Fluoroquinolones for intra-abdominal infection

29 October, 2022

Dr. Vichit Prasanthai
Infectious Disease Physician
Phyathai 1 Hospital
Bangkok, Thailand

Intra-abdominal infections (IAIs) are associated with significantly high rates of morbidity and mortality in the critical care setting, globally.¹ IAIs remain one of the most challenging infections to treat, owing to the multiple aetiologies and the severity of infection. Majority of cases ultimately require surgical exploration to identify the source of infection.^2,3 The treatment of IAIs involves optimising antimicrobial therapy, while considering the changing susceptibility patterns and the rise ‏of antimicrobial resistance (AMR).^4,5

Dr. Vichit Prasanthai describes the challenges and treatment strategies for IAIs, including the role of fluoroquinolones such as sitafloxacin in an era of emerging AMR.

Q1. From a clinical viewpoint, IAIs can be classified into two major types: uncomplicated and complicated.⁶ What are the differences in the treatment approach between the two types of IAIs in the intensive care setting?

The universally accepted classification categorises IAIs into complicated and uncomplicated subtypes. With uncomplicated IAIs, the infection only involves a single organ and does not extend to the peritoneum, while in complicated IAIs, the infection extends beyond a single organ, causing either localised or diffuse peritonitis.⁷

Effective treatment and management of IAIs in critically ill patients requires – (a) early recognition, (b) adequate control of the source of infection, (c) appropriate antimicrobial therapy, (d) prompt physiologic stabilisation with early and adequate fluid management, (e) re-evaluation of the clinical response and (f) appropriate adjustment of the management strategy.

In the ICU setting, patients typically have complicated IAIs and multi-organ involvement or sepsis/septic shock, so patients should be treated according to the Surviving Sepsis Campaign Bundle guideline.⁸

Q2. What are the pathogens most frequently responsible for IAIs and how does this relate to the antibacterial spectrum of fluoroquinolones?

The most common pathogens responsible for IAIs are facultative and Gram-negative bacterial groups (Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Proteus mirabilis and Enterobacter species) and anaerobic bacteria (Bacteroides fragilis, other Bacteroides species, Clostridium species, Prevotella species, Peptostreptococcus species, Fusobacterium species and Eubacterium species).⁹ In 2010, international guidelines on the empirical treatment of community-acquired complicated IAIs in adult and paediatric patients were published by the Infectious Diseases Society of America (IDSA) and Surgical Infection Society (SIS). These guidelines recommend the use of a fluoroquinolone (ciprofloxacin or levofloxacin) plus metronidazole for mild, moderate and high severity IAI cases in adults.¹⁰ Moxifloxacin is a broad-spectrum fluoroquinolone with good activity against both aerobic and anaerobic pathogens, good tissue penetration into the gastrointestinal tract, and a good tolerability profile.¹⁰ However, owing to nosocomial infections caused by the spread of multidrug-resistant (MDR) pathogens acquired via invasive procedures, empirical treatment of healthcare- or hospital-acquired IAIs should be adjusted accordingly.^{7, 10}

Q3a. What is your opinion on the role of sitafloxacin in the treatment of patients with IAIs? What are the major advantages that sitafloxacin could offer in comparison to other antimicrobials, including β-lactam-based regimens and other fluoroquinolones?

In our clinical practice, we use selected oral agents with good bioavailability as substitute for intravenous (IV) agents in patients with IAIs who have adequate gastrointestinal function.¹¹ Oral antibiotics must be prescribed for a short course, and use should not be prolonged beyond current recommendations.¹¹

Fluoroquinolones are reported to have good penetration, which makes them useful in treating soft tissue infections with inflammation, compared with β-lactam antibiotics. Resistance against β-lactam antibiotics such as amoxicillin/clavulanate and oral third generation cephalosporins among E. coli and other Enterobacteriaceae is increasing at a significant rate, thus limiting the clinical utility of these drugs for empirical therapy of serious Gram-negative infections. Therefore, β-lactams should be used based on local rates of resistance, and use should be avoided if local Enterobacteriaceae resistance is >20%. Fluoroquinolones provide an additional empirical treatment alternative to broad-spectrum β-lactams (BSBL) for Gram-negative bloodstream infections (GN-BSI) in the absence of antimicrobial resistance.¹²

Sitafloxacin provides coverage for some multi-drug resistant (MDR) E. coli and other Enterobacteriaceae infections in patients with IAIs. In my clinical opinion, once we obtain microbiological data (culture and susceptibility results), we can consider the prescription of sitafloxacin if the causative bacteria are known to be susceptible to this agent.

Q3b. What are the dosing regimens that you would employ, based on available data, including dose selection and duration of treatment?

Optimisation of antimicrobial therapy and duration is dependent on – (1) the clinical response of patients, (2) type of infection (community or hospital-acquired), (3) organ involvement while considering the spread of the infection, and (4) adequate source control of infection. The antibiotic dose and schedule should be optimised to ensure that pharmacokinetic/pharmacodynamic (PK/PD) targets are achieved.

In 2017, a global declaration on the appropriate use of antimicrobial agents was published by the Global Alliance for Infections in Surgery, which encompassed the principles of appropriate antibiotic therapy across the surgical pathways. Once an appropriate initial loading dose is prescribed, daily re-evaluation of duration and appropriateness of the antimicrobial treatment is necessary.¹³ Short courses of antimicrobials should be considered for most patients regardless of signs of inflammation, once infection source control is established, as short courses may be as effective as longer courses.¹³

The 2017 guidelines recommend the following antibiotic therapies across surgical departments worldwide.¹³

Intra-abdominal infection – 4 days are as effective as 8 days in moderately ill patients
Blood stream infection – 5 to 7 days are as effective as 7 to 21 days for most patients
Failure of antibiotic therapy in patients having continual evidence of active infection may require a second intervention for infection source control.

The clinical outcomes in patients with IAIs may be improved by implementing combined infection prevention and control with antimicrobial stewardship joint program in surgical departments.¹³ These interventions and programs typically involve an antimicrobial committee, and continuous and systematic monitoring to assess the compliance with, and efficacy of, antimicrobial therapy.¹² Recommendations for empiric antimicrobial therapy of IAIs are summarised as follows.⁷

For patients with normal renal function, the proposed empiric antibiotic regimens include the following intravenous antibiotic regimens:
- Amoxicillin/clavulanate 2.2 g every 6–8 h +/− gentamicin 5–7 mg/kg every 24 h
- Piperacillin/tazobactam loading dose 6 g/0.75 g then 4 g/0.5 g every 6 h or 16 g/2 g by continuous infusion +/− Gentamicin 5-7 mg/kg every 24 h (in critically ill patients)
- Cefuroxime 1.5 g every 8 h + metronidazole 500 every 8 h
- Ceftriaxone 2 g every 24-hourly + metronidazole 500 mg every 8 h
- Cefotaxime 2 g every 8 h + metronidazole 500 mg every 8 h
- In patients with β-lactam allergy, a fluoroquinolone-based regimen or an aminoglycoside-based regimen is recommended:
- Ciprofloxacin 400 mg every 8 or 12 h + metronidazole 500 mg every 8 h, Amikacin 15–20 mg/kg every 24 h + metronidazole 500 mg every 8 h
In patients at high risk for infection with community-acquired ESBL-producing Enterobacteriaceae, one of the following intravenous antibiotics is recommended:
- Tigecycline 100 mg LD, then 50 mg every 12 h (carbapenem-sparing strategy)
- Ertapenem 1 g every 24 h
- Meropenem 1 g every 8 h (only in patients with septic shock)
- Doripenem 500 mg every 8 h (only in patients with septic shock)
- Imipenem/cilastatin 500 mg every 6 h (only in patients with septic shock)

Q4. Diseases such as appendicitis, diverticulitis and peptic ulcer disease may contribute to the development of IAIs.⁶ What are the challenges faced in the management of IAIs associated with these specific diseases? What are the factors that dictate your choice of fluoroquinolones such as sitafloxacin in the treatment of IAIs associated with specific disease states?

In critically ill patients, the diagnosis of infections including IAIs can be a challenge to physicians because of the lack of or unclear signs and symptoms in an unconscious or sedated patient. The treatment of patients with IAIs involves both surgical and antibiotic therapy. The recommended approach for the treatment of IAIs in patients with specific diseases are summarised as follows.⁷

Acute appendicitis

Appendicitis may be classified into uncomplicated acute appendicitis and complicated appendicitis.

Treatment

Uncomplicated appendicitis

Laparoscopic appendectomy (current standard surgical treatment where appropriate resources and skills are available) or open appendectomy. Post-operative antibiotics are unnecessary if source infection control is adequate.
Antibiotic therapy without surgery (in selected patients)

Complicated appendicitis

Laparoscopic appendectomy (current standard surgical treatment where appropriate resources and skills are available) or open appendectomy, and antibiotic therapy for 4 days if source infection control is adequate (immunocompetent patients)

Acute colonic diverticulitis

Uncomplicated acute diverticulitis

Conservative treatment without antibiotics in patients with computed tomography (CT) diagnosis of uncomplicated acute diverticulitis
Antibiotic therapy for 5–7 days in patients with CT diagnosis of uncomplicated acute diverticulitis and with immunocompromised states or signs of sepsis

Abdominal abscess

Antibiotic therapy alone in patients with small diverticular abscesses
Percutaneous drainage combined with antibiotic therapy for 3–5 days in large diverticular abscesses. Whenever percutaneous drainage of the abscess is not feasible or not available, based on the clinical conditions, unless emergency surgery is needed, antibiotics could be considered as the primary treatment.

Diffuse peritonitis

Primary resection and anastomosis with or without a diverting stoma (in clinically stable patients with no comorbidities)
Hartmann’s procedure (HP) (in critically ill patients and/or in patients with multiple major comorbidities).
Laparoscopic peritoneal lavage and drainage in patients with purulent (but not faecal) peritonitis due to complicated diverticulitis, with add-on antibiotic therapy for 4 days. This is a very controversial approach.

Gastroduodenal ulcer perforation

Treatment

Laparoscopic/open simple or double-layer suture with or without an omental patch is a safe and effective procedure to address small, perforated ulcers (standard procedure).
Distal gastrectomy (large perforations near the pylorus; suspicion of malignancy)
+ antibiotic therapy for 4 days (immunocompetent and stable patients), and more days if there are signs of ongoing sepsis.

In Thailand, sitafloxacin is one of the oral antibiotics that is used to treat infections caused by some MDR Gram-negative bacteria. The key factors that encourage the use of sitafloxacin among treating physicians are its good tissue penetration, and fewer side effects compared to other fluoroquinolones. Sitafloxacin has shown high in vitro activity against Gram-negative bacteria, such as Escherichia coli and Hemophilus influenzae.¹⁴ As compared with ciprofloxacin and levofloxacin, sitafloxacin has a significantly lower minimum inhibitory concentration (MIC), and the rate of resistance to sitafloxacin is significantly low.¹⁴ In our clinical practice, the recommended dose of sitafloxacin in patients with normal kidney function is 100 mg every 12 hours.

References