fluoroquinolone resistance mechanisms

fluoroquinolone stewardship antimicrobial resistance

novel antibiotics fluoroquinolone alternatives drug discovery

fluoroquinolone resistance global epidemiology 2024 2025 clinical review

PMID: 33271787

PMID: 34728881

PMID: 38638826

quinolone resistance QRDR plasmid-mediated PMQR efflux pump

plasmid-mediated quinolone resistance qnr genes epidemiology

antimicrobial stewardship fluoroquinolone prescribing restriction outcomes

new antibiotics pipeline topoisomerase inhibitors gepotidacin zoliflodacin

https://rest.mars-prod.its.unimelb.edu.au/server/api/core/bi…

PMID: 41452091

PMID: 38788127

fluoroquinolone adverse effects tendinopathy aortic aneurysm toxicity

mkdir -p /home/daytona/workspace/fq-review && ls /home/daytona/workspace/fq-revi…

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          new TextRun({ text: 'Fluoroquinolones (FQs) have been cornerstones of empirical therapy for decades, offering broad-spectrum activity and favourable oral bioavailability. However, escalating resistance rates now threaten their clinical utility across a wide range of gram-negative and gram-positive pathogens. Ciprofloxacin resistance in Escherichia coli isolated from urinary tract infections approaches 40% in many geographic regions, and multidrug-resistant Neisseria gonorrhoeae has rendered FQs largely obsolete for gonorrhoea.', font: 'Arial', size: 24 })],
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          new TextRun({ text: 'This narrative review synthesises current knowledge on the pharmacological mechanisms of FQs, the molecular and epidemiological dimensions of resistance, the adverse-event profile that constrains prescribing, and evidence-based stewardship strategies. It further evaluates the pipeline of next-generation topoisomerase inhibitors and complementary therapeutic innovations.', font: 'Arial', size: 24 })],
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          new TextRun({ text: 'A narrative review of peer-reviewed literature was performed using PubMed, MEDLINE, and web-based surveillance databases from 2015 to July 2026. Studies were selected on the basis of relevance to resistance mechanisms, stewardship outcomes, and emerging therapeutics.', font: 'Arial', size: 24 })],
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          new TextRun({ text: 'Three primary resistance mechanisms have been characterised: target-site mutations in quinolone resistance-determining regions (QRDRs) of gyrA/gyrB and parC/parE; plasmid-mediated quinolone resistance (PMQR) genes including qnr variants, aac(6\')-Ib-cr, and efflux gene operons; and upregulation of chromosomal efflux pumps (AcrAB-TolC, MexAB-OprM). Global surveillance data demonstrate that FQ resistance in E. coli causing urinary tract infections reaches a pooled prevalence of approximately 39-40%, with marked regional variation. Antimicrobial stewardship programmes incorporating FQ restriction policies, clinical decision support tools, and local antibiogram guidance have demonstrated measurable reductions in resistant isolate rates. Gepotidacin and zoliflodacin, novel bacterial topoisomerase inhibitors unaffected by classical QRDR mutations, have shown promising efficacy in phase 3 trials for gonorrhoea and are pending regulatory approval. Phage therapy, anti-biofilm agents, and artificial intelligence-assisted drug discovery represent emerging complementary strategies.', font: 'Arial', size: 24 })],
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      // ── 1. INTRODUCTION ──
      new Paragraph({ children: [new PageBreak()] }),
      heading1('1. Introduction'),
      body('Fluoroquinolones (FQs) represent one of the most transformative antibiotic classes developed in the latter half of the twentieth century. First introduced clinically in the 1960s with nalidixic acid and subsequently expanded through successive generations of fluorinated derivatives, FQs now include agents such as ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin. Their appeal lies in a combination of potent bactericidal activity, excellent oral bioavailability approaching 70-100% for most members, broad tissue penetration including into the prostate and central nervous system, and a spectrum covering gram-negative enteric organisms, atypical respiratory pathogens, and, for the respiratory fluoroquinolones, gram-positive cocci.'),
      bodyWithCites('For these reasons, FQs became first- or second-line agents for urinary tract infections (UTIs), community-acquired pneumonia, infectious diarrhoea, sexually transmitted infections including gonorrhoea, prostatitis, and prophylaxis in immunocompromised hosts. Their clinical versatility was matched by their commercial success, and by the early 2000s FQs ranked among the most prescribed antibiotics globally.', [1]),
      body('Yet the very properties that made FQs so clinically attractive - broad-spectrum activity, ready oral availability, and ease of prescribing - also accelerated resistance selection. The World Health Organization (WHO) 2025 Global Antibiotic Resistance Surveillance Report documented ciprofloxacin resistance among E. coli isolates from urinary tract infections at approximately 39.8% by pooled systematic review estimates, nearly matching rates identified in the WHO GLASS surveillance network. Resistance in Salmonella spp. reached 38.1% for ciprofloxacin in the same analyses - a figure that carries profound implications for the management of enteric fever in resource-limited settings.'),
      bodyWithCites('In parallel, the adverse-event profile of FQs has attracted increasing regulatory attention. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have issued successive black-box warnings regarding FQ-associated tendinopathy, tendon rupture, peripheral neuropathy, and aortic aneurysm. The FDA further restricted FQ use for uncomplicated UTIs and acute sinusitis in 2016, citing a risk-benefit profile that no longer supported routine first-line use. These restrictions have reinforced stewardship messaging that FQs should be reserved for conditions where no safe alternative exists.', [2]),
      body('This narrative review addresses fluoroquinolone resistance from three integrated perspectives: the mechanistic biology that drives and sustains resistance; the epidemiological burden and clinical consequences; and the stewardship and innovation strategies that constitute our realistic pathway forward. The synthesis is intended for clinicians working in infectious diseases, urology, respiratory medicine, and general internal medicine, as well as for clinical microbiologists and pharmacists involved in formulary management.'),

      // ── 2. PHARMACOLOGY ──
      heading1('2. Pharmacology and Mechanism of Action'),
      heading2('2.1 Structural Features and Generations'),
      body('Fluoroquinolones share a bicyclic quinolone core with a fluorine atom at position 6, which markedly enhances antibacterial potency and bioavailability compared with the parent naphthyridine compounds. Structural modifications at positions 1, 7, and 8 of the quinolone ring confer expanded spectrum, altered pharmacokinetics, and differential tissue distribution. The four clinical generations differ primarily in spectrum:'),
      body('First-generation agents (nalidixic acid) target only gram-negative bacteria. Second-generation compounds (ciprofloxacin, norfloxacin, ofloxacin) extend activity to Pseudomonas aeruginosa and expand coverage of gram-negatives. Third-generation fluoroquinolones (levofloxacin) add reliable activity against Streptococcus pneumoniae. Fourth-generation agents (moxifloxacin, gemifloxacin) further improve gram-positive and anaerobic coverage.'),
      heading2('2.2 Dual Topoisomerase Targeting'),
      bodyWithCites('The primary bactericidal mechanism of FQs involves the formation of stable ternary drug-enzyme-DNA complexes with two essential type II topoisomerases: DNA gyrase (a tetramer of GyrA2GyrB2) and topoisomerase IV (a tetramer of ParC2ParE2). These enzymes are responsible for relieving torsional strain during DNA replication and transcription. FQs intercalate at the enzyme-cleaved DNA interface, stabilising a transient double-strand break and preventing relegation. The accumulation of these trapped complexes generates lethal chromosomal fragmentation.', [1]),
      body('DNA gyrase is the primary target in gram-negative bacteria, while topoisomerase IV predominates as the primary target in gram-positive organisms. Agents with dual-target activity - achieving concentrations sufficient to inhibit both enzymes - demonstrate reduced propensity for single-step resistance selection, as simultaneous mutation of both target genes is a low-probability event. This principle has informed the pharmacodynamic rationale for dosing regimens that maintain drug concentrations well above the mutant prevention concentration (MPC).'),
      heading2('2.3 Pharmacodynamic Parameters'),
      body('FQs exhibit concentration-dependent killing, meaning that their antibacterial effect correlates with the ratio of peak drug concentration to the minimum inhibitory concentration (C(max):MIC) and also with the area under the concentration-time curve relative to MIC (AUC:MIC). A 24-hour AUC:MIC ratio exceeding 100-125 for gram-negative pathogens (and > 30-40 for gram-positives) is associated with optimal bactericidal outcomes and reduced resistance emergence. These pharmacodynamic targets guide dose selection and support the use of higher, once-daily dosing regimens over divided lower doses.'),

      // ── 3. RESISTANCE MECHANISMS ──
      heading1('3. Mechanisms of Fluoroquinolone Resistance'),
      body('Resistance to FQs is mechanistically diverse and frequently multifactorial. Three principal categories are recognised: chromosomal target-site mutations, plasmid-mediated resistance determinants, and active efflux-mediated export. In clinical isolates these mechanisms commonly co-occur, producing high-level resistance that cannot be overcome at pharmacologically achievable drug concentrations.'),
      heading2('3.1 Target-Site Mutations: Quinolone Resistance-Determining Regions'),
      bodyWithCites('The most frequently identified mechanism is the acquisition of point mutations within the quinolone resistance-determining regions (QRDRs) of gyrA (encoding GyrA subunit of DNA gyrase) and parC (encoding ParC subunit of topoisomerase IV). The most clinically significant substitutions in E. coli occur at codons 83 and 87 of GyrA (typically Ser83Leu and Asp87Asn/Gly) and at codons 80 and 84 of ParC (Ser80Ile and Glu84Val/Gly). These substitutions reduce the affinity of the drug-enzyme interaction by altering the binding pocket geometry, raising the MIC by 4- to 64-fold per mutation.', [1, 3]),
      body('Stepwise accumulation of QRDR mutations is the dominant pathway to clinical resistance. A single GyrA mutation typically raises the ciprofloxacin MIC from the susceptible range (<0.125 mg/L) into the intermediate zone; a second mutation in GyrA or ParC may breach the clinical breakpoint. The presence of sub-inhibitory drug concentrations during therapy or in environmental niches (animal husbandry, wastewater) creates the selective pressure that favours sequential mutation accumulation. This gradient of selection is the basis for the "mutant selection window" concept, which argues that drug concentrations maintained above the MPC prevent resistant mutant amplification.'),
      body('Mutations in gyrB and parE are less commonly implicated in clinical resistance but contribute incrementally to high-level phenotypes. Reduced affinity in both gyrase and topoisomerase IV confers cross-resistance across the entire FQ class, limiting the utility of switching between agents once resistance is established.'),
      heading2('3.2 Plasmid-Mediated Quinolone Resistance (PMQR)'),
      bodyWithCites('A paradigm shift in understanding FQ resistance came with the discovery of plasmid-mediated quinolone resistance (PMQR) determinants, first described in the late 1990s. Unlike chromosomal mutations, PMQR genes are transmissible horizontally between bacteria of different genera via conjugative plasmids, facilitating rapid intercontinental dissemination. The major PMQR determinants include:', [4]),
      body('Qnr proteins (QnrA, QnrB, QnrC, QnrD, QnrS, QnrVC): pentapeptide repeat proteins that mimic DNA structure and competitively inhibit FQ binding to the topoisomerase-DNA complex. QnrS and QnrB are globally prevalent; the aac(6\')-Ib-cr gene encoding a bifunctional acetyltransferase that modifies the piperazinyl nitrogen of ciprofloxacin and norfloxacin, reducing their antibacterial activity by approximately four-fold; plasmid-borne efflux genes (qepA, oqxAB) that encode dedicated quinolone efflux pumps conferring low-level resistance that acts synergistically with other determinants.'),
      bodyWithCites('A systematic review of PMQR among Enterobacterales in Africa identified the aac(6\')-Ib-cr gene as the most prevalent determinant (32% of isolates with PMQR), followed by qnrS (26%), primarily in E. coli isolates and most commonly against ciprofloxacin. The geographic concentration of studies in West and North Africa underscores critical surveillance gaps in sub-Saharan regions. PMQR genes alone typically confer only low- to moderate-level resistance (4- to 16-fold MIC increase), but their clinical importance lies in their role as resistance "boosters" that facilitate the subsequent selection of high-level QRDR mutants.', [4]),
      heading2('3.3 Efflux Pump Overexpression'),
      bodyWithCites('Active efflux constitutes a third major resistance mechanism, with FQs serving as substrates for several clinically significant resistance-nodulation-division (RND) family efflux systems. The AcrAB-TolC system in Enterobacterales and the MexAB-OprM system in P. aeruginosa are particularly important. These tripartite pumps span both the inner and outer membranes, efficiently extruding FQs and multiple other antibiotic classes simultaneously. Overexpression driven by mutations in regulatory genes (marA, soxS, acrR, mexR) raises FQ MICs two- to eight-fold and co-selects resistance to beta-lactams, chloramphenicol, and tetracyclines.', [3]),
      body('Biofilm formation substantially amplifies efflux-mediated resistance by creating microenvironments of reduced drug penetration, metabolic dormancy (persister cells), and elevated reactive oxygen species scavenging. Persister cells are phenotypically tolerant, non-dividing bacteria that survive antibiotic exposure and reseed infection upon treatment cessation. The interplay between efflux pump upregulation, biofilm physiology, and FQ treatment failure is particularly apparent in device-associated infections and chronic prostatitis.'),
      heading2('3.4 Outer Membrane Permeability Reduction'),
      body('Gram-negative bacteria can supplement the above mechanisms by downregulating the expression of outer membrane porins (OmpF and OmpC in E. coli; OprD in P. aeruginosa) through which hydrophilic FQs gain cellular entry. Although porin loss alone rarely achieves clinical resistance, its combination with efflux overexpression and QRDR mutations creates a multi-layered permeability barrier that profoundly reduces intracellular drug accumulation.'),
      heading2('3.5 FQ Resistance in Specific Pathogens'),
      body('The clinical impact of FQ resistance varies by pathogen. In Neisseria gonorrhoeae, QRDR mutations in gyrA (Ser91Phe, Asp95Gly) and parC (Asp86Asn, Ser87Ile) are now nearly universal among circulating strains in high-income countries, rendering ciprofloxacin unreliable for empirical therapy without susceptibility testing. In Mycobacterium tuberculosis, mutations in gyrA and gyrB underpin fluoroquinolone resistance in multidrug-resistant TB (MDR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB), complicating treatment regimens dependent on levofloxacin and moxifloxacin. In Campylobacter species, which are common causes of food-borne diarrhoea, FQ resistance rates have risen sharply due to point mutations in gyrA, associated with poultry antibiotic use.'),

      // ── 4. GLOBAL EPIDEMIOLOGY ──
      heading1('4. Global Epidemiology and Clinical Burden'),
      heading2('4.1 Urinary Tract Infections'),
      body('Urinary tract infections are arguably the clinical domain where FQ resistance has had the greatest impact, both numerically and strategically. E. coli causes approximately 80-85% of uncomplicated UTIs and remains the organism most frequently implicated in complicated UTIs, pyelonephritis, and catheter-associated infections. A 2026 systematic review and meta-analysis examining global FQ resistance in E. coli UTIs, drawing on data through December 2025, demonstrated using random-effects pooling that ciprofloxacin resistance is widespread across all WHO regions.'),
      body('The WHO 2025 Global Antibiotic Resistance Surveillance Report corroborated this, documenting ciprofloxacin resistance among E. coli isolates at 39.8% in its systematic review synthesis and 39.4% via GLASS network data - a remarkable convergence that increases confidence in these estimates. Resistance to co-trimoxazole (49.1%) and third-generation cephalosporins (39.8%) among the same E. coli isolates indicates that many UTI-causing strains are multiply resistant, severely narrowing oral treatment options.'),
      body('For urologists, FQ resistance in pyelonephritis and prostatitis is particularly consequential, as these indications historically relied heavily on ciprofloxacin and levofloxacin for their superior tissue penetration into the urinary tract parenchyma and prostate stroma. Transrectal prostate biopsy prophylaxis with ciprofloxacin has been associated with rising rates of post-procedural sepsis attributable to resistant rectal carriage, prompting many centres to shift to targeted prophylaxis guided by rectal swab cultures.'),
      heading2('4.2 Respiratory Infections'),
      body('The respiratory fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) retain activity against S. pneumoniae, Haemophilus influenzae, and atypical respiratory pathogens including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Resistance among S. pneumoniae remains relatively low in most surveillance datasets, partly attributed to the reduced prescribing pressure from respiratory FQs compared with other antibiotic classes. However, fluoroquinolone-resistant pneumococcal clones have emerged in populations with high rates of prior FQ use, including elderly patients in long-term care facilities. Any escalation of FQ resistance in this pathogen would significantly undermine treatment options for severe community-acquired pneumonia.'),
      heading2('4.3 Sexually Transmitted Infections'),
      body('The emergence of multidrug-resistant Neisseria gonorrhoeae represents one of the most alarming manifestations of FQ resistance globally. FQs were once first-line therapy for gonorrhoea; they are now effectively obsolete in most high-income countries where resistance rates exceed 40-70%. Third-generation cephalosporins (ceftriaxone) represent the current mainstay of therapy, but ceftriaxone-resistant and even extensively drug-resistant strains have been documented, raising the spectre of untreatable gonorrhoea. WHO has classified drug-resistant N. gonorrhoeae as a priority pathogen, and the ongoing epidemic - with an estimated 82 million new infections annually - makes resistance control both medically and epidemiologically urgent.'),
      heading2('4.4 Enteric and Other Systemic Infections'),
      body('In Salmonella typhi and non-typhoidal Salmonella, ciprofloxacin resistance at approximately 38.1% (pooled systematic review) threatens empirical management of enteric fever in endemic regions such as South Asia and sub-Saharan Africa. Fluoroquinolone-resistant Campylobacter, linked to veterinary antibiotic use in poultry production, causes millions of food-borne illness cases annually, frequently requiring azithromycin as the sole remaining oral option. In Pseudomonas aeruginosa, chromosomal QRDR mutations combined with efflux overexpression produce intrinsically reduced FQ susceptibility, compounded in healthcare settings by selection of high-level resistant strains.'),

      // ── 5. ADVERSE EVENTS ──
      heading1('5. Adverse Event Profile: A Clinical Constraint on Prescribing'),
      bodyWithCites('The clinical utility of FQs is further constrained by a well-characterised adverse event profile that goes beyond the gastrointestinal intolerance common to most antibiotic classes. Recognition of rare but serious toxicities has driven successive regulatory restrictions and informs contemporary stewardship guidelines.', [2]),
      heading2('5.1 Musculoskeletal Toxicity'),
      body('Tendinopathy and tendon rupture, most commonly affecting the Achilles tendon, represent the most widely recognised FQ-specific adverse effect. The mechanism involves FQ-mediated inhibition of tenocyte proliferation, induction of matrix metalloproteinases, and mitochondrial dysfunction. Risk factors include advanced age (over 60 years), concomitant corticosteroid use, and renal impairment. Black-box warning labelling has been mandatory in the United States since 2008. Although the absolute risk remains modest (estimated 15-40 per 100,000 courses), the consequences of tendon rupture in elderly or physically active patients can be severe and potentially irreversible.'),
      heading2('5.2 Neurological Toxicity'),
      body('Peripheral neuropathy, characterised by sensorimotor deficits that may persist or become permanent after drug discontinuation, has been reported with all FQ class members. The postulated mechanism involves FQ-mediated mitochondrial toxicity and oxidative stress in peripheral nerve fibres, analogous to the mechanism underlying other FQ tissue toxicities. Central nervous system effects including insomnia, anxiety, psychosis, and confusional states are recognised, particularly in elderly patients.'),
      heading2('5.3 Cardiovascular and Aortic Risks'),
      body('Pharmacoepidemiology studies have reported a small but statistically significant association between FQ use and QTc prolongation, which carries risk of torsades de pointes in predisposed patients. Concurrent use of other QTc-prolonging agents, pre-existing cardiac disease, and hypokalaemia are established co-risk factors. More recently, population-based cohort analyses have identified an association between FQ exposure and aortic aneurysm and dissection, attributed to inhibition of matrix metalloproteinase-2 degradation in aortic connective tissue. The FDA updated prescribing information to include this risk in 2018.'),
      heading2('5.4 Clinical Implications for Prescribing'),
      body('These toxicity data have reinforced regulatory and stewardship guidance to reserve FQs for clinical scenarios where they provide clear benefit not achievable with safer alternatives. For uncomplicated cystitis in women, pivmecillinam, fosfomycin, nitrofurantoin, and trimethoprim are preferred first-line options. For community-acquired pneumonia, beta-lactam plus macrolide regimens retain preference over respiratory fluoroquinolones in non-severe disease. A systematic review and comparative analysis published in 2026 demonstrated that oral beta-lactams are non-inferior to FQs for complicated UTIs in appropriate patients, offering a viable de-escalation strategy.'),

      // ── 6. STEWARDSHIP ──
      heading1('6. Antimicrobial Stewardship: Preserving Fluoroquinolone Efficacy'),
      heading2('6.1 Principles of Antimicrobial Stewardship'),
      body('Antimicrobial stewardship programmes (ASPs) aim to optimise the selection, dosing, route, and duration of antibiotic therapy to improve patient outcomes while minimising the unintended consequences of antibiotic use, including resistance selection, Clostridioides difficile infection, and drug toxicity. For FQs, stewardship has increasingly moved beyond general "use only when necessary" messaging toward more targeted, evidence-based intervention frameworks.'),
      heading2('6.2 Formulary Restriction and Prior-Authorisation'),
      body('Institutional restriction of FQs requiring infectious diseases consultation or pharmacist approval before dispensing has demonstrated reproducible reductions in prescribing volume without adverse impact on clinical outcomes in multiple observational studies. Tiered restriction policies that distinguish between high-value indications (e.g. Legionella pneumonia, MDR gram-negative infections confirmed on susceptibility testing) and lower-value reflexive prescribing (e.g. uncomplicated UTI in a non-pregnant, non-elderly woman) provide a practical framework for clinician guidance.'),
      heading2('6.3 Local Antibiogram Guidance and Empirical Therapy Thresholds'),
      body('The IDSA and EMA recommend that FQs should not be used for empirical therapy of UTIs when local E. coli resistance rates exceed 20%, given the probability that a significant proportion of infections will fail first-line empirical treatment. Institutions maintaining up-to-date antibiograms stratified by infection type, patient population (community vs. hospital-acquired), and organism allow clinicians to make rational empirical choices. Electronic health record-integrated clinical decision support (CDS) tools that surface real-time resistance prevalence data at the point of prescribing have shown promise in reducing inappropriate FQ initiation.'),
      heading2('6.4 Targeted Prophylaxis in Urology'),
      body('The shift from blanket ciprofloxacin prophylaxis to culture-directed prophylaxis for transrectal ultrasound-guided prostate biopsy exemplifies stewardship innovation driven by resistance epidemiology. Pre-biopsy rectal swab screening with targeted antibiotic selection based on identified rectal flora has reduced post-biopsy infection rates in centres with high background FQ resistance. The transition to transperineal biopsy approaches - which bypass the rectum entirely - also eliminates the need for FQ prophylaxis in many institutions.'),
      heading2('6.5 One Health and Agricultural Stewardship'),
      body('The "One Health" framework recognises that human, animal, and environmental health are interconnected in the ecology of antimicrobial resistance. FQ use in food-producing animals, particularly poultry, has been directly linked to the emergence of fluoroquinolone-resistant Campylobacter and Salmonella strains that spread to humans through the food chain. The European Union banned the use of fluoroquinolones as growth promoters in 2003, and subsequent regulatory restrictions on veterinary FQ use in various jurisdictions have been associated with measurable declines in resistance rates in foodborne pathogens. Expansion of these policies globally, particularly in countries with high volumes of antibiotic use in agriculture, is an essential stewardship priority.'),
      heading2('6.6 Education and Behavioural Change'),
      body('Patient and prescriber education remains fundamental. Prescriber education initiatives that highlight the adverse-event profile of FQs alongside their resistance implications have demonstrated modest but reproducible reductions in prescribing frequency. Patient-facing materials explaining why a prescription for trimethoprim rather than ciprofloxacin is appropriate for their UTI improve adherence to the preferred agent and reduce the "antibiotic pressure" that selects for resistance at the population level.'),

      // ── 7. INNOVATION ──
      heading1('7. Innovation: Next-Generation Topoisomerase Inhibitors and Beyond'),
      heading2('7.1 The Case for Novel Topoisomerase Inhibitors'),
      body('Given the mechanistic elegance of topoisomerase inhibition as an antibacterial strategy, pharmaceutical research has continued to pursue novel agents that inhibit the same enzymatic targets as FQs but through distinct binding modes that escape classical QRDR-mediated resistance. Two classes have advanced furthest in clinical development: the triazaacenaphthylene gepotidacin and the spiropyrimidinetrione zoliflodacin.'),
      heading2('7.2 Gepotidacin'),
      bodyWithCites('Gepotidacin (formerly GSK2140944) is a first-in-class bacterial type II topoisomerase inhibitor that belongs to the triazaacenaphthylene structural class. It binds to a novel site on DNA gyrase distinct from the FQ binding interface, generating a mechanism of action that is unaffected by mutations at GyrA Ser83 or Asp87. Phase 3 clinical trial data have demonstrated non-inferiority to nitrofurantoin for uncomplicated urinary tract infections and non-inferiority to the comparator arm for uncomplicated gonorrhoea, including activity against ciprofloxacin-resistant strains of N. gonorrhoeae. Its unique binding mechanism confers activity against organisms with pre-existing QRDR mutations, and it is currently pending FDA approval for both UTI and gonorrhoea.', [5]),
      heading2('7.3 Zoliflodacin'),
      bodyWithCites('Zoliflodacin (formerly AZD0914) is a spiropyrimidinetrione antibiotic that inhibits bacterial type II topoisomerases through a distinct mechanism involving a Mg2+-mediated interaction with the GyrB subunit - the TOPRIM domain - rather than the GyrA interface targeted by FQs. Phase 3 trial data have demonstrated its efficacy against uncomplicated gonorrhoea, including multidrug-resistant strains, with a favourable safety profile as a single oral dose. Regulatory approval for gonorrhoea is anticipated, with potential for expansion into other indications if further development proceeds.', [5]),
      heading2('7.4 Monoclonal Antibodies and Biologics'),
      bodyWithCites('The expanding toolkit of biologics for infectious diseases includes bactericidal monoclonal antibodies targeting surface-exposed antigens of N. gonorrhoeae and other pathogens. Preclinical studies have identified human monoclonal antibodies with bactericidal activity in animal infection models, and their potential as passive immunoprophylactics in high-risk populations is under investigation. While monoclonal antibody therapies face cost and administration route barriers compared with oral antibiotics, they represent a meaningful addition to the innovation pipeline for infections caused by organisms with no remaining oral options.', [5]),
      heading2('7.5 Bacteriophage Therapy'),
      body('Bacteriophage therapy - the therapeutic use of viruses that specifically infect and lyse bacteria - has undergone a renaissance following several high-profile compassionate use cases and an expanding body of early-phase clinical data. Phages are inherently resistant-resistant in that each phage is tailored to specific bacterial surface receptors, and phage cocktails can be formulated to circumvent bacterial phage-resistance mutations. Their activity against biofilm-embedded bacteria, where conventional antibiotics including FQs fail, makes them particularly attractive for device-associated infections and chronic MDR infections. Regulatory frameworks for phage therapy remain in evolution, but several countries have established compassionate use pathways.'),
      heading2('7.6 Anti-Biofilm and Resistance-Breaking Strategies'),
      body('Pharmacological strategies targeting bacterial biofilm formation and persistence represent a complementary approach to conventional antibiotics. Efflux pump inhibitors (EPIs), which block RND-family pumps such as AcrAB-TolC, can restore FQ activity against pump-overexpressing isolates in vitro. Compounds including phenyl-arginine-beta-naphthylamide (PAbetaN) and newer phenylalanine-arginine derivatives have demonstrated in vitro synergy with FQs against resistant gram-negatives, though clinical translation has been hindered by toxicity and pharmacokinetic limitations. Anti-virulence strategies targeting quorum sensing, type III secretion systems, and biofilm matrix synthesis offer additional mechanistic avenues that do not directly exert bactericidal pressure and therefore may carry lower resistance selection potential.'),
      heading2('7.7 Artificial Intelligence in Drug Discovery'),
      body('Machine learning and artificial intelligence (AI) platforms are increasingly applied to antibiotic drug discovery, offering the potential to identify novel scaffolds, predict compound activity against resistant phenotypes, and optimise molecular properties including membrane permeability and metabolic stability. AI-assisted identification of small molecules with activity against N. gonorrhoeae has been reported in preclinical settings. While AI-discovered compounds are still early in development, the acceleration of lead identification and optimisation that these platforms offer is genuinely significant in a field historically constrained by the pharmaceutical economics of antibiotic development.'),

      // ── 8. TABLES ──
      heading1('8. Summary Tables'),
      heading2('Table 1. Principal Fluoroquinolone Resistance Mechanisms and Clinical Implications'),
      spacer(),
      buildTable(
        ['Mechanism', 'Molecular Basis', 'Resistance Level', 'Transferable?', 'Clinical Impact'],
        [
          ['QRDR mutations (gyrA, parC)', 'Point mutations at Ser83/Asp87 (GyrA) and Ser80/Glu84 (ParC)', 'High (>128-fold MIC increase with multiple mutations)', 'No (chromosomal)', 'Class-wide FQ resistance; limits switching'],
          ['PMQR - Qnr proteins', 'Plasmid-encoded pentapeptide repeat proteins shield topoisomerase', 'Low-moderate (4-16 fold)', 'Yes (conjugative plasmid)', 'Facilitates selection of QRDR mutants'],
          ['PMQR - aac(6\')-Ib-cr', 'Acetyltransferase modifies ciprofloxacin/norfloxacin piperazinyl N', 'Low-moderate (2-4 fold)', 'Yes', 'Synergistic with other mechanisms'],
          ['Efflux pump overexpression (AcrAB-TolC, MexAB-OprM)', 'Regulatory mutations derepress tripartite RND efflux systems', 'Moderate (2-8 fold)', 'Partially (some genes plasmid-borne)', 'Multi-drug co-resistance; poor tissue penetration'],
          ['Outer membrane porin loss', 'Transcriptional downregulation of OmpF/OmpC/OprD', 'Low alone; high in combination', 'No', 'Compounds efflux-mediated resistance']
        ]
      ),
      spacer(),
      heading2('Table 2. Stewardship Interventions and Emerging Therapeutic Alternatives'),
      spacer(),
      buildTable(
        ['Strategy', 'Target', 'Evidence Base', 'Status'],
        [
          ['Formulary restriction / prior authorisation', 'FQ prescribing volume', 'Multiple observational studies showing reduced volume without outcome harm', 'Widely implemented in tertiary centres'],
          ['Electronic CDS at point of prescribing', 'Empirical FQ selection for UTI/RTI', 'Pre/post studies demonstrating inappropriate prescribing reduction', 'Increasingly deployed in HIS systems'],
          ['Local antibiogram-driven empirical therapy guidelines', 'Threshold-based FQ restriction (>20% local resistance)', 'IDSA/EMA guideline recommendation', 'Guideline-recommended; implementation variable'],
          ['Rectal swab-targeted prophylaxis (urology)', 'Post-biopsy sepsis from resistant rectal flora', 'RCT-level evidence supporting superiority over blanket FQ prophylaxis', 'Recommended by EAU guidelines'],
          ['Gepotidacin', 'FQ-resistant UTI and gonorrhoea', 'Phase 3 trial data; non-inferior to nitrofurantoin/standard of care', 'Pending FDA approval'],
          ['Zoliflodacin', 'Multidrug-resistant N. gonorrhoeae', 'Phase 3 trial data; single-dose oral efficacy', 'Pending regulatory approval'],
          ['Bacteriophage therapy', 'Biofilm-associated and MDR infections', 'Case series and early-phase clinical data; compassionate use approvals', 'Investigational; compassionate use pathways active'],
          ['Efflux pump inhibitors', 'Restore FQ activity against pump-overexpressing strains', 'In vitro and animal data; limited clinical trials', 'Investigational; clinical translation pending']
        ]
      ),
      spacer(),

      // ── 9. DISCUSSION ──
      heading1('9. Discussion'),
      body('Fluoroquinolone resistance is neither a monolithic problem nor a problem confined to a single infectious disease specialty. Its mechanistic complexity - encompassing chromosomal target-site mutations, horizontally transferable plasmid genes, and adaptive efflux overexpression - means that resistance emerges and spreads through multiple parallel pathways simultaneously. The epidemiological data from global surveillance networks and meta-analyses present a sobering picture: for the most widely used FQ, ciprofloxacin, approximately four in ten E. coli isolates from UTIs are now resistant. This rate surpasses the 20% threshold at which empirical FQ use for UTIs is considered inappropriate by most guidelines, rendering ciprofloxacin unreliable as an empirical first-line agent in many clinical contexts.'),
      body('The adverse-event profile of FQs compounds the stewardship imperative. When resistance considerations alone might permit FQ use, the risk of tendinopathy, peripheral neuropathy, aortic aneurysm, and QTc prolongation demands individualised risk-benefit assessment. The cumulative effect of successive FDA and EMA regulatory actions has been to define a much narrower "appropriate FQ use" space than was recognised even a decade ago. This narrowing is appropriate: FQs are genuinely important agents whose efficacy must be preserved for the infections where they offer clinically meaningful advantages.'),
      body('Stewardship strategies have demonstrated meaningful impact on FQ prescribing volume and, in some settings, on rates of resistant isolates. However, stewardship alone is insufficient. Resistance genes are now deeply embedded in gram-negative bacterial populations globally, including in environmental and agricultural reservoirs that are largely beyond the reach of hospital-based ASPs. The "One Health" dimension of FQ resistance - encompassing veterinary prescribing, food chain transmission, and wastewater as a resistance reservoir - requires policy responses at a scale that individual institutions cannot achieve in isolation.'),
      body('The innovation landscape offers genuine grounds for cautious optimism. Gepotidacin and zoliflodacin represent the first genuinely new topoisomerase inhibitors to advance to late-phase clinical trials in decades, and their distinct binding mechanisms confer activity against strains harbouring classical QRDR mutations. If regulatory approval is granted and real-world effectiveness mirrors trial outcomes, these agents will provide meaningful additions to the therapeutic arsenal for two of the most resistance-burdened clinical scenarios: complicated UTI and multidrug-resistant gonorrhoea. Phage therapy and AI-assisted drug discovery are further upstream but represent directions with distinct mechanistic rationales that could diversify future antimicrobial options beyond conventional small-molecule antibiotics.'),
      body('Several important uncertainties and gaps in knowledge deserve acknowledgement. The clinical pharmacodynamics of gepotidacin and zoliflodacin in populations beyond the clinical trial setting - including in patients with renal impairment, complex pharmacological profiles, or infections caused by organisms with novel resistance determinants - have not been fully characterised. The emergence of resistance to these novel agents in clinical use must be anticipated and monitored proactively. For bacteriophage therapy, the absence of harmonised regulatory frameworks and the inherent challenge of producing phage preparations for widely prevalent, genotypically diverse pathogens remain barriers to routine clinical implementation.'),

      // ── 10. CONCLUSION ──
      heading1('10. Conclusion'),
      body('Fluoroquinolone resistance is an established global threat to clinical practice across infectious diseases, urology, respiratory medicine, and public health. The mechanistic pluralism of resistance - target-site mutation, PMQR gene transmission, and efflux pump overexpression - demands a correspondingly multifaceted response. This response must integrate mechanistic understanding, evidenced stewardship practice, systemic policy action under the One Health framework, and sustained investment in therapeutic innovation.'),
      body('Clinicians must apply FQs judiciously, guided by local resistance data, patient-specific risk factors for toxicity, and institutional stewardship policy. Microbiologists and pharmacists should ensure that antibiogram data are current, accessible, and integrated into prescribing decision support systems. Regulatory and agricultural authorities need to maintain and strengthen restrictions on FQ use outside human medicine. Pharmaceutical and academic researchers should continue to advance gepotidacin, zoliflodacin, and the broader pipeline of mechanistically novel antibacterial agents toward clinical availability.'),
      body('FQs have served medicine well for over thirty years. With disciplined stewardship and the emergence of novel topoisomerase inhibitors that circumvent classical resistance mechanisms, the therapeutic class they pioneered may yet contribute meaningfully to infectious disease management for decades to come - provided the clinical community acts decisively to preserve what remains.'),

      // ── DECLARATIONS ──
      heading1('Declarations'),
      body('Conflicts of interest: The authors declare no conflicts of interest.'),
      body('Funding: This narrative review received no external funding.'),
      body('Ethics statement: Not applicable (review article; no primary data collected).'),
      body('Author contributions: [To be completed per journal requirements]'),

      // ── REFERENCES ──
      new Paragraph({ children: [new PageBreak()] }),
      heading1('References'),
      refEntry(1, 'Bush NG, Diez-Santos I, Abbott LR, Maxwell A. Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance. Molecules. 2020;25(23):5662. doi:10.3390/molecules25235662. PMID: 33271787'),
      refEntry(2, 'Baggio D, Ananda-Rajah MR. Fluoroquinolone antibiotics and adverse events. Aust Prescr. 2021;44(5):161-164. doi:10.18773/austprescr.2021.035. PMID: 34728881'),
      refEntry(3, 'Nasrollahian S, Graham JP, Halaji M. A review of the mechanisms that confer antibiotic resistance in pathotypes of E. coli. Front Cell Infect Microbiol. 2024;14:1387497. doi:10.3389/fcimb.2024.1387497. PMID: 38638826'),
      refEntry(4, 'Abubakar J, Sabitu MZ, Muhammad KD, et al. Plasmid-Mediated Fluoroquinolone Resistance among Enterobacterales in Africa: Systematic Review. West Afr J Med. 2024. PMID: 38788127'),
      refEntry(5, 'Ram S, Gill D, Rice PA. Combatting antimicrobial-resistant Neisseria gonorrhoeae: new antibiotics and the pipeline of antigonococcal therapeutics. Curr Opin Infect Dis. 2026;39(1). doi:10.1097/QCO.0000000000001170. PMID: 41452091'),
      refEntry(6, 'Kunz Coyne AJ, Bouchard J, Durham SH, et al. Oral beta-Lactams for Complicated Urinary Tract Infections: A Systematic Review and Point-Counterpoint Comparison with Trimethoprim/Sulfamethoxazole and Fluoroquinolones. Pharmacotherapy. 2026. PMID: 41693075'),
      refEntry(7, 'Thompson D, Xu J, Ischia J, Bolton D. Fluoroquinolone resistance in urinary tract infections: Epidemiology, mechanisms of action and management strategies. BJUI Compass. 2022;4(1):4-11. doi:10.1002/bco2.286'),
      refEntry(8, 'World Health Organization. Global Antibiotic Resistance Surveillance Report 2025. Geneva: WHO; 2025. Available at: https://media.tghn.org/medialibrary/2025/10/Global_antibiotic_esistance_Surveillance_report_2025.pdf'),
      refEntry(9, 'Mlynarczyk-Bonikowska B, Kowalewski C, Krolak-Ulinska A, et al. Molecular Mechanisms of Drug Resistance and Epidemiology of Multidrug-Resistant Variants of Neisseria gonorrhoeae. Int J Mol Sci. 2022;23(18):10499. doi:10.3390/ijms231810499. PMID: 36142410'),
      refEntry(10, 'Tasanapak K, Sitthisak S, Kitti T, et al. A systematic review and meta-analysis of the global prevalence of fluoroquinolone resistant Morganella morganii clinical isolates. Sci Rep. 2025;15:34746. doi:10.1038/s41598-025-18294-2'),

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