fluoroquinolones Flashcards
fluoroquinolones
ciprofloxacin, levofloxacin,
moxifloxacin
All of the quinolones available today are structural derivatives of the original prototype agent of this class, nalidixic acid**
FQ chemistry
Currently available fluoroquinolones contain two six-membered rings with a nitrogen atom at position 1, a carboxylic acid moiety at position 3, a carbonyl group at position 4, a fluorine at position 6, and a piperazine moiety or other group at position 7.
FQ MOA
The FQs have a unique mechanism of action that includes inhibition of DNA synthesis by binding to and inhibiting bacterial topoisomerases*, which are enzymes needed for maintaining cellular DNA in an appropriate state of supercoiling in both the replicating and nonreplicating regions of the bacterial chromosome.
The FQs target bacterial DNA gyrase (topoisomerase type II) and topoisomerase IV:
-Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. The FQs form a stable complex with DNA and DNA gyrase, which blocks the replicating fork leading to a sudden and lethal cessation of DNA replication. For many Gram-negative bacteria, DNA gyrase is the primary target of the FQs.
-Inhibition of topoisomerase IV** interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division that are the product of DNA replication, causing a cessation in DNA replication. For many Gram-positive bacteria (S. aureus), topoisomerase IV is the primary target of the FQs.
The FQs display concentration-dependent bactericidal activity.**
FQ MOR
Alteration in binding sites – chromosomal mutations in the genes that code for the subunits of DNA gyrase or topoisomerase IV lead to decreased binding affinity** of the FQs to these target sites.
Expression of active efflux – an efflux pump is turned on that enhances the transfer of FQs out of the cell*; has been reported in P. aeruginosa and S. pneumoniae.
Alteration in cell wall permeability – chromosomal mutations cause decreased expression of porin proteins that are responsible for FQ transit inside the cell leading to decreased FQ accumulation within the cell (especially in Pseudomonas).
Cross-resistance is usually observed between the FQs.
FQ spectrum of activity
older (ciprofloxacin) versus newer/respiratory (levofloxacin, moxifloxacin) FQs
Gram-positive aerobes – ciprofloxacin has poor** activity against Gram-positive bacteria; the newer FQs** (levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin, gemifloxacin) have enhanced activity against some Gram-positive bacteria*
-Group and viridans streptococci, Enterococcus spp. – limited activity
-Streptococcus pneumoniae (including PRSP* – except ciprofloxacin)
-Methicillin-susceptible S. aureus (not MRSA)
Gram-negative aerobes – some FQs have excellent activity against Enterobacteriaceae (ciprofloxacin=levofloxacin>gemifloxacin, moxifloxacin), H. influenzae, M. catarrhalis, and Neisseria species
-Enterobacteriaceae: Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus spp., Morganella morganii, Providencia spp., Serratia marcescens, Salmonella spp., Shigella spp.
- Pseudomonas aeruginosa (cipro ≥ levo; NOT moxi** or gemi)**
Anaerobes – trovafloxacin had adequate activity against anaerobes including Bacteroides fragilis; moxifloxacin has some activity but resistance is emerging
Atypical Bacteria – most FQs are extremely active against Legionella*, Chlamydophila, Mycoplasma, and Ureaplasma
Other Organisms – Mycobacterium tuberculosis (cipro, levo, moxi) and Bacillus anthracis (cipro, levo)
FQ pharmacology
FQs exhibit rapid, concentration-dependent* bactericidal activity. The AUC/MIC {30 to 50 for S. pneumoniae; 100 to 125 for Gram-negatives} or Peak/MIC correlate with clinical efficacy; FQs display a PAE against both Gram-positive (2 hours) and Gram-negative aerobic bacteria (2 to 4 hours).
FQ absorption
FQs are well absorbed after oral administration (except for norfloxacin, F = 50%); oral bioavailability is 70 to75% for ciprofloxacin and > 90% for levofloxacin and moxifloxacin allows for early conversion to oral therapy.
Tmax is achieved within 1 to 2 hours; coingestion with food delays peak serum concentrations.
FQ distriution
Most of the FQs display extensive tissue penetration obtaining therapeutic concentrations in the prostate, liver, lung, bronchial mucosa, sputum, bile, saliva, skin and soft tissue, bone* and into alveolar macrophages.
Some FQs achieve high urinary concentrations (not moxifloxacin and gemifloxacin*) making them useful for the treatment of urinary tract infections and prostatitis.
FQs achieve minimal penetration into the CSF.
FQ elimination
FQs are eliminated by various pathways
- Renal elimination – levofloxacin, ofloxacin, and gatifloxacin are eliminated primarily by the kidney (glomerular filtration and tubular secretion); dosage adjustments of these agents are necessary in the presence of renal insufficiency***
- Hepatic metabolism/elimination – trovafloxacin and moxifloxacin are primarily metabolized
- Ciprofloxacin and gemifloxacin undergo both renal and hepatic elimination***; doses of both agents should be adjusted in the presence of renal insufficiency
- NONE of the FQs are removed during hemodialysis
FQ clinical uses
Community-acquired pneumonia – levofloxacin, moxifloxacin, and gemifloxacin
Acute exacerbations of chronic bronchitis and sinusitis – ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin
Bacterial exacerbations in cystic fibrosis (P. aeruginosa) - ciprofloxacin
Nosocomial pneumonia – ciprofloxacin and levofloxacin
Urinary tract infections (cystitis, pyelonephritis) – ciprofloxacin, levofloxacin; norfloxacin (cystitis only)
Chronic bacterial prostatitis – ciprofloxacin and levofloxacin
Osteomyelitis - ciprofloxacin and levofloxacin
Other – intraabdominal infections (ciprofloxacin or levofloxacin with** metronidazole, moxifloxacin alone); traveler’s diarrhea (ciprofloxacin, norfloxacin); tuberculosis (ciprofloxacin, levofloxacin, moxifloxacin); STDs; febrile neutropenia prophylaxis and treatment (ciprofloxacin); eye infections
FQ AEs
ADVERSE EFFECTS – many FQs have been removed from the market due to significant adverse effects; FQs still available are fairly safe and well-tolerated.
- Gastrointestinal (5%) – nausea, vomiting, diarrhea, dyspepsia, Clostridium difficile colitis
- Neurologic – headache, confusion, agitation, insomnia, dizziness (trovafloxacin 11%); rarely hallucinations and seizures; peripheral neuropathy** (new black box warning)
- Hepatotoxicity – transaminase elevation; trovafloxacin** was associated with 140 cases of severe liver injury and 14 cases of fulminant liver failure, use was restricted** to the treatment of severe infections in hospitalized or LTCF patients where therapy could be closely monitored but is now withdrawn from market; moxifloxacin has also been associated with a few cases of liver failure
- Phototoxicity – highest incidence with earlier FQs that contained an additional fluorine or chlorine at position 8 (lomefloxacin, sparfloxacin and enoxacin); patients are required to avoid exposure to sunlight or UV light
- Cardiac – FQs may cause a prolongation in QTc interval and excessive prolongation can lead to Torsades; most significant with sparfloxacin and grepafloxacin (both removed from the market); several case reports of Torsades have been reported with ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin; FQs should be used with caution in patients with hypokalemia, concomitant use of class III antiarrhythmics (amiodarone, sotalol), preexisting QTc prolongation
- Articular Damage – arthropathy (articular cartilage damage, arthralgias and joint swelling) observed in young experimental animals led to the contraindication in pediatric patients and the warning to avoid their use in pregnant (Pregnancy Category C) or breastfeeding patients; FQs have been used in a substantial number of pediatric patients without apparent arthropathy (risk versus benefit)
- Tendonitis and Tendon Rupture – especially in patients over 60 years of age receiving corticosteroids, or who have undergone a renal, heart or lung transplant; patient should avoid exercise if tendon pain develops while on therapy
- Other: allergic reactions (rare), dysglycemias (gatifloxacin removed from market)
FQ DIs
Divalent and trivalent cations (Zinc, Iron, Ca, Al, Mg or ZICAM – including antacids, ddI, sucralfate, enteral feeds) impair the absorption of ANY ORAL fluoroquinolone because of chelation and can lead to clinical failure; FQ doses should be given at least 2 hours before or 2-6 hours after these agents (tube feedings must be stopped for several hours surrounding FQ administration); give FQ first
Warfarin – idiosyncratic interaction leading to increased prothrombin time and potential bleeding; has been reported with most FQs
Theophylline – inhibition of theophylline metabolism leading to increased serum theophylline concentrations and potential toxicity; may occur with ciprofloxacin, but does not occur with levofloxacin or moxifloxacin
Cyclosporine – ciprofloxacin may inhibit cyclosporine metabolism leading to increased cyclosporine levels and potential toxicity
