling microfluidic chip with optical tweezing [] in order to isolate bacteria with altered phenotype directly from the analytical matrix. Rapid diagnostic methods have also been trialled as antimicrobial stewardship interventions to influence the healthcare drivers of AMR.

Serum procalcitonin measurement has been shown to reduce mortality rate, antimicrobial consumption and antimicrobial-related side-effects in patients with respiratory infections, but impact on AMR has not yet been demonstrated. Currently it is unclear if rapid viral testing affects antibiotic use in children.

Microorganisms usually do not develop resistance to vaccines because vaccines reduce the spread of the infection and target the pathogen in multiple ways in the same host and possibly in different ways between different hosts.

Furthermore, if the use of vaccines increases, there is evidence that antibiotic resistant strains of pathogens will decrease; the need for antibiotics will naturally decrease as vaccines prevent infection before it occurs. While theoretically promising, antistaphylococcal vaccines have shown limited efficacy, because of immunological variation between Staphylococcus species, and the limited duration of effectiveness of the antibodies produced.

Development and testing of more effective vaccines is underway. Two registrational trials have evaluated vaccine candidates in active immunization strategies against S.

aureus infection. After 40 weeks following vaccination a protective effect was seen against S. aureus bacteremia, but not at 54 weeks following vaccination. Merck tested V, a vaccine targeting IsdB, in a blinded randomized trial in patients undergoing median sternotomy.

The trial was terminated after a higher rate of multiorgan system failure—related deaths was found in the V recipients. Vaccine recipients who developed S. aureus infection were five times more likely to die than control recipients who developed S.

Numerous investigators have suggested that a multiple-antigen vaccine would be more effective, but a lack of biomarkers defining human protective immunity keep these proposals in the logical, but strictly hypothetical arena. Alternating therapy is a proposed method in which two or three antibiotics are taken in a rotation versus taking just one antibiotic such that bacteria resistant to one antibiotic are killed when the next antibiotic is taken.

Studies have found that this method reduces the rate at which antibiotic resistant bacteria emerge in vitro relative to a single drug for the entire duration. Studies have found that bacteria that evolve antibiotic resistance towards one group of antibiotic may become more sensitive to others.

used for the treatment of drug-resistant tuberculosis and cystic fibrosis can cause respiratory disorders, deafness and kidney failure.

The potential crisis at hand is the result of a marked decrease in industry research and development. In particular, apart from classical synthetic chemistry methodologies, researchers have developed a combinatorial synthetic biology platform on single cell level in a high-throughput screening manner to diversify novel lanthipeptides.

In the 5—10 years since , there has been a significant change in the ways new antimicrobial agents are discovered and developed — principally via the formation of public-private funding initiatives. These include CARB-X , [] which focuses on nonclinical and early phase development of novel antibiotics, vaccines, rapid diagnostics; Novel Gram Negative Antibiotic GNA-NOW , [] which is part of the EU's Innovative Medicines Initiative ; and Replenishing and Enabling the Pipeline for Anti-infective Resistance Impact Fund REPAIR.

The delivery of these trials is facilitated by national and international networks supported by the Clinical Research Network of the National Institute for Health and Care Research NIHR , European Clinical Research Alliance in Infectious Diseases ECRAID and the recently formed ADVANCE-ID, which is a clinical research network based in Asia.

The discovery and development of new antimicrobial agents has been facilitated by regulatory advances, which have been principally led by the European Medicines Agency EMA and the Food and Drug Administration FDA.

These processes are increasingly aligned although important differences remain and drug developers must prepare separate documents. New development pathways have been developed to help with the approval of new antimicrobial agents that address unmet needs such as the Limited Population Pathway for Antibacterial and Antifungal Drugs LPAD.

These new pathways are required because of difficulties in conducting large definitive phase III clinical trials in a timely way. Some of the economic impediments to the development of new antimicrobial agents have been addressed by innovative reimbursement schemes that delink payment of antimicrobials from volume-based sales.

In the UK, a market entry reward scheme has been pioneered by the National Institute for Clinical Excellence NICE whereby an annual subscription fee is paid for use of strategically valuable antimicrobial agents — cefiderocol and ceftazidime-aviabactam are the first agents to be used in this manner and the scheme is potential blueprint for comparable programs in other countries.

The available classes of antifungal drugs are still limited but as of novel classes of antifungals are being developed and are undergoing various stages of clinical trials to assess performance. Scientists have started using advanced computational approaches with supercomputers for the development of new antibiotic derivatives to deal with antimicrobial resistance.

Using antibiotic-free alternatives in bone infection treatment may help decrease the use of antibiotics and thus antimicrobial resistance.

During the last decades, copper and silver nanomaterials have demonstrated appealing features for the development of a new family of antimicrobial agents.

Similar to the situation in malaria therapy, where successful treatments based on ancient recipes have been found, [] there has already been some success in finding and testing ancient drugs and other treatments that are effective against AMR bacteria. One of the key tools identified by the WHO and others for the fight against rising antimicrobial resistance is improved surveillance of the spread and movement of AMR genes through different communities and regions.

Recent advances in high-throughput DNA sequencing as a result of the Human Genome Project have resulted in the ability to determine the individual microbial genes in a sample. In doing so, a profile of these genes within a community or environment can be determined, providing insights into how antimicrobial resistance is spreading through a population and allowing for the identification of resistance that is of concern.

Phage therapy is the therapeutic use of bacteriophages to treat pathogenic bacterial infections. Phage therapy relies on the use of naturally occurring bacteriophages to infect and lyse bacteria at the site of infection in a host.

Due to current advances in genetics and biotechnology these bacteriophages can possibly be manufactured to treat specific infections. Bioengineering can play a role in creating successful bacteriophages. Understanding the mutual interactions and evolutions of bacterial and phage populations in the environment of a human or animal body is essential for rational phage therapy.

Bacteriophagics are used against antibiotic resistant bacteria in Georgia George Eliava Institute and in one institute in Wrocław , Poland. After a single course of phage therapy, no recurrence of infection occurred and no severe side-effects related to the therapy were detected.

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Infections – bacterial and viral Treatment suggestions for DTR- P. Scientists have long recognized that people who live in poverty and are malnourished are more vulnerable to infectious diseases. Vaccination for these kinds of viruses is difficult, because the viruses have already changed their format by the time vaccines are developed. Links with this icon indicate that you are leaving the CDC website. Additionally, the direct bactericidal effects and synergy of AgNPs with aminoglycoside antibiotics, as seen with a fold reduction in minimum inhibitory concentration MIC of amikacin, suggest a promising utility of AgNPs as antibiotic adjuvants. Otherwise, over-fitting an undesirable situation occurs.
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