Antibiotic Stewardship in Hospitalized Patients, Part 1: Principles, Common Pathogens, and Empiric Choices

Bottom line

The stewardship loop that applies to every syndrome

• Cultures first: two sets of blood cultures and the relevant site culture (urine, sputum or tracheal aspirate, abscess fluid, CSF, bone biopsy) before the first dose, without delaying therapy more than a few minutes in a sick patient. The one deliberate exception is a stable patient with suspected vertebral osteomyelitis, where antibiotics are held until biopsy because prior therapy sterilizes the culture.
• Choose empirically by four steps: severity of illness, patient-specific risk factors for resistant organisms (prior ESBL, Pseudomonas, or MRSA isolation; IV antibiotics, hospitalization, or long-term care within 90 days; immunosuppression), patient-specific adverse-event considerations (renal function, allergy, C. difficile history, QT, drug interactions), and the local antibiogram.
• Review at 48–72 hours (an antibiotic time-out on day 3): narrow to the narrowest active agent once susceptibilities return, stop anti-MRSA coverage when the MRSA nares screen and cultures are negative, and stop antibiotics entirely when cultures are negative and another diagnosis explains the fever.
• Switch IV to oral once the patient is afebrile for about 24 hours, hemodynamically stable, improving, absorbing enterally, and a susceptible high-bioavailability oral agent exists (TMP-SMX, a fluoroquinolone, or an adequately dosed beta-lactam). The switch shortens length of stay and avoids line complications.
• Write the indication, the agent, and a stop date in the orders and the daily note. Count ED and IV days toward the total course.
• Take a structured penicillin allergy history on admission; low-risk histories (an isolated rash more than 10 years ago, GI intolerance, family history) warrant delabeling by direct oral challenge rather than reflexive aztreonam or fluoroquinolone use. Cefazolin is usually tolerated in penicillin allergy because it shares no R1 side chain; anaphylaxis, SJS/TEN, DRESS, or other severe delayed reactions need allergy consultation and continued avoidance.
• Avoid redundant coverage: no empiric vancomycin for urinary infection (MRSA is a rare uropathogen), no double anaerobic coverage (piperacillin-tazobactam plus metronidazole), and no repeat ceftriaxone after a recent third-generation cephalosporin course because it selects AmpC-producing Enterobacterales and Pseudomonas.
• Weigh every course against C. difficile: clindamycin, fluoroquinolones, third- and fourth-generation cephalosporins, and carbapenems carry the highest risk, and stopping unnecessary antibiotics is the single most effective prevention. Test only clinically significant diarrhea (3 or more unformed stools in 24 hours without laxatives), never asymptomatic patients, and treat per the C. difficile guide.

Complicated vs uncomplicated: why the label changes the plan

• Urinary tract infection: uncomplicated means cystitis in a healthy, non-pregnant patient with a normal urinary tract, treated with a short oral course (nitrofurantoin, fosfomycin, or TMP-SMX). Complicated UTI includes pyelonephritis, infection with fever or sepsis, a catheter, obstruction or stones, urologic abnormality, pregnancy, immunosuppression, or male sex. It needs blood and urine cultures, a systemic agent that reaches renal tissue and blood (nitrofurantoin and fosfomycin do not), imaging if there is no improvement by 48–72 hours, flank pain, stones, or persistent bacteremia, and about 7 days of therapy with a prompt response.
• Gram-negative bacteremia: uncomplicated means a controlled source (for example a urinary source with obstruction relieved or a catheter removed), prompt clinical response, and no immunocompromise; 7 days is non-inferior to 14, repeat blood cultures and echocardiography are not routine, and early oral step-down to a fluoroquinolone or TMP-SMX is appropriate. Complicated means an undrained focus, persistent bacteremia, or an immunocompromised host, and the course extends with source control.
• S. aureus bacteremia is never 'simple'. Uncomplicated requires all of: endocarditis excluded by echocardiography, no prosthetic material (valve, graft, pacemaker, joint), follow-up blood cultures at 2–4 days negative, defervescence within 72 hours of effective therapy and source removal, and no evidence of metastatic infection — and even then it gets 14 days of IV therapy from the first negative culture. Failing any criterion makes it complicated and extends therapy to 4–6 weeks. The full bundle is in part 2.
• Intra-abdominal infection: uncomplicated means inflammation confined to the wall of the organ (uncomplicated appendicitis or diverticulitis), often treated with a short course or source control alone. Complicated means the infection has extended beyond the hollow viscus into the peritoneal space with peritonitis or an abscess, which requires source control (drainage or surgery) and about 4 days of antibiotics after the source is controlled.
• Pneumonia: community-acquired pneumonia is driven by pneumococcus, Haemophilus, atypicals, and viruses and treated for 5 days once stable. Hospital-acquired pneumonia (onset 48 hours or more after admission) and ventilator-associated pneumonia are driven by S. aureus including MRSA, Pseudomonas, Enterobacterales, and occasionally Acinetobacter or Stenotrophomonas, and need an antipseudomonal beta-lactam with MRSA coverage when risk factors are present, for 7 days.
• Skin and soft tissue: non-purulent cellulitis is streptococcal and treated with cefazolin for 5–6 days; purulent infection or an abscess is staphylococcal (including MRSA) and needs incision and drainage plus MRSA-active therapy. Necrotizing infection, crepitus, or pain out of proportion is a surgical emergency.

Which bugs cause which infections

• Urinary tract: Enterobacterales (E. coli, Klebsiella, Proteus) dominate; Enterococcus and Staphylococcus saprophyticus follow. ESBL producers rise with prior isolation, recent antibiotics, and healthcare exposure. MRSA is rare in urine.
• Community-acquired pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma, Legionella, and respiratory viruses. Cover MRSA or Pseudomonas only with prior respiratory isolation or recent hospitalization plus IV antibiotics.
• Hospital-acquired and ventilator-associated pneumonia: S. aureus including MRSA, Pseudomonas aeruginosa, Enterobacterales, and less commonly Acinetobacter and Stenotrophomonas. IV antibiotics within 90 days, onset after day 5, and a high unit MRSA prevalence are the MRSA risk factors.
• Skin and soft tissue: beta-hemolytic streptococci for non-purulent cellulitis; S. aureus including MRSA for abscesses and purulent cellulitis; polymicrobial flora including anaerobes in diabetic foot infection.
• Intra-abdominal infection: polymicrobial colonic flora — Enterobacterales (E. coli, Klebsiella), Bacteroides and other anaerobes, and streptococci. Enterococcus and Candida matter mainly in healthcare-associated, postoperative, recurrent, or immunosuppressed disease, or after upper-GI perforation.
• Bacteremia: the organism tracks the source — Enterobacterales from the urinary tract and abdomen, S. aureus and coagulase-negative staphylococci from catheters, skin, bone, and joints, streptococci from skin and the oropharynx, and Candida from central lines and total parenteral nutrition.
• Endocarditis: native valve — S. aureus is most common overall, then viridans streptococci, enterococci, coagulase-negative staphylococci, and HACEK organisms. Early prosthetic-valve endocarditis (within 12 months of surgery) — coagulase-negative staphylococci, S. aureus, gram-negative bacilli, and Candida; late prosthetic-valve disease resembles native-valve disease. Injection drug use — S. aureus with tricuspid involvement, plus Pseudomonas, other gram-negatives, polymicrobial infection, and Candida.
• Meningitis: adults 18–50 — S. pneumoniae and Neisseria meningitidis. Adults over 50, and anyone with alcohol use or cirrhosis, pregnancy, malignancy, steroids or immunosuppression, or chronic renal failure — add Listeria monocytogenes. Post-neurosurgical or nosocomial meningitis — Pseudomonas, other gram-negatives, and staphylococci.
• Osteomyelitis: hematogenous vertebral osteomyelitis — S. aureus (MSSA more than MRSA), then coagulase-negative staphylococci, streptococci and enterococci, and gram-negatives such as E. coli from a urinary source. Contiguous diabetic-foot osteomyelitis — polymicrobial (S. aureus, streptococci, anaerobes, aerobic gram-negatives). Post-surgical or hardware infection — S. aureus, coagulase-negative staphylococci, Cutibacterium acnes, and gram-negatives. Consider tuberculosis, Brucella, and fungi in a subacute course or with exposure.
• Reading the same list by organism: S. aureus owns skin abscesses, bone, catheters, blood, and valves; streptococci own cellulitis, community pneumonia, and viridans endocarditis; Enterococcus appears in urine, the postoperative abdomen, and endocarditis; Enterobacterales own urine, abdomen, and gram-negative bacteremia; Pseudomonas belongs to the hospital lung, the instrumented urinary tract, and injection-drug-use endocarditis; anaerobes live in the abdomen, the diabetic foot, and aspiration; Listeria is the meningitis organism of older and immunocompromised adults; Candida follows central lines, TPN, and upper-GI perforation.

Empiric regimens by syndrome

• Complicated UTI and pyelonephritis: stable without resistance risk — ceftriaxone 1–2 g IV every 24 hours. Sepsis, or ESBL or Pseudomonas risk — piperacillin-tazobactam 4.5 g IV every 6 hours (or extended infusion every 8 hours), or a carbapenem (ertapenem 1 g every 24 hours when not critically ill, meropenem if bacteremic or unstable). Remove or exchange catheters; relieve obstruction.
• Community-acquired pneumonia: ceftriaxone plus azithromycin (or doxycycline); add vancomycin or linezolid for MRSA and an antipseudomonal beta-lactam for Pseudomonas only with prior isolation or recent hospitalization plus IV antibiotics.
• Hospital-acquired or ventilator-associated pneumonia: one antipseudomonal beta-lactam — piperacillin-tazobactam 4.5 g IV every 6 hours (extended infusion preferred) or cefepime 2 g IV every 8 hours — plus vancomycin 15–20 mg/kg every 8–12 hours dosed to an AUC/MIC of 400–600 (loading dose 25–30 mg/kg in severe illness) or linezolid 600 mg IV or oral every 12 hours when MRSA risk factors are present. Add a second antipseudomonal agent only for septic shock, ventilation for pneumonia, bronchiectasis or cystic fibrosis, prior Pseudomonas, or local gram-negative resistance above about 10%. Send an MRSA nares PCR.
• Skin and soft tissue: cefazolin for non-purulent cellulitis; incision and drainage plus TMP-SMX or doxycycline (vancomycin if severe) for purulent infection; broad coverage with surgical consultation for diabetic foot or suspected necrotizing infection.
• Complicated intra-abdominal infection: community-acquired, mild to moderate — ceftriaxone 2 g IV every 24 hours plus metronidazole 500 mg IV every 8 hours, or ertapenem 1 g IV every 24 hours. Healthcare-associated, recent broad-spectrum antibiotics, prior ESBL, immunosuppression, or severe physiology — piperacillin-tazobactam 4.5 g IV every 6–8 hours (extended infusion) or meropenem 1 g IV every 8 hours. Add enterococcal coverage only for healthcare-associated or postoperative infection, immunosuppression, a prosthetic valve or vascular graft, or enterococci on a reliable culture; add an antifungal only for upper-GI perforation, recurrent or persistent leak, immunosuppression, or Candida on culture; add vancomycin only for known MRSA.
• Endocarditis, bacterial meningitis, vertebral osteomyelitis, and spinal epidural abscess have syndrome-specific empiric regimens, timing rules, and bundles that are covered in part 2 of this guide; C. difficile treatment (fidaxomicin or oral vancomycin, never IV vancomycin) is covered in its own guide.
• Bacteremia of unknown source: cover by suspected source and Gram stain, draw repeat cultures, and add vancomycin when gram-positive cocci in clusters are seen, a line is suspected, or the patient has known MRSA colonization. Narrow immediately once the organism is identified — a beta-lactam (cefazolin or nafcillin) is clearly superior to vancomycin for MSSA.

De-escalation, oral switch, and durations by syndrome

• Complicated UTI and pyelonephritis: about 7 days with a prompt response; 10–14 days for an undrained abscess, persistent obstruction, or delayed response. Oral step-down to TMP-SMX, a fluoroquinolone, or an adequately dosed beta-lactam.
• Community-acquired pneumonia: 5 days once afebrile for 48 hours and clinically stable. Hospital-acquired or ventilator-associated pneumonia: 7 days, extended only for empyema, abscess, bacteremia with a metastatic focus, immunosuppression, or poor response.
• Cellulitis: 5–6 days. Complicated intra-abdominal infection: about 4 days after adequate source control; about 7–10 days when treated with antibiotics alone.
• Uncomplicated gram-negative bacteremia: 7 days. S. aureus bacteremia: 14 days IV minimum, 4–6 weeks if complicated. Endocarditis: typically 6 weeks IV from the first negative culture.
• Meningitis: 7 days for meningococcus and Haemophilus, 10–14 days for pneumococcus, 21 days for gram-negative bacilli, at least 21 days for Listeria. Vertebral osteomyelitis and epidural abscess: 6 weeks, 8 weeks or longer without complete source control. C. difficile: 10 days for a first episode. Details are in part 2 and the C. difficile guide.

Monitoring and disposition

• Daily vitals and fever curve, symptom trajectory, and creatinine; expect defervescence within 48–72 hours of effective therapy for most syndromes and within 3–5 days for C. difficile.
• Drug monitoring: vancomycin AUC-guided levels and daily creatinine (nephrotoxicity rises with piperacillin-tazobactam); CK weekly on daptomycin; CBC for thrombocytopenia beyond 7–10 days of linezolid; twice-weekly creatinine and CBC on cefazolin or nafcillin for prolonged courses; potassium and creatinine on TMP-SMX.
• Repeat blood cultures only for ongoing bacteremia risk (S. aureus, Candida, persistent fever); no test-of-cure urine culture or stool test in a patient who has improved; no routine repeat chest radiograph in a responding pneumonia.
• Discharge when afebrile for about 24 hours, improving, tolerating an oral regimen or with outpatient parenteral therapy and weekly labs arranged, and source control complete, on the narrowest agent with an explicit stop date. Arrange primary care or ID follow-up within 1–2 weeks with return precautions for recurrent fever, flank or back pain, new neurologic symptoms, vomiting, or diarrhea.

Escalate care if

• Fever or symptoms persist beyond 48–72 hours on appropriate therapy — image the source for obstruction, abscess, empyema, or an undrained collection and repeat cultures rather than reflexively broadening antibiotics.
• An ESBL-producing Enterobacterales grows — switch to a carbapenem (ertapenem when not critically ill; meropenem if bacteremic or unstable); piperacillin-tazobactam is not a reliable alternative for ESBL bacteremia. Pseudomonas grows — continue susceptibility-guided antipseudomonal therapy rather than de-escalating to ceftriaxone. A carbapenem-resistant organism or a non-fermenter grows — ID consultation for definitive agent selection.
• Blood cultures grow S. aureus or Candida — ID consultation, source evaluation (echocardiography, line removal, ophthalmologic exam for candidemia), and repeat cultures to document clearance.
• Hypotension, rising lactate, or new organ dysfunction — sepsis resuscitation, antibiogram-guided broadening, urgent source control, and a higher level of care.
• New significant diarrhea on therapy — test for C. difficile and treat per its guide; new distension, ileus, or shock on C. difficile therapy is fulminant disease and needs surgical consultation.

Duration

Match the course to the syndrome and to whether it is complicated: 5 days for community pneumonia, 7 days for complicated UTI, hospital pneumonia, and uncomplicated gram-negative bacteremia, about 4 days after source control for intra-abdominal infection, 10 days for C. difficile, 14 days minimum for S. aureus bacteremia, 6 weeks for endocarditis and vertebral osteomyelitis, and organism-specific courses for meningitis. Write the stop date in the order.

Caveats

• The narrow-first approach assumes no prior ESBL, Pseudomonas, or MRSA isolation, no recent broad-spectrum antibiotic or healthcare exposure, and no retained source — any of these justifies broad coverage until cultures return.
• Piperacillin-tazobactam combined with vancomycin materially increases AKI risk; avoid unnecessary combination and monitor creatinine daily.
• Fluoroquinolone oral step-down carries risks of tendinopathy, QT prolongation, CNS effects, delirium in older adults, and C. difficile — use only with documented susceptibility when safer options are unavailable. TMP-SMX needs potassium and creatinine monitoring and interacts with warfarin, ACE inhibitors or ARBs, and spironolactone. Linezolid interacts with serotonergic drugs. Metronidazole interacts with alcohol and warfarin.
• Nitrofurantoin and fosfomycin do not reach adequate renal parenchymal or bloodstream levels and are inappropriate for pyelonephritis or bacteremic UTI; IV vancomycin does not treat C. difficile colitis; daptomycin does not treat pneumonia.
• Never substitute vancomycin for a beta-lactam in MSSA bacteremia for convenience — failure and mortality are higher. Any implanted hardware automatically makes S. aureus bacteremia complicated.
• Do not delabel penicillin allergy by direct challenge after anaphylaxis, SJS/TEN, DRESS, or other severe delayed reactions — these need allergy consultation and continued avoidance.

References

1. IDSA 2025 Guideline Update on Complicated Urinary Tract Infections. (2025) · Primary guideline“For patients with sepsis due to complicated UTI, we suggest initially selecting among the following antibiotics, using the four-step assessment: third- or fourth-generation cephalosporins, carbapenems, piperacillin-tazobactam, or fluoroquinolones.”
2. IDSA 2024 Guideline Update on the Risk Assessment, Diagnostic Imaging, and Microbiological Evaluation of Complicated Intra-abdominal Infections in Adults, Children, and Pregnant People. (2024) · Primary guideline“A complicated intra-abdominal infection (cIAI) extends beyond the hollow viscus of origin into the peritoneal space or an otherwise sterile region of the abdominal cavity and is associated with peritonitis with or without abscess formation.”
3. Diagnosis and Treatment of Adults with Community-acquired Pneumonia (ATS/IDSA). Am J Respir Crit Care Med. (2019) · Primary guideline
4. Complicated urinary tract infections: New guidelines Q&A. (2025) · Guideline-derived“To optimize the selection of empiric antibiotics for patients with suspected cUTI, we recommend clinicians follow these four steps: Assess the severity of illness (to determine the risk/benefit of narrower spectrum antibiotic selection). Consider patient-specific risk factors for resistant uropathogens. Evaluate other patient-specific considerations (focusing on minimizing risk of adverse events). For patients with sepsis, consult a relevant local antibiogram if available.”
5. The effectiveness of intravenous (IV) to oral (PO) antibiotic switch (IVOS) interventions in managing community- and hospital-acquired pneumonia — a systematic review. (2026) · Systematic review“One of the aims of AMS is to ensure that patients receive the 'right' antimicrobial at the correct dose, via the most appropriate route, for an optimal duration of time.”
6. Systematic review of ceftaroline fosamil in the management of patients with methicillin-resistant Staphylococcus aureus pneumonia. · Systematic review“For patients with HAP/VAP, prior antimicrobial therapy within 90 days is considered a risk factor for MRSA involvement.”