You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Cefiderocol is a novel parenteral siderophore cephalosporin currently being developed to treat serious infections, including those due to carbapenem-resistant gram-negative strains \[[@CIT0001]\]. Cefiderocol has a unique mechanism of cell entry via bacterial iron transport channels. This allows it to enter gram-negative bacteria efficiently, even when accumulation of other agents is reduced due to porin channel loss and increased expression of efflux pumps. Cefiderocol has good stability to all classes of beta-lactamases, including serine- or metallo-carbapenemases that hydrolyze most or all other beta-lactam antibiotics. This combination of properties allows potent antibacterial activity against a wide variety of Enterobacteriaceae and nonfermenting gram-negative bacteria including *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, and *Stenotrophomonas maltophilia*, even when these have a potent combination of beta-lactamases. Activity is poor against gram-positive bacteria and anaerobic bacteria \[[@CIT0001], [@CIT0003]\].

Cefiderocol has been assessed in early-phase clinical trials for safety, tolerability, and pharmacodynamic behavior \[[@CIT0004], [@CIT0005]\]. Cefiderocol was shown to be safe and effective for the treatment of complicated urinary tract infection in a recently completed phase 2 study (APEKS-cUTI study) involving 452 randomized patients \[[@CIT0006]\]; it is now being evaluated in phase 3 studies (CREDIBLE-CR and APEKS-NP). Shionogi, the developers of cefiderocol, will consider unsolicited requests for compassionate use and were approached to assist with treatment in the following case.

A 78-year-old woman was admitted from an intensive care unit in Kuwait to London Bridge Hospital on 30 October 2017 for specialist urological and respiratory management. She had been in hospital in Kuwait for 3 months following complications of hydronephrosis secondary to a spontaneous ureteric hematoma. She had a past medical history of aortic stenosis, ischemic heart disease, and cerebral infarction and was in remission from breast cancer.

On arrival in London, she was ventilated and received intermittent hemofiltration without hemodynamic support or antimicrobials. Admission blood cultures grew extremely drug-resistant (XDR) *P. aeruginosa* susceptible to gentamicin, amikacin, and colistin (minimum inhibitory concentration \[MIC\] \<3 mg/L) but resistant to all beta-lactams and quinolones. There was no in vitro synergy between antipseudomonal agents and fosfomycin or rifampicin. The isolate lacked carbapenemase genes, and resistance to these agents was inferred to reflect loss of porin (OprD). A *bla*~(Vietnam\ ESBL)~ gene was found by polymerase chain reaction (PCR) assay and was considered to account for resistance to penicillins and cephalosporins, including ceftazidime/avibactam and ceftolozane/tazobactam. The patient also had rectal colonization with OXA-48 *Klebsiella pneumoniae* and OXA-23/OXA-51 *A. baumannii*. She was commenced empirically on colistin (9 megaunits (MU) loading dose followed by 3 MU 3 times per day, subsequently changed to 4.5 MU 2 times per day) together with intermittent gentamicin based on serum levels. A transthoracic echocardiogram showed a thickened aortic valve but no obvious regurgitation or vegetation. Representative clinical and microbiological features from her admission are presented in [Figure 1](#F1){ref-type="fig"}.

![Clinical, microbiological, and antimicrobial treatment course. Abbreviations: BC, blood culture positive (+) *Pseudomonas aeruginosa* or negative (−); ECHO, transthoracic echocardiogram.](ciy96301){#F1}

She became clinically septic following insertion of percutaneous nephrostomies and started high-flow continuous veno-venous hemofiltration (estimated creatinine clearance 40--50 mL/minute). Blood cultures again grew *P. aeruginosa* on days 3, 7, and 10. Gentamicin was stopped after the third dose on day 5 and replaced with meropenem 2 g 2 times per day, although MICs of the drug for all the *P. aeruginosa* isolates were \>32 mg/L. Sepsis resolved on day 14, with a negative blood culture and C-reactive protein (CRP) falling from 212 to 41; this improvement prompted cessation of antibiotic therapy. Sepsis returned within a few days, however, and the CRP rose to 267 mg/L, with day 22 and 27 blood cultures again growing *P. aeruginosa*, leading to recommencement of colistin and gentamicin. CRP continued to rise to 327 mg/L, and a day 27 *P. aeruginosa* isolate was reported as intermediately resistant to gentamicin, so gentamicin was again switched to meropenem. A second transthoracic echocardiogram showed possible vegetation on a tricuspid aortic valve with mild to moderate regurgitation.

Blood cultures were negative on days 38, 49, and 52, and the patient initially improved clinically while undergoing assessment for aortic valve surgery. However, during that time, there was a significant neurological deterioration with a computed tomography scan showing multifocal infarcts consistent with embolization; blood cultures again became positive (days 56, 62, and 68). A decision was made to source additional active antibiotics to control bacteremia prior to valve surgery.

ADJUNCTIVE TREATMENT WITH CEFIDEROCOL {#s1}
=====================================

Accordingly, a formal request was made to Shionogi on day 73 for compassionate use of cefiderocol. The request was granted, and the drug was obtained after appropriate governance approvals. Disk diffusion testing performed on day 3 and day 68 isolates gave zones of 17.4 and 21.3 mm, respectively, against a prospective 18-mm breakpoint for a 30-μg disk. Cefiderocol was administered from day 83 while continuing meropenem and colistin, and aortic valve replacement was performed on day 85. Intensivists decided on a cefiderocol dose of 2 g administered over 3 hours 3 times a day for the first 2 days then 2 g twice daily, based on a combination of renal function, septic state, complexity of the infection, and laboratory susceptibility testing. Blood culture taken before the first cefiderocol dose remained positive, but a blood culture taken after the sixth dose, on the day before surgery, was negative after 5 days of culture. The valve appeared heavily infected and disrupted at surgery and was positive for *P. aeruginosa* by PCR. Nevertheless, no gram-negative bacteria were seen on microscopy, and no growth was obtained, including on enrichment culture. Meropenem was stopped a week after surgery, but the cefiderocol/colistin combination was continued for an additional 3 weeks. The neutrophil count fell during the last 4 days of antibiotic treatment to a low of 0.2 10^9^/L on the planned last day of antibiotics, then returned to the normal range within a few days after stopping antibiotics. Neutropenia was reported in the serious adverse event report form, with either colistin or cefiderocol being considered the most likely potential causes. Multiple blood cultures after surgery and after stopping antibiotics were negative up to day 275 while the patient received convalescent care with slow neurological recovery leading to transfer back to Kuwait.

DISCUSSION {#s2}
==========

Infective endocarditis due to *P. aeruginosa* is rare, except among intravenous drug users, accounting for \<0.5% of all endocarditis cases \[[@CIT0007]\]. A recent literature review of 27 cases over 20 years reported 75% as healthcare associated, of which half required surgery and a third relapsed after apparent adequate treatment \[[@CIT0008]\]. *Pseudomonas aeruginosa* endocarditis is usually treated with combination therapy, such as meropenem or ceftazidime plus an aminoglycoside \[[@CIT0007]\], but these regimens are compromised against XDR strains, as in this case. Colistin is usually used as backbone therapy for XDR gram-negative bacterial infections, often with meropenem. However, in this case, a combination of these agents achieved only temporary blood culture sterility, with no other identified available options. Antibiotic dosing was at the high end of the recommended range, and a trough colistin serum level was measured at 6.3 mg/mL (target 2--4 mg/mL) 2 weeks prior to surgery, so it was considered that adequate doses were used.

The cause of the endocarditis was not identified but was probably present prior to transfer from Kuwait. *Pseudomonas aeruginosa* was not grown from any other cultures, including samples from the urinary tract. There were no predisposing factors such as a prosthetic valve or the presence of pacing wires, as reported in other studies \[[@CIT0009]\]. Although *P. aeruginosa* endocarditis can be treated with antibiotics alone, the failure to achieve sterility in this case combined with evolving valvular destruction meant surgery was essential for any prospect of cure. However, this was delayed in part due to embolization and was considered unlikely to succeed with persistently positive blood cultures on antibiotic therapy. The addition of cefiderocol led to blood culture sterility within 2 days, allowing potentially curative surgery to proceed. It is not possible to ascribe the relative contribution of surgery vs cefiderocol, but the rapid blood and valve sterility after starting cefiderocol suggest that this cephalosporin made a significant contribution. This report adds to the evidence from ongoing randomized studies that cefiderocol holds promise of being a useful new agent for treating XDR gram-negative bacteria, including when no other options exist.

From a microbiological perspective, it is striking that for *P. aeruginosa*, where there is easy mutational resistance to carbapenems, an extended-spectrum beta-lactamase (ESBL) gave the broadest spectrum of resistance. Also striking, and typical of VEB ESBLs in *P. aeruginosa*, is the fact that resistance included ceftolozane/tazobactam and ceftazidime/avibactam \[[@CIT0010]\]. Although VEB enzymes are uncommon in the United Kingdom (and the United States), the number of producer is increasing, often via imports from the Middle East and Eastern Europe \[[@CIT0010]\], where these enzymes appear to be more prevalent.

CONCLUSIONS {#s3}
===========

The emergence of multiresistant and extremely resistant gram-negative pathogens presents a global health challenge and underscores the urgent need for new antibiotics \[[@CIT0011], [@CIT0012]\]. Cefiderocol is being developed to address this need, targeting Enterobacteriaceae, *P. aeruginosa*, *A. baumannii*, and *S. maltophilia* \[[@CIT0001], [@CIT0002]\].

This case report documents a patient with XDR *P. aeruginosa* who was successfully managed with the addition of cefiderocol to control bacteremia and to allow aortic valve replacement. Compassionate use of cefiderocol was opted for this patient because there were no other available therapeutic options and because conventional agents were failing to control persistent bacteremia. An episode of transient acute neutropenia occurred during the last few days of treatment with both cefiderocol and colistin, highlighting the importance of continued pharmacovigilance during extended courses of antibiotics.

***Acknowledgments.*** We are grateful to Rachel Pike and Daniele Meunier at Public Health England (PHE) for susceptibility testing and molecular characterization of the isolates. We are also grateful to Hamish Rankin at Shionogi Limited London UK for the clinical operations activities that led to the provision of cefiderocol.

***Financial support.*** PHE is funded by the UK government.

***Potential conflicts of interest.*** J. D. E. served on advisory boards for Pfizer and Merck. D. W. reports personal fees from Merck, Pfizer, Johnson & Johnson, and Fisher & Paykel. D. M. L. has served on advisory boards or ad-hoc consultancy for Accelerate, Achaogen, Adenium, Allecra, Basilea, BioVersys, Centauri, Integra Holdings, Meiji, Melinta, Nordic Pharma, Pfizer, F Hoffmann-la-Roche, Shionogi, Taxis, T.A.Z., Tetraphase, the Medicines Company, VenatoRx, Wockhardt, and Zambon; has received personal fees for paid lectures from Astellas, AstraZeneca, bioMérieux, Beckmann Coulter, Cardiome/Correvio, Cepheid, Merck, Pfizer, and Nordic; has received research funding from Melinta, Merck, Paratek, Roche, and VenatoRx outside the submitted work; has performed contract research for Merck, Melinta, Pfizer, and Wockhardt; and has relevant shareholdings with Dechra, GlaxoSmithKline, Merck, Perkin Elmer, and Pfizer amounting to \<10% of portfolio value. D. M. L.'s affiliation, PHE, is funded by the UK government and has undertaken contract research on cefiderocol for Shionogi. D. M., S. P., T. D. N, and M. A. are employees of Shionogi Ltd. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.