Can precision antibiotic prescribing help prevent the spread of carbapenem-resistant organisms in the hospital setting?

Carbapenem-resistant organisms (CROs)—including carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA)—are rising globally and pose a major threat due to limited treatment options and high mortality (up to 50%). CRE can be carbapenemase-producing (CP-CRE) or non-CP-CRE, with CP-CRE particularly problematic due to plasmid-mediated horizontal transfer. CRO transmission is common in hospitals and entails substantial direct and indirect costs. Core infection prevention strategies include surveillance, hygiene, isolation, stewardship, decolonization, and environmental measures. Antibiotic stewardship emphasizes reducing inappropriate use, optimization, diagnostics, and programme measurement; reductions in carbapenem use are associated with decreases in CRE, CRPA, and CRAB. However, widespread ESBL-producing Enterobacterales (ESBL-E) have driven increased carbapenem use. The paper explores whether precision prescribing—tailoring agent selection, dosing, and duration—can help prevent CRO emergence and transmission in hospitals.

The review synthesizes evidence on how antibiotic selection, dosing, and duration influence CRO emergence, and evaluates carbapenem-sparing strategies for ESBL-E. - Agent selection and resistance: A meta-analysis (Sulis et al.) found carbapenem exposure is the strongest risk factor for CRO colonization/infection. Associations (ORs) include CRPA 3.2 (95% CI 2.5–4.2), CRE 2.5 (2.2–2.7), CRAB 2.2 (1.8–2.6). Other classes associated with CRO include lincosamides, polymyxins, tigecycline, linezolid, 4th-gen cephalosporins, glycopeptides, daptomycin, macrolides, fluoroquinolones, and piperacillin/tazobactam, though confounding is substantial and many analyses are at population level. Machine learning may help disentangle patient-level effects but CRO-specific models are lacking. - Carbapenem agent differences: Any carbapenem can select for CRE; ertapenem appears least selective within Enterobacterales and is not associated with CRPA/CRAB emergence in several studies. However, stewardship strategies substituting group 2 carbapenems with ertapenem did not consistently reduce CRO rates. - Combination therapy: While combination therapy suppresses resistance in mycobacterial infections, clinical data in P. aeruginosa are mixed; early studies suggested delay of resistance with beta-lactam plus aminoglycoside, but later trials/meta-analyses show no clear benefit and toxicity concerns. Fluoroquinolone plus beta-lactam combinations lack clinical data for resistance suppression. - Dosing and resistance: Resistance selection often follows an inverted-U curve relative to exposure; standard clinical exposures may maximize selection. In P. aeruginosa, CRPA emerged in ~35% during carbapenem therapy without necessarily causing failure, suggesting higher PK/PD targets may suppress resistance (not necessarily improve outcomes). For Enterobacterales, exposures for maximal kill align with resistance suppression; CRE and CRAB rarely emerge during therapy (<1%). Systemic exposure can still drive gut resistome changes even with low biliary excretion agents; higher PK/PD targets did not consistently reduce resistance emergence in commensals and might amplify resistance genes (e.g., ceftriaxone). - Duration: Longer antibiotic courses correlate with increased CRO acquisition (e.g., per-day increases with BL-BLIs/carbapenems/fluoroquinolones for CRE; high RRs for CRAB with prolonged fluoroquinolones/cephalosporins/carbapenems). Early carbapenem de-escalation reduced CRAB acquisition and trended to lower CRE/CRPA. A resistome substudy found 7 vs 14 days did not reduce carbapenem-resistance genes in gut microbiota. - Carbapenem-sparing options in ESBL-E: For cystitis/urinary infections without bacteremia, fluoroquinolones and TMP-SMX are options; nitrofurantoin, piperacillin/tazobactam, amoxicillin/clavulanate, cefepime may be used for cystitis. Outside the urinary tract, carbapenems remain preferred. Piperacillin/tazobactam shows variable in vivo activity due to inoculum effect; the MERINO RCT failed to show non-inferiority versus meropenem for ceftriaxone-non-susceptible E. coli/K. pneumoniae bacteremia, partly due to susceptibility misclassification; ongoing trials are evaluating extended infusion regimens. Cephamycins may be options in non-severe infections but are limited by AmpC. Aminoglycosides may be effective for bacteremia (with nephrotoxicity considerations). Temocillin shows promise (high cure rates in observational studies; trial ongoing). Ertapenem is active vs ESBL-E but not Pseudomonas/Acinetobacter; generally not recommended empirically in severe sepsis/bacteremia, though some retrospective data suggest comparable mortality. - Dosing optimization: Approaches include nomograms and therapeutic drug monitoring (TDM). Beta-lactam TDM is recommended in critically ill patients but adoption is limited due to assay complexity and turnaround times. Emerging biosensors and point-of-care/rapid assays may enable timely dose adjustments. - Shorter effective durations: Multiple RCTs support shorter courses: 7 days for uncomplicated Gram-negative bacteremia; ≤7 days for pyelonephritis (with caveats in complicated cases); 4–8 days for intra-abdominal infections with adequate source control; 8 days for VAP (with higher recurrence in non-fermenters).

Narrative review. The authors summarize and synthesize published evidence (meta-analyses, randomized trials, observational studies, in vitro/PK-PD studies) on the impact of antibiotic selection, dosing, and duration on the emergence and transmission of carbapenem-resistant organisms, and appraise carbapenem-sparing strategies for ESBL-producing Enterobacterales. No explicit systematic search strategy, databases, inclusion/exclusion criteria, or formal risk-of-bias assessment are described. The review defines CRO emergence as isolation of CRO from any specimen during or after antibiotic exposure (distinct from resistance causing treatment failure to the same agent during the same infection).

- Carbapenem exposure is the strongest risk factor for CRO colonization/infection (meta-analysis): CRPA OR 3.2 (95% CI 2.5–4.2); CRE OR 2.5 (2.2–2.7); CRAB OR 2.2 (1.8–2.6). - Other antibiotics associated with CRO include lincosamides (e.g., OR 2.4 for CRE), polymyxins (OR 2.4 for CRE), tigecycline (OR 2.4 for CRE), linezolid (OR 2.1 for CRE), 4th-generation cephalosporins (OR ~1.7–2.0), glycopeptides (OR ~1.5–1.9), daptomycin (OR 1.8 for CRE), macrolides (OR 1.6 for CRE), fluoroquinolones (OR ~1.4–1.9), and piperacillin/tazobactam (OR ~1.3–1.5), acknowledging confounding. - Among carbapenems, ertapenem appears least selective for Enterobacterales and is not associated with CRPA/CRAB emergence, but stewardship programs substituting broad-spectrum carbapenems with ertapenem did not reliably reduce CRO rates. - Combination therapy to suppress resistance shows limited clinical benefit in Gram-negatives; aminoglycoside combinations raise toxicity concerns; clinical evidence for beta-lactam–fluoroquinolone combinations in resistance suppression is lacking. - Resistance selection vs exposure follows an inverted-U; CRPA emerged during carbapenem therapy in ~35% of cases without necessarily causing failure. Higher PK/PD targets may suppress resistance in P. aeruginosa; for Enterobacterales, exposures for maximal kill also suppress resistance, and CRE/CRAB rarely emerge during therapy (<1%). Systemic antibiotics can still amplify gut resistome elements. - Longer antibiotic duration increases CRO acquisition risk (e.g., per-day increases with BL-BI/carbapenems/fluoroquinolones for CRE; markedly elevated RRs for CRAB with prolonged fluoroquinolones/cephalosporins/carbapenems). Early carbapenem de-escalation reduced CRAB acquisition and shortened carbapenem duration by 2 days. - ESBL-E carbapenem-sparing options: For cystitis/UTI without bacteremia, fluoroquinolones or TMP-SMX (and in some cases nitrofurantoin, piperacillin/tazobactam, amoxicillin/clavulanate, cefepime) are options; outside UTI, carbapenems remain preferred. Piperacillin/tazobactam failed non-inferiority vs meropenem in MERINO for ESBL bacteremia (confounded by susceptibility misclassification); extended-infusion trials are ongoing. Cephamycins/aminoglycosides/temocillin are potential alternatives in selected contexts. - Dosing optimization: Nomograms for continuous-infusion meropenem suggest 3 g/day sufficient for susceptible organisms in normal renal function; beta-lactam TDM in critically ill improves target attainment and is associated with better survival, though direct outcome benefits remain unproven and adoption is limited by assay/logistics; biosensors/rapid assays may facilitate real-time dosing. - Shorter courses are effective and safe for many Gram-negative infections: 7 days for uncomplicated bacteremia; ≤7 days for pyelonephritis (with caution in complicated cases); 4–8 days for intra-abdominal infections with source control; 8 days for VAP with higher recurrence in non-fermenters.

The evidence indicates precision prescribing can mitigate the emergence and spread of CROs in hospitals. The most effective approach is avoiding carbapenems when equally effective alternatives exist, especially for ESBL-E urinary infections, thereby reducing the strongest selective pressure. When carbapenems are necessary, optimizing PK/PD exposure for efficacy and minimizing treatment duration can limit resistance selection without compromising outcomes. However, resistance dynamics are complex, influenced by patient-level factors, sites of infection, collateral selection in the gut, and co-administered agents. Routine beta-lactam TDM and advanced dosing tools (e.g., Bayesian software) can improve target attainment, but practical barriers (assay availability, turnaround) limit widespread use; emerging biosensors and point-of-care assays offer potential solutions. Combination therapy does not consistently suppress resistance in Gram-negative infections and may increase toxicity, suggesting selective use. Overall, integrating targeted agent selection, appropriate dosing, and shortest effective durations into stewardship and infection prevention strategies addresses the research question by providing actionable levers to reduce CRO selection pressure and transmission risk.

Precision antibiotic prescribing—choosing alternative non-carbapenem agents with comparable efficacy, optimizing dosing to achieve PK/PD targets, and prescribing the shortest effective duration—can help prevent carbapenem-resistant organisms and associated hospital-acquired infections and should be embedded in infection prevention and control strategies. More research is needed to evaluate the impact of specific carbapenem-sparing regimens on CRO emergence, to determine optimal empirical and targeted therapy for ESBL-E, and to develop and implement rapid technologies for antibiotic concentration measurement to enable timely dose adjustments.

- Narrative review without a stated systematic search strategy or formal quality/risk-of-bias assessment limits completeness and may introduce selection bias. - Many associations between antibiotic exposure and CRO emergence are derived from population-level data with substantial confounding (e.g., illness severity, co-therapies, colonization pressure); patient-level causal inference is limited. - Evidence for combination therapy to suppress resistance in Gram-negatives is mixed, with limited high-quality clinical data and toxicity concerns. - Data on the comparative resistance selection pressure of individual carbapenems (e.g., ertapenem) are observational; stewardship substitutions have not consistently reduced CROs. - PK/PD-based resistance suppression strategies may not translate to clinical benefit and can have unintended effects on the gut resistome; clinical validation is limited. - TDM for beta-lactams is not widely available; logistical constraints (assay complexity, turnaround) hinder real-time dose optimization in routine care. - Several clinical trials informing duration or carbapenem-sparing strategies exclude patients with severe infections, CRO infections, or complex comorbidities, limiting generalizability.