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A 65-year-old man undergoes percutaneous nephrostomy for acute nephrolithiasis and urosepsis while travelling in India*. He receives systemic antimicrobial therapy with ciprofloxacin for 7 days and completely recovers. Two weeks later he returns to the USA and presents to the emergency department with confusion, dysuria, and chills. Physical exam reveals a blood pressure of 90/50, pulse 120, temperature 38.5°C and respiratory rate 24. The patient is disoriented but the physical exam is otherwise unremarkable. Laboratory test shows WBC 24,000/mm3 and elevated serum lactate; urinalysis shows 300 WBC per high power field and 4+ bacteria. What possible organisms are likely to be responsible for the patient’s symptoms? What antibiotic(s) would you choose for initial therapy of this potentially life-threatening infection?

The development of antimicrobial drugs represents one of the most important advances in therapeutics, both in the control or cure of serious infections and in the prevention and treatment of infectious complications of other therapeutic modalities such as cancer chemotherapy, immunosuppression, and surgery. However, evidence is overwhelming that antimicrobial agents are vastly overprescribed in outpatient settings in the USA, and the availability of antimicrobial agents without prescription in many developing countries has—by facilitating the development of resistance—already severely limited therapeutic options in the treatment of life-threatening infections.

The threat of antimicrobial resistance and its impact on treatment of severe infections is urgent. Antibiotic-resistant bacteria, especially the “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and other Enterobacteriaciae species) have been identified as specific MDR (multidrug-resistant) pathogens by the US Centers for Disease Control and Prevention, and the World Health Organization. The Infectious Disease Society of America has launched the “10 × ‘20 initiative” encouraging the development of 10 novel, efficacious, and safe systemically administered antibacterial agents by 2020. As of 2019, 7 novel agents have received FDA approval and 9 are in advanced clinical development.

Therefore, the clinician should first determine whether antimicrobial therapy is warranted for a given patient. The specific questions one should ask include the following:

  1. Is an antimicrobial agent indicated on the basis of clinical findings? Or is it prudent to wait until such clinical findings become apparent?

  2. Have appropriate clinical specimens been obtained to establish a microbiologic diagnosis?

  3. What are the likely etiologic agents for the patient’s illness?

  4. What measures should be taken to protect individuals exposed to the index case to prevent secondary cases, and what measures should be implemented to prevent further exposure?

  5. Is there clinical evidence (eg, from well-executed clinical trials) that antimicrobial therapy will confer clinical benefit for the patient?

Once a specific cause is identified based on specific microbiologic tests, the following further questions should be considered:

  1. If a specific microbial pathogen is identified, can a narrower-spectrum agent be substituted for the initial empiric drug?

  2. Is one agent or a combination of agents ...

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