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What's New for Fluoroquinolones in the Treatment of Acute Bacterial Skin and Skin Structure Infections

INTRODUCTION TO FLUOROQUINOLONES

The quinolone antibiotics were first described in the early 1960s with the introduction of nalidixic acid.1 Since that time, chemical modifications to the characteristic 4-quinolone or dual-ring system, such as the addition of fluorine, have improved the utility of this original class: the fluorine addition produced a new class—the fluoroquinolone antibiotics, which were introduced into clinical practice in the 1980s and now represent a broad class of synthetic antimicrobial agents.2 The early fluoroquinolones, such as norfloxacin and ciprofloxacin, primarily have activity against gram-negative pathogens. Further modifications to these early agents created ofloxacin and levofloxacin, which retained the class’s gram- negative activity but added activity against Streptococcus pneumoniae. Later, moxifloxacin was added to the class: it has S. pneumoniae activity and some anaerobic activity but less activity against gram- negative organisms than its older cousins.3 Recently, delafloxacin, which has activity against gram- positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and gram-negative organisms, including Pseudomonas aeruginosa, received approval from the United States (U.S.) Food and Drug Administration (FDA).4

Fluoroquinolones are direct inhibitors of DNA synthesis. All of the agents in this class of antibiotics exert bactericidal activity by inhibiting bacterial topoisomerase II, also known as DNA gyrase, and topoisomerase IV. These enzymes are necessary for bacterial DNA replication, transcription, repair, and recombination.2

Resistance to the fluoroquinolone antibiotics develops because of target site mutations or reduction in drug accumulation. Target site mutations occur through chromosomal mutations in specific regions of the target enzymes, DNA gyrase and topoisomerase IV. These regions are called quinolone resistance- determining regions (QRDR). Mutations in the QRDR of the genes encoding for DNA gyrase (gyrA, gyrB) or topoisomerase IV (parC, parE) will confer resistance to the fluoroquinolone antibiotics. Reduction in drug accumulation in the bacteria may also result in fluoroquinolone resistance. This type of resistance develops because of reduced drug penetration, which is primarily mediated by porin or through active efflux of the drug from the bacterial cell.5

The fluoroquinolone antibiotics are generally well-tolerated. The most common adverse reactions reported in clinical trials affect the gastrointestinal tract and include nausea, diarrhea, and vomiting; headache and liver transaminase elevations have also been reported. The use of fluoroquinolones has been associated with the development of Clostridium difficile diarrhea.2,6

Less commonly, the fluoroquinolones are associated with serious adverse effects to the nervous system, cardiovascular system, and musculoskeletal system that have prompted the FDA to require a boxed warning on their product labelings.4,6 Such serious adverse effects include tendonitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. Several risk factors for tendonitis and tendon rupture have been identified including age older than 60 years, concomitant corticosteroid use, and receipt of a kidney, heart, or lung transplant. Strenuous activity, renal failure, and prior tendon disorders, including rheumatoid arthritis, may also contribute to tendonitis and tendon rupture in patients taking fluoroquinolones.4 Peripheral neuropathy, which manifests as pain, numbness, and tingling that often begins in the hands and feet and may spread to other parts of the body, is another potentially severe and long-term effect that has been associated with the fluoroquinolones; its onset may be sudden and its effects may be permanent. Fluoroquinolones may also alter cardiac conduction, prolong the QT interval, and produce phototoxicity. Several fluoroquinolones have been removed from the market for safety concerns related to 1 or more of these reasons6 (Table 1). Fluoroquinolones are available in oral, intravenous (IV), and topical formulations and the likelihood of adverse effects changes with the method of administration: for example, the risk of serious, systemic effects that is associated with oral or IV formulations is not significant with topical solutions for ear or eye infections.

Table 1: Oral Fluoroquinolone Antibiotics That Have Been Withdrawn From the United States Market
Generic name Brand name Reason for withdrawal
Norfloxacin*     
Temafloxacin
Gatifloxacin       
Trovafloxacin
Grepafloxacin
Sparfloxacin
Gemifloxacin*
Noroxin               
Omniflox
Tequin 
Trovan 
Raxar    
Zagam
Factive 
Low sales7
Hemolytic anemia, life-threatening allergic reactions, hypoglycemia8
Dysglycemia (hyperglycemia and hypoglycemia)9
Hepatic toxicity, acute liver failure10
Cardiac events, QT prolongation11
QT prolongation, Stevens-Johnson syndrome6
Low sales7
*Still available in other countries.

The fluoroquinolone antibiotics have been widely adopted into clinical practice due to their favorable pharmacokinetic profile, ease of administration, and broad spectrum of activity. They are commonly used to treat a variety of infections, including urinary tract, intra-abdominal, and respiratory tract infections.2 All currently available fluoroquinolone antibiotics in the U.S. are also FDA approved for acute bacterial skin and skin structure infections (ABSSSIs).

INTRODUCTION TO SKIN AND SKIN STRUCTURE INFECTIONS

As the name specifies, skin and skin structure infections (also termed skin and soft tissue infections) are infections of the skin and surrounding soft tissue including the loose connective tissue and mucous membranes. Bacterial pathogens are usually the cause of skin and skin structure infections and these infections require systemic antibiotic therapy.

Epidemiology, hospitalizations, and costs

It is estimated that more than 15 million bacterial skin and skin structure infections occur in the U.S. annually, causing considerable morbidity.12 More than 870,000 hospital admissions are attributed to serious ABSSSIs each year.13 The incidences of cellulitis and abscess, which are common skin and skin structure infections, are increasing: the most recent data available indicate that these infections accounted for nearly 10% of infectious disease-related hospitalizations in the U.S. from 1998 to 2006.14 In one study, admissions for primary skin and soft tissue infections increased steadily between 2005 and 2011 from 1.64% to 1.95% of all hospital admissions. Over the same timeframe, the mortality rate of skin and skin structure infections remained stable while the length of stay and number of patients without comorbidities decreased.15 Outpatient visits for skin infections, including visits to ambulatory clinics and emergency departments, increased from 4.6 million in 1997 to 9.6 million in 2005.14

The economic liability for hospitalization due to skin and skin structure infections is more than $3.7 billion dollars per year.16 The average total cost for adult inpatients with a primary skin and soft tissue infection was estimated to be approximately $10,000; this figure remained steady between 2005 and 2011.15 Compared to other patient groups, patients with postoperative wound infections had the longest hospital stays and highest total costs associated with care. Overall, patients who are hospitalized with ABSSSIs are increasingly complicated patients and are treated for an average of 5 days as an inpatient. Together, these findings indicate that skin and soft tissue infections remain a common, and burdensome, cause of hospitalization.

Etiology

The causes of most of ABSSSIs are presumed to be gram-positive organisms known to colonize the skin. The beta-hemolytic streptococci, including Streptococcus pyogenes, sometimes also called group A streptococcus or GAS, Streptococcus agalactiae (group B streptococcus or GBS), and the Streptococcus anginosus group, which includes Streptococcus anginosus, Streptococcus intermedium, and Streptococcus constellatus, are considered the most common cause of cellulitis without a culturable source.17,18 The most frequent cause of skin infection when the causative organism is able to be identified is S. aureus, including methicillin-susceptible and methicillin-resistant strains.2 Traditional risk factors for infection with MRSA include intravenous (IV) drug use, HIV infection, colonization with MRSA, and previous antibiotic use or hospitalization.19

Gram-negative pathogens, including resistant organisms, are increasingly recognized as a cause of skin and skin structure infections. Immunocompromised states, such as organ transplantation, neutropenia, HIV, IV drug use, diabetes, cirrhosis, and colonization with resistant organisms, increase a patient’s risk for ABSSSI caused by gram-negative bacilli. Patients having a prolonged length of stay in the hospital, particularly burn patients, are at high risk for infection with resistant species of Pseudomonas or Acinetobacter.19

Treatment of ABSSSIs

The Infectious Diseases Society of America (IDSA) published guidelines for the treatment of skin and soft tissue infections in 2014.17 The guidelines focus on the diagnosis and appropriate treatment of a diverse group of infections, ranging from minor superficial infections to life-threatening infections, including postoperative wound infections. The guidelines recommend that the treatment of typical cases of cellulitis should include an oral antibiotic with activity against streptococci, the most frequent cause of these types of infections.17 Potential treatment options suggested for mild cases of non-purulent infections include penicillin, amoxicillin, amoxicillin-clavulanate, dicloxacillin, cephalexin, and clindamycin. Antibiotics with activity against MRSA should be considered when the infection is associated with penetrating trauma, such as IV drug use, when the would exhibits purulent drainage, or if the patient is colonized with MRSA or has a history of infection with MRSA.

Treatment of purulent skin and skin structure infections, notably abscesses, should include incision and drainage of the abscess and treatment with antibiotics that are active against MRSA. Oral and IV options for the treatment of ABSSSIs with activity against MRSA include several long-standing therapies such as sulfamethoxazole-trimethoprim, clindamycin, minocycline, doxycycline, vancomycin, daptomycin, linezolid, ceftaroline, and telavancin. Since the publication of the IDSA guidelines, several antimicrobials have been approved by the FDA for the treatment of ABSSSIs: dalbavancin, oritiavancin, tedizolid, and delafloxacin. Delafloxacin, approved in June 2017, is the first antimicrobial approved by the FDA for the treatment of ABSSSI since 2014.4

USE OF FLUOROQUINOLONES IN ABSSSI

Fluoroquinolones are not listed as first-line agents for the treatment of ABSSSIs in the IDSA guidelines, but they are included as alternative agents, and all fluoroquinolones carry FDA indications for skin and skin structure infections, including ciprofloxacin, levofloxacin, moxifloxacin, and the recently approved delafloxacin. For patients with cellulitis also exhibiting systemic signs of infection such as fever or elevated white blood cell count, hospitalization and parenteral antibiotics are recommended. Patients with risk factors for infection with MRSA, such as patients colonized with MRSA or those who experienced penetrating trauma, an agent with activity against MRSA should be selected. Immunocompromised patients may require treatment with an agent with gram-negative activity such as ciprofloxacin or levofloxacin. The fluoroquinolones are recommended to be given with metronidazole for surgical site infections following operations on the axilla, gastrointestinal tract, perineum, or female genital tract. (Metronidazole compliments fluoroquinolone activity by offering activity against gram-positive and gram-negative anaerobic bacteria that are known to cause infections in these areas of the body.) In addition, the IDSA guidelines for diabetic foot infections include recommendations for the use of fluoroquinolone antibiotics.20

Delafloxacin for ABSSSI

The novel agent delafloxacin is the newest fluoroquinolone approved for ABSSSI. It is marketed under the brand name Baxdela as an oral tablet and a solution for IV administration. Its unique structure and spectrum of activity provide safety and efficacy in the treatment of infections caused by bacteria that harbor resistance to other antibiotic agents.

Structural characteristics

Delafloxacin is a fluorinated quinolone. Unlike other agents in its class, it is weakly acidic due to the lack of a basic group next the fluorinated ring. This results in increased activity and lower minimum inhibitory concentrations under low-pH conditions, such as in an abscess, compared to other fluoroquinolones. The mechanism of action of delafloxacin is the same as other fluoroquinolone antibiotics: the inhibition of bacterial DNA gyrase (topoisomerase II) and topoisomerase IV interferes with bacterial DNA replication. Delafloxacin displays concentration-dependent bactericidal activity against a variety of organisms, including both gram-positive and gram-negative organisms.4

Spectrum of activity

The spectrum of activity of delafloxacin is broad, displaying in vitro activity against gram-positive, gram- negative, and anaerobic organisms. It also displays in vitro activity against Mycobacterium tuberculosis. In vitro studies have demonstrated that delafloxacin has activity against S. aureus and coagulase- negative staphylococci, including strains resistant to levofloxacin and methicillin.21 It is also active against other streptococcal species and Enterococcus faecalis. It is not active against Enterococcus faecium.

Delafloxacin has FDA approved breakpoints (i.e., susceptibility criteria) for S. aureus (including methicillin-sensitive [MSSA] and MRSA), Staphylococcus haemolyticus, S. pyogenes, S. agalactiae, S. anginosus, S. constellatus, and S. intermedius.4 It has excellent activity against streptococcal species and staphylococci, including MRSA, which makes delafloxacin a reasonable choice for skin and skin structure infections, even in the absence of culture-identified causes of infection.

Delafloxacin is also active against clinically important gram-negative pathogens. The FDA has approved breakpoints for delafloxacin for Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, and P. aeruginosa4 It has also demonstrated activity against a variety of other gram-negative pathogens, including Haemophilus influenza, Moraxella catarrhalis,22 Acinetobacter species, and Stenotrophomonas maltophilia.23

Resistance to delafloxacin occurs through the same mechanisms propagated by other fluoroquinolones: namely, mutations in the genes encoding for DNA gyrase and topoisomerase IV. In vitro studies of resistance have shown strains with mutations in both gyrA and gyrB to have lower fitness than susceptible strains.24

Efficacy

Delafloxacin was granted approval for the treatment of ABSSSIs under the Qualified Infectious Disease Products priority review process because of its activity against difficult-to-treat pathogens, MRSA, and P. aeruginosa. Clinical trials for additional therapeutic indications, such as community-acquired pneumonia, are underway. Approval of delafloxacin was based on 2 phase III, multicenter, multinational double-blind, non-inferiority clinical trials that included a total of more than 1500 patients with ABSSSIs.4,25

In the first trial, patients were randomized to receive either delafloxacin 300 mg IV or vancomycin 15 mg/kg IV plus aztreonam IV twice daily.25 The overall response rates at 48 to 72 hours were 78.2% and 80.9% in the delafloxacin and vancomycin plus aztreonam groups, respectively. Similarly, in the second trial, patients received delafloxacin 300 mg IV every 12 hours for 6 doses followed by 450 mg orally twice daily.4 As in the first trial, the comparator was vancomycin plus aztreonam. The overall response rates in the second trial were 83.7% for delafloxacin and 80.6% for vancomycin plus aztreonam. In both trials, the intent-to-treat and clinically evaluable patients at follow-up (days 13-15) and late follow-up (days 21-28) were not statistically different between the groups. In both studies, the most frequently identified causative pathogen was S. aureus. Among patients with positive baseline pathogens identified, the combined clinical response rates for S. aureus, both MSSA and MRSA, in both studies were 85% for delafloxacin and 83% for the comparator. The clinical response rate for MRSA was 87% for delafloxacin and 86% for vancomycin plus aztreonam. Additionally, in pooled trial data from both the first and second trials, the clinical response rates for patients infected with P. aeruginosa were 82% (9/11 patients) for delafloxacin and 92% (11/12 patients) for vancomycin plus aztreonam. However, the number of patients in each group was very low, which is a limitation to widespread extrapolation of the data.

Nearly 10% of patients included in the first phase III trial had diabetes.25 In a subset of patients undergoing intensive monitoring for pharmacokinetic assessment, as well as intense glucose monitoring, no differences in glucose concentrations were observed between patients treated with delafloxacin and those treated with vancomycin plus aztreonam.25 In this same trial, nearly 30% of patients in each arm were obese (body mass index ≥ 30 kg/m2). In the obese subset, objective response and investigator- assessed cure at follow-up were not significantly different between the treatment groups. However, investigator-assessed cure at long-term follow-up appeared to favor delafloxacin. The groups were not stratified for obesity and a weight limit of 140 kg was applied to mitigate the difficulties of blinding of vancomycin in an obese population.25

Safety

Similar to other fluoroquinolone antibiotics, the most common adverse effects of delafloxacin occurring during clinical trials affected the gastrointestinal tract and included nausea, diarrhea, and vomiting.25,26 Other reactions that occurred at a rate of more than 2% were headache and transaminase elevations. Delafloxacin did not have any clinically relevant effect on the QTc interval nor did it produce significant phototoxic potential when administered to healthy volunteers.4,27

There is limited information regarding the use of delafloxacin in pregnant women. Animal studies of delafloxacin show maternal toxicity, reduced fetal body weights, and fetal ossification delays, all of which are seen with other fluoroquinolones, as well. Delafloxacin is excreted in the breast milk of rats, although no data on delafloxacin in human breast milk are available. The use of delafloxacin in patients under the age of 18 years is not recommended, since safety in this population has not been established.4

Dosage and administration

Delafloxacin is administered intravenously at a dose of 300 mg every 12 hours. The oral formulation is administered as a 450-mg dose twice daily. Suggested total treatment duration is 5 to 14 days. This duration is sufficient even for patients who are switched from the IV to the oral formulation. When administered orally, delafloxacin may be taken with or without food. However, it should be given 2 hours before or 6 hours after food or products containing aluminum, magnesium, iron, zinc, or sucralfate or any product containing divalent cations, since these may result in substantially lower serum concentrations of delafloxacin by interfering with its absorption. The IV formulation contains sulfobutylether-β-cyclodextrin, which may accumulate in patients with moderate-to-severe renal impairment. The IV dosage for patients with mild-to-moderate renal impairment (i.e., an estimated glomerular filtration rate [eGFR] of 15-29 mL/min/1.73 m2) is 200 mg every 12 hours. It is advisable to switch patients with mild renal impairment to the oral formulation at 450 mg daily, if possible, to avoid the potential for vehicle accumulation. It is important to note that the dosage is based upon the eGFR, which is calculated using the Modification of Diet in Renal Disease study equation instead of the Cockroft and Gault formula. The IV formulation is not recommended in patients with end-stage renal disease, including those receiving hemodialysis.4

At the time of dispensing delafloxacin, pharmacists should counsel patients and take care to include warnings about potential serious adverse reactions, such as tendonitis, tendon rupture, peripheral neuropathy, and central nervous system effects. Patients should also be informed about the potential interactions with food and pharmacists should ensure that patients understand the timing of doses in relation to food and products containing aluminum, magnesium, iron, zinc, sucralfate, and divalent cations. Delafloxacin is contraindicated in patients with known hypersensitivity to delafloxacin or any other fluoroquinolone.4

Delafloxacin is the first new antibiotic approved by the FDA for the treatment of ABSSSI since 2014. It has activity against both P. aeruginosa and MRSA. It has advantages over other fluoroquinolones since it does not have significant effects on cardiac conduction or the development of phototoxicity. It may have a role in the treatment of ABSSSI in patients at risk for resistant pathogens or those with significant drug allergies to other commonly used antibiotics. Its availability as both an IV infusion and oral tablets makes transition from IV to oral therapy simple.

CASE STUDIES

Pharmacists should understand the use of fluoroquinolone antibiotics in various patient scenarios and in the setting of various infections. While fluoroquinolones are not always the preferred or first-line treatment choices for infections, they are useful therapeutic alternatives when considering patient allergies, medication history, the bacterial cause of infection, and other patient-specific factors.

Cellulitis

A 34-year-old man has a mild skin infection on his arm from a scratch he received while working. The area is tender and red but there is no abscess. He does not have a significant medical history and he takes no medications on a regular basis. In a case such as this—a non-purulent mild cellulitis—the most likely organisms causing the infection are beta-hemolytic streptococci. According to the IDSA guidelines, the drugs of choice include penicillin, cephalexin, or clindamycin. The choice among these 3 drug therapy options should be made by considering the patient’s history of drug allergy. In a patient with no drug allergies, cephalexin may be an appropriate choice because of its ease of administration compared to penicillin. Additionally, penicillin needs to be taken on an empty stomach but cephalexin does not. In the case of penicillin allergy and cephalosporin intolerance, an alternative non-β-lactam antibiotic such as clindamycin could be chosen to treat this infection.

Surgical site infection

A 54-year-old woman has a surgical site infection following a hysterectomy for benign fibroid tumors. She is known to be colonized with MRSA and has a penicillin allergy, which is described as difficulty breathing. She is 64 inches tall and weighs 63 kg. She has a serum creatinine level of 1.3 mg/dL. Her eGFR is 42 mL/min/1.73 m2. The IDSA guidelines suggest that a fluoroquinolone antibiotic in combination with metronidazole may be selected for surgical site infections following surgery of the female genital tract. However, since delafloxacin has demonstrated efficacy in clinical trials without metronidazole, and since it has activity against gram-positive, gram-negative, and anaerobic pathogens, it may be considered a single-drug alternative.

Delafloxacin is well suited to this clinical scenario, since it has activity against MRSA and gram-negative organisms, which may be causative agents of infection in the female genital tract. The patient has a drug allergy to β-lactams, precluding the use of all penicillins and cephalosporins. Since her eGFR is greater than 30 mL/min/1.73 m2, there is no need to adjust the dose of delafloxacin. She could receive IV therapy and then be changed to oral therapy when she is able to take oral tablets, or she may be a candidate for oral tablets from the initiation of therapy. Patient counseling upon discharge should include education about possible adverse effects and the potential for an interaction with antacids or multivitamins containing minerals.

REFERENCES

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