Specific Quinolone Class Antibacterial Drugs

• Ciprofloxacin (Cipro)¹

  • Ciprofloxacin

  • Ciprofloxacin is a prototypical fluoroquinolone with very good activity against Gram-negative bacterial organisms.¹  

  • Ciprofloxacin is especially potent against bacteria belonging to the Enterobacteriaceae class such as E. coli, Salmonella, Shigella, and Klebsiella.

    • E. coli	Salmonella Typhimurium
      "Low-temperature electron micrograph of the cluster of E. coli bacteria, magnify 10,000 times. "Each individual bacterium is oblong shaped. (March 2005) Attribution Photo by Eric Erbe, digital colorization by Christopher Pooley, both of USDA, ARS, EMU., Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:E_coli_at_10000x,_original.jpg	"Color-enhanced scanning electron micrograph showing Salmonella Typhimurium (red) invading cultured human cells." (November 10, 2002 Attribution Rocky Mountain Laboratories, NIAID, NIH All the images, except specified ones from the World Health Organization (WHO), are in the public domain. For the public domain images, there is no copyright, no permission required, and no charge for their use. https://commons.wikimedia.org/wiki/File:SalmonellaNIAID.jpg

    • Shigella	Klebsiella
      Attribution Center for Disease Control (CDC):  Shigella-Shigellosis https://www.cdc.gov/shigella/about/index.html	Attribution Center for Disease Control (CDC):  Klebsiella https://www.cdc.gov/klebsiella/about/index.html

    • Ciprofloxacin is likely the most active fluorquinolone against Pseudomonas aeruginosa.

      • Gram-positive coverage is more limited with the drug exhibiting only modest activity against Staphylococcus aureus (MSSA) and Streptococcus species.

        • However, Streptococcus pneumoniae is often either resistant or only intermediate insensitivity.

          • This resistance profile limits the use of ciprofloxacin in pneumococcal pneumonia.

            • Ciprofloxacin therefore would not be first-line empirical treatment for respiratory tract infections if the primary pathogen is penicillin-susceptible Streptococcus pneumoniae.

          • Ciprofloxacin is also useful in treating "atypical" pathogens including Legionella, Mycoplasma, and Chlamydia.

            • Ciprofloxacin is not considered effective in treating infections due to anaerobes.¹

  • Ciprofloxacin: Pharmacokinetics

    • Oral bioavailability ~70%-80%.²

      • Given the oral availability of about 75% and an IV dose with the bioavailability of 100%, the oral dose would theoretically require about 1.25 times the IV dose in order to obtain of similar tissue exposure.

      • Peak plasma levels (after a 250 mg oral dose) are around 1.25 µg/mL.

      • Ciprofloxacin’s Vd is large (~2–3 L/kg total distribution), indicating extensive tissue penetration.² 

        • Ciprofloxacin exhibits 83 compartment distribution model with the central compartment volume estimated at 0.161 L/kg. The range for the total volume of distribution is 2-3 L/kg.^2,4  

      • Protein binding is low (20–40%).⁴

      • Ciprofloxacin is metabolized in the liver (CYP1A2 substrate) to four metabolites (each ~3–8% of dose), but the majority of the drug is excreted unchanged: ~30% in urine (after oral dose) and another fraction (~62%) in feces.² 

        • Attribution Metabolism Section Ciprofloxacin. DrugBank. https://go.drugbank.com/drugs/DB00537

        • The elimination half-life is about 4 hours.² 

      • Ciprofloxacin achieves very high concentrations in the urinary tract (making it ideal for UTIs)⁶  and also penetrates well into prostate, lungs, bile, and bone.⁵

  • Ciprofloxacin Therapeutic Uses

    • Ciprofloxacin is widely used for urinary tract infections, including pyelonephritis and prostatitis, due to its strong activity against uropathogens and high urinary level.^1,7,8 

      • Ciprofloxacin is first-line agent for complicated UTIs and an important option for prostatitis that may require  4–6 weeks treatment to clear chronic bacterial prostatitis).¹ 

      • Ciprofloxacin is a drug of choice for infectious diarrhea (bacterial gastroenteritis) caused by organisms like Traveler’s diarrhea (enterotoxigenic E. coli) Campylobacter jejuni, Shigella boydii, Shigella dysenteriae or Shigella flexneri or Shigella sonnei.

      • In intra-abdominal infections, ciprofloxacin combined with metronidazole for coverage of anaerobic Gram-negative bacilli is used for diverticulitis⁹  or abdominal abscess.¹¹

        • Historically abdominal abscess was often favored, in combination with metronidizole for treating intra-abdominal infections.¹⁰ 

        • More recently, a number of agents have been identified that have proveneffective in treating abdominal abscess. The choice of the agent, either single agent treatment or combination therapy,  was classified on the basis of the infection being at community acquired infection in children or community acquired infection in adult with the infection being of varied severity. (2010)

          • "Pharmacologic Options for Initial Empiric Treatment of Extrabiliary Complicated Intra-abdominal Infection"

            Attribution The table above is the slight adaptation of table 2 of reference 11 Armstong  C Updated Guidelines on Diagnosis and Treatment of Intra-abdominal Infections. Am Fam Physician. 2010;82(6): 694-709. https://www.aafp.org/pubs/afp/issues/2010/0915/p694.html

        • Even more recently, a very complete, evidenced-based set of guidelines for managing intra-abdominal infection has been published, including the role of ciprofloxacin as well as the number of other agents depending on the specific circumstances.¹²

      • Ciprofloxacin’s excellent Gram-negative coverage makes it useful in hospital-acquired infections¹³ for example for febrile neutropenia in oncology patients it can be part of prophylaxis or therapy¹⁴.

        • However, ciprofloxacin is not generally recommended as first-line therapy for pneumonia due to limited efficacy against such, pneumonia-causative bacteria e.g. Streptococcus pneumoniae.

        • Ciprofloxacin does have a role in particular situations in which pneumonia is caused by Pseudomonas aeruginosa or certain Gram-negative bacteria in the hospital-acquired pneumonia setting.¹⁵

      • Ciprofloxacin is indicated for bioterrorism-related infections: it is the first-line prophylaxis and treatment for inhalational anthrax (post-exposure to B. anthracis)¹⁶

      • Ciprofloxacin is also recommended  for plague (Yersinia pestis) treatment.

  • Safety Concerns

    • Ciprofloxacin is generally well-tolerated but has typical fluoroquinolone precautions (see next section below).

      • A notable distinction is that ciprofloxacin is one of the fluoroquinolones that inhibit CYP1A2, which can raise levels of drugs like theophylline, caffeine, and tizanidine.¹⁸  

        • Concurrent administration of theophylline use can lead to toxicity (seizures, arrhythmias) due to this interaction, so dose adjustment and monitoring may be required.¹⁹ 

        • Ciprofloxacin also may increase warfarin levels/effects, so INR (Prothrombin time) monitoring is needed when co-administered.²⁰ 

        • Like all systemic quinolones, it carries a risk of tendonitis/tendon rupture, neuropathy, CNS effects, etc., especially in older patients.²¹ 

        • Because of limited pneumococcal activity, it should not be used for community-acquired respiratory infections where S. pneumoniae is suspected.

• Levofloxacin (3rd Generation)

  Levofloxacin:  Audio Overview

  • Levofloxacin (Levaquin)

  • Spectrum:

    • Levofloxacin, the L-isomer of ofloxacin exhibiting about twice the potency, is often termed a “respiratory fluoroquinolone.” Respiratory quinolones, as monotherapy, exhibits shows an advantage in clinical cure compared to a beta-lactam combined with a macrolide antibiotic.²³

    • Levofloxacin and moxifloxacin are examples of respiratory quinolones.²³

    • Levofloxacin has broad activity against Gram-positive Streptococcus pneumoniae (including many penicillin-resistant strains) and Staph aureus (MSSA), while retaining excellent Gram-negative coverage (most Enterobacteriaceae, H. influenzae, M. catarrhalis, etc.)²⁴

    •  Its Pseudomonas activity is moderate, not as potent as ciprofloxacin, but high-dose levofloxacin can treat Pseudomonas in urinary or respiratory infections if susceptible.²⁴

      • The FDA has suggested that the ofloxacin be used only for strongly suspected bacterial infections in order to reduce the likelihood of drug-resistance bacteria development. Furthermore, levofloxacin is not recommended for empiric use in individuals at the risk of multi-drug-resistant Escherichia coli. Levofloxacin is recommended for infections due to extended-spectrum betalactamase producing enterobacterales, AmpC-E beta-lactamase-produces enterobacterales or Stenotrophomonas maltophilia (mild).

        • AmpC are clinically notable cephalosporinases encoded in many of the Enterbacteriaceae and some other bacteria, mediating resistance to many antibiotics including most penicillins and ß-lactamase inhibitor-ß-lactam combinations.²⁵

    •  Levofloxacin is also active against atypicals (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumoniae) making it effective for atypical pneumonia.²⁶ 

      • Levofloxacin exhibits limited activity against anaerobes; therefore, levofloxacin is not a first-line anaerobic drug.²⁷

  • Pharmacokinetics²⁸  

    • Levofloxacin’s pharmacokinetic profile is favorable with nearly 100% oral bioavailability.

      • Oral and IV doses are interchangeable (500 mg IV = 500 mg PO yields equivalent exposure). Absorption is rapid (T_max ~1–2 h).

      • Distribution is wide (V_d ~1.1–1.3 L/kg) penetrating well into lung tissue, bronchial secretions, sinuses, skin, and urinary tract.

      • Protein binding is ~30% (24-38%)

      • Levofloxacin undergoes minimal metabolism (<5%)

        • Levofloxacin Metabolites

      • The vast majority is excreted unchanged in urine with about 85–87% of a dose recovered unchanged in the urine within 48 hours. 

        • Its elimination half-life is approximately 6-8 hours.

        • If the patient presents with renal impairment, dose or interval may require adjustment.²⁴ 

  • Therapeutic uses:

    •  Levofloxacin is often used to treat respiratory tract infections.

      • Levofloxacin, frequently used for monotherapy to cover both typical and atypical pneumonia pathogens, is often administered in treating community-acquired pneumonia (CAP).²⁹

      • Guidelines consider respiratory fluoroquinolones (levofloxacin or moxifloxacin) as first-line options for CAP in patients with comorbidities or requiring hospitalization.²³ 

        • Levofloxacin may be used for treating acute bacterial sinusitis and acute exacerbations of chronic bronchitis; however, the FDA has advised that fluoroquinolones should be used only in patients who have no other treatment options for managing acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated urinary tract infections. This update from the FDA reflects the conclusion that side effect risk usually outweighs the benefit for these patients. The exception would be in certain serious bacterial infections in which case the benefits of fluroquinolone administration outweigh the risks.³⁰

          • Beyond respiratory uses, levofloxacin is used for complicated urinary tract infections,³⁰  

            • A complicated urinary tract infection is an infection associated with an elevated treatment failure risk.

              • For example, a complicated UTI diagnosis would be appropriate in immunocompromised patients males, pregnant patients and those patients presenting with fever, stones, sepsis, catheters, urinary obstruction or kidney involvement.³¹

        • Levofloxacin may be appropriate in treating pyelonephritis.³²  

          • Although fluoroquinolones and trimethoprim/sulfamethoxazole in most cases will be effective oral antibiotics for treating pyelonephritis, increasing resistance make empiric use more problematic.

            • Hospitalized patients would more likely receive parenteral antibiotic treatment and those with sepsis or infection risk with the multidrug-resistant bacteria should probably receive antibiotics exhibiting activity against extended-spectrum beta-lactamase-producing organisms.³²

            • Levofloxacin appears to be a reasonable choice for treating prostatitis.can be used for prostatitis.³³

            • Levofloxacin, described as the second-line treatment) is an alternative agent for tuberculosis.³⁴

            • Skin and soft tissue infections Is an FDA approved indication for levofloxacin use.²⁴

            • Levofloxacin (like ciprofloxacin) is FDA-approved for inhalational anthrax post-exposure³⁵  and for plague treatment/prophylaxsis.³⁶

  • Tolerability and special points:

    • Levofloxacin does not inhibit cytochrome P450 significantly, so it has fewer drug interactions than ciprofloxacin.³⁷ 

      • Levofloxacindoes not prolong the QT interval to a significant degree at least compared to most other fluoroquinolones.  Moxifloxacin has more pronounced effect.

        • When  analyzing several fluoroquinolones with respect to the risk of inducing ventricular arrhythmias in Korea's general population, ciprofloxacin and levofloxacin, during the week after administration, were not associated with increased risk; whereas ofloxacin showed reduce risk and moxifloxacin increase the risk of serious arrhythmias.³⁸

      • The results of the study may suggest that levofloxacincan could be a safer choice in patients at risk for arrhythmias.

        • Nonetheless, caution is still advised with other QT-prolonging drugs.

      • Like all fluoroquinolones, levofloxacin can cause tendinopathy, CNS effects (insomnia, dizziness), and rarely peripheral neuropathy or dysglycemia.

        • Because of the risk of side effects, in 2016 the FDA recommended that for uncomplicated sinusitis, bronchitis, and uncomplicated UTIs, fluoroquinolones (including levofloxacin) should be reserved for patients who have no alternative treatment options.

          • In practice, this recommendation cautions that primary care clinicians use levofloxacin for these common infections only if first-line antibiotics (e.g. amoxicillin-clavulanate for sinusitis, or trimethoprim-sulfamethoxazole for UTI) cannot be used.³⁰ 

        • Levofloxacin and fluoroquinolones in general have in the past been contraindicated in children and pregnant/nursing women due to the class’s cartilage toxicity concerns; however, this use been challenged since the evidence is weak and the American Academy of pediatrics recommend fluoroquinolones as second-line antibiotic with restricted uses.⁵

  Moxifloxacin (3rd/4th Generation)

  Moxifloxacin Audio Overview

  • Moxifloxacin

  • Spectrum

    • Moxifloxacin is a “fourth-generation” fluoroquinolone with broad coverage including Gram-positives, atypicals, and some anaerobes.^39,40 

      • Moxifloxacin exhibits excellent activity against Streptococcus pneumoniae (including PRSP), Streptococcus pyogenes, and good activity against Methicillin-Susceptible Staphylococcus Aureus (MSSA) (but not Methicillin-Resistant Staphylococcus Aureus, MRSA).

      • Gram-negative spectrum of moxifloxacin:

        • Haemophilus, Moraxella

        • (Many) Enterobacteriaceae, but not Pseudomonas

        • Moxifloxacin is notable in its activity against anaerobic bacteria such as Bacteroides fragilis.⁴²  

          • Because of this activity, moxifloxacin can be used in some polymicrobial intra-abdominal infections as a single agent.⁴¹ 

          • Moxifloxacin is also effective in covering atypical bacterial infections due to for example Mycoplasma, Chlamydia, Legionella.⁴³

  • Pharmacokinetics⁴⁴

    • Moxifloxacin is very well absorbed orally (~85–90% bioavailability) allowing once-daily oral dosing of 400 mg to achieve therapeutic levels similar to IV.

    • Moxifloxacin is widely distributed, penetrating lung tissue, sinuses, etc.,  (V_d ~1.7–2.7 L/kg).

    • Moxifloxacin’s clearance is predominantly hepatic via conjugation (glucuronidation and sulfation).

      • This drug is not metabolized utilizing the cytochrome p450 drug metabolizing system; therefore, drug-drug interactions depending on cytochrome p450 are not of concern.

    • About half an administered dose is excreted as unchanged drug: ~20% in urine and ~25% in feces with the remainder excreted as metabolites.

    • Because only 20% of the drug Is excreted in urine, moxifloxacin achieves relatively low urinary concentrations and is therefore not typically appropriate for treating urinary tract infections.

    • The relatively long half-life, ~12–15 hours, provides the rationale for once-daily dosing.

      • Since the kidneys do not represent the major drug elimination pathway, a moxifloxacin dose adjustment is Not required in the presence of renal insufficiency. By contrast, in severe hepatic impairment moxifloxacin should be used cautiously or avoided due to reduced metabolism.

  • Therapeutic uses^39,45,46,47  

    • Moxifloxacin is primarily used for respiratory infections. It is indicated for community-acquired pneumonia, including aspiration pneumonia (due to its anaerobe coverage) and is very effective for community acquired pneumonia (CAP), including cases with high penicillin-resistant pneumococci.

      • Moxifloxacin has been FDA-approved for treating CAP infections due to susceptible Streptococcus pneumonia strains and Mycoplasma pneumonia strains.

        • This agent is also approved for treating:

          • Acute bacterial exacerbation of chronic bronchitis⁴⁸

          • Acute bacterial sinusitis

          • Complicated skin and skin structure infections, including abscessus, cellulitis and surgical wound infections.

        • Other uses include uncomplicated skin and skin structure infections, complicated inter-abdominal infections as well as treatment of plague (pneumonic and septicemic forms) as result of Yersinia pestis infections.³⁹

    • Moxifloxacin monotherapy is effective in treating polymicrobial intra-abdominal infections of mild-to-moderate severity.⁴⁹ 

      • Moxifloxacin is one of the options for bacterial conjunctivitis as a topical ophthalmic solution, owing to its broad coverage.⁵⁰

  • Safety considerations

    • QT interval prolongation is an adverse effect of moxifloxacin administration⁵¹  and appears present to a greater degree relatives other fluroquinolone antibiotics.

      • Moxifloxacin can cause QT prolongation and even torsades de pointes in rare cases.⁵² 

        • ECG:  Note QT Interval

          Attribution Burns E Buttner QT Interval Life in the FASTLANE https://litfl.com/qt-interval-ecg-library/  (October 8, 2024)

           

        • Torsades de Pointes

          Attribution Jer5150, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Torsades_de_Pointes_TdP.png

        • Therefore, it is contraindicated in patients with known QT prolongation or receiving antiarrhythmic drug therapy,³⁹  and caution is urged if other QT-prolonging risk factors are identified.

          • Unlike levofloxacin, moxifloxacin should be avoided in patients with significant arrhythmia risk factors.

      • Other adverse effect profiles are similar to fluroquinolone effects (GI upset, CNS effects, etc.).

      • Moxifloxacin in pregnancy should be evaluated on a case-by-case basis, which considers balancing benefits and risk to the developing fetus.³⁹ 

      • The safety of moxifloxacin has not been established for use in patients under the age of 18.⁵³  

        • "Moxifloxacin may cause problems with bones, joints, and tissues around joints in children. Moxifloxacin should not be given to children younger than 18 years old."⁵⁴

• Other Quinolones

  • Ofloxacin:

    • A second-generation agent, ofloxacin is the racemic mixture from which levofloxacin (the L-isomer) is derived.

      • Ofloxacin has broad activity similar to levofloxacin but slightly less potency against susceptible strains of Streptococcus pneumoniae given that half the mixture is the less-active D-isomer.⁵⁵

      • Susceptible bacteria include:⁵⁵

        • Aerobic Gram-positive bacteria

          • Staphylococcus aureus (methicillin-susceptible strains)

          • Streptococcus pneumoniae (penicillin-susceptible strains)

          • Streptococcus pyrogenes

        • Aerobic Gram-negative bacteria

          • Citrobacter koseri (Citrobacter diversus)

          • Enterobacter aerogenes

          • Escherichia coli

          • Haemophilus influenzae

          • Neisseria gonorrhoeae

            • Fluoroquinolones, including ofloxacin, used to be favored for gonorrhea treatment (1980s). Fluoroquinolones, due to resistance development by Neisseria gonorrhoeae, were generally no longer used by the late 1990s.

          • Proteus mirabilis

          • Pseudomonas aeruginosa

        • Other bacteria:⁵⁵

          • Chlamydia trichomonas

    •  Ofloxacin may be used to treat is used for UTIs, prostatitis, certain infectious diarrheas.aOfloxacin’s half-life ~7–8 hours, and it is dosed BID.

  • Gemifloxacin

    Gemifloxacin Audio Overview

    •  

      Gemifloxaxacin (2D and 3D Representations)

      	Attribution Siddiqui S Rasheed T Faisal M Pandey A Spectroscopy 27(3) June 2012. (CC BY 3.))

    •  A newer respiratory fluoroquinolone (oral only) indicated for mild-to-moderate community-acquired pneumonia and acute exacerbation of bronchitis.⁵⁶ 

    • Gemifloxacin may be used to treat bacterial infections caused by susceptible strains including:

      • Streptococcus pneumoniae (S. pneumoniae)

      • Haemophilus influenzae (H. influenzae)

      • Moraxella catarrhalis (M catarrhalis)

      • Multidrug-Resistant Streptococcus pneumoniae (MDRSP)

      • Chlamydia pneumoniae (C. pneumoniae)

      • Klebsiella pneumoniae (K. Pneumoniae)

    • Adverse Effect:⁵⁷ 

      • In some patients, typically female, an uncommon delayed onset skin rash may develop. The presence of asthma tend to increase the risk of the skin rash.⁵⁷

      • The combination of this side effect in the narrow antibacterial indications for gemifloxacin may have limited its clinical use.

      • The overall adverse effect profile for gemifloxacin is in accord with that of the fluoroquinolone class.⁵⁸

  • Delafloxacin⁵⁹

    Delafloxacin Audio Overview

    • This fluoroquinolone  is active against MRSA in addition to Pseudomonas and other typical organisms.

      • Delafloxacin is indicated for acute bacterial skin and skin structure infections and also approved for community-acquired bacterial pneumonia.  

      • Delafloxacin may be used to treat I variety of bacterial infections caused by susceptible strains such as:

        • Gram-positive organisms:

          • Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates.

          • Staphylococcus haemolyticus

          • Staphylococcus lugdunensis

          • Staphylococcus agalactiae

          • Staphylococcus anginosus group [Staphylococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus]

          • Streptococcus pyrogenes

          • Enterococcus faecalis

        • Gram-negative organisms:

          • Escherichia coli

          • Enterobacter cloacae

          • Klebsiella pneumoniae

          • Pseudomonas aeruginosa

        • Susceptible bacteria for Community-Acquired Bacterial Pneumonia (CABP)

          • Streptococcus pneumoniae

          • Staphylococcus aureus (methicillin-susceptible MSSA isolates only

          • Klebsiella pneumoniae

          • Escherichia coli

          • Pseudomonas aeruginosa

          • Haemophilus influenzae

          • Haemophilus parainfluenza

          • Chlamydia pneumoniae

          • Legionella pneumophila

          • Mycoplasma pneumoniae

      • Delafloxacin does not appear to cause QT prolongation to a significant degree. However, Delafloxacin’s side effect profile still includes tendon and neuropathy warnings.⁶⁰