Current Options for the Treatment of Urinary Tract Infections Caused by Multiresistant Acinetobacter baumannii

Abstract

Urinary tract infections (UTIs) are the main etiological agent of Gram-negative bacteria. UTI and pneumonia are the main causes of sepsis in older people. With the advance of medicine, the increase in life expectancy, more frequent prescription of immunosuppressive therapies, and indiscriminate use of antibiotics, multidrug-resistant (MDR) pathogens have become a global public health problem. Among them, the rise of MDR Acinetobacter baumannii infections is observed in hospitals, especially in patients accommodated in intensive care units (ICU) and/or in the use of medical devices, such as urinary catheters. Treating UTIs caused by carbapenem-resistant Acinetobacter baumannii became a challenge, given the few therapeutic options and low penetration of polymyxin B into the renal parenchyma.

1. Introduction

Urinary tract infection (UTI) is one of the most common infections in humans. The Gram-negative bacteria represent the main etiological group in community and nosocomial cases [1, 2].

Nowadays, Acinetobacter baumannii — a coccobacillus Gram-negative — is an important pathogen to hospitals worldwide, becoming a public health problem when multidrug-resistant (MDR) [3]. Its ability to overlap resistance mechanisms culminated in the appearance of strains resistant to all available antibiotics in the industry [4]. Most infections are healthcare-associated and linked to invasive devices such as urinary catheters [5].

The World Health Organization (WHO) listed carbapenem-resistant strains as one of the priority agents for developing new antibiotics [6]. This chapter aims to bring options for treating UTI caused by MDR A. baumannii, given that the urinary concentration of drugs restricts the choice of the therapeutic regimen [7, 8].

2. Epidemiology

MDR strains have become frequent causes of nosocomial infections since the 1980s. In a study from 2007 that involved 100 hospitals worldwide, 34% of Acinetobacter isolates were resistant to ceftazidime and 41% to ciprofloxacin. From 1999 to that year, the carbapenem resistance increased from 10 to 54% [9].

In a recent study conducted by Seifer et al., between 2016 and 2018, the global resistance to meropenem reached 67%, while the overall resistance to colistin was 7%. The highest percentage of carbapenem resistance of over 90% was reported in the Mediterranean region, imposing serious burdens on healthcare systems [10].

Di Venanzio et al. analyzed Acinetobacter isolates identified in the BJC Healthcare System from January 2007 to August 2017. The study showed that, among the over 19,000 cases, 17.1% came from the urinary tract [11]. But only 2% of UTIs are caused by this pathogen. However, A. baumannii is the main agent causing UTIs associated with using catheters in ICUs. More than 50% of the isolated strains from urine come from catheterized patients [12].

There are some risk factors for developing infections caused by MDR A. baumannii (Table 1) [13, 14, 15, 16].

Risk factors

ICU hospitalization (previous or current)

Recent surgical procedures

Previous colonization by Methicillin-Resistant Staphylococcus aureus (MRSA)

Invasive devices such as central venous and urinary catheters

Hemodialysis

Malignant neoplasms

Previous administration of beta-lactams (mainly carbapenems) and fluoroquinolones

Infusion of neurobiological or chemotherapeutic agents

Bed restriction

Burns

Preterm birth

Table 1.

Risk factors involving infections caused by MDR A. baumannii.

3. Clinical presentation

The signs and symptoms vary according to the affected segment of the urinary tract. The main manifestations of acute cystitis include dysuria, pollakiuria, suprapubic pain, urinary urgency, and even hematuria. In older patients, the identification could be more difficult due to a higher frequency of nonspecific symptoms. Those patients can present delirium, change in level of consciousness, prostration, and inappetence [17].

Fever and other systemic symptoms (nausea, vomiting, and nonmechanical back pain) suggest a complicated UTI or upper urinary tract involvement. Hypotension, tachycardia, tachypnea, and oliguria suggest a more severe infection, such as sepsis and septic shock [18].

The anamnesis may assess, beyond the medical history, the use (current or prior) of invasive devices, particularly urinary catheterization, recent hospitalization (especially in ICU and emergency departments), and recent use of antibiotics [19].

It is fundamental to differentiate a context of infection from colonization, which will lead to different approaches [20, 21].

4. Diagnosis

In addition to the clinical evaluation, it is recommended to request complementary exams. In front of a suspicion of a not complicated UTI, it is important to perform a urinalysis and urine culture. Patients with preserved consciousness and urinary continence may spontaneously collect a midstream urine specimen after proper hygiene of the genitourinary region [22].

In patients with systemic symptoms, especially the elderly, diabetic, with an immunosuppressive condition, blood cultures and imaging exams (ultrasound or computed tomography) must be performed to screen for pyelonephritis or complications, such as kidney abscess (Figure 1) [23].

Figure 1.

Perinephric abscess compromising the mid pole of right kidney, with thickening of Gerota’s fascia. Case courtesy of Ian Bickle, Radiopaedia.org, rID: 29853.

5. Treatment

In a first medical evaluation, in front of a urinary tract infection, the physician will not know the etiological agent, even if the patient has risk factors for MDR pathogens, and an empiric treatment would be initiated. In these cases, broad-spectrum antibiotics are recommended with coverage for Gram-negative bacilli. Prior — and particularly current — cultures can guide the chosen scheme. If the patient uses a urinary catheter, it is part of the treatment to remove or exchange it for a new one [24, 25].

After identifying a strain of A. baumannii in the cultures, the treatment must be based on the sensitivity profile of the antibiogram (Figure 2).

Figure 2.

An example of an antibiogram with a MDR pathogen. Ak = amikacin; AMP = ampicillin; C = chloramphenicol; Cl = colistin; CIP = ciprofloxacin; E = erythromycin; EX = enrofloxacin; GEN = gentamicin; S = streptomycin; Te = tetracycline.

The therapeutic scheme is divided into first-line, second-line, and synergistic agents (not recommended monotherapy) [26].

5.1 First-line agents

When susceptible to the antibiogram, a first-line antibiotic must be chosen. The main options are listed below with the indicated dosage for a patient with normal renal function (Table 2) [27, 28, 29, 30, 31, 32].

Antibiotic	Dosage
Ciprofloxacin	750 mg orally bid or 400 mg every 8 hours
Levofloxacin	750 mg orally or intravenously qd
Trimethoprim-sulfamethoxazole	1 tablet (160 + 800 mg) bid
Ampicillin-sulbactam	Carbapenem-susceptible infections: 3 g intravenously every 6 hours; carbapenem-resistant conditions: 3 g intravenously every 4 hours; Severe conditions: 9 g intravenously every 8 hours (or 27 g at continuous infusion)
Ceftazidime	2 g intravenously every 8 hours
Cefepime	2 g intravenously every 8 hours
Tazobactam-piperacillin	4.5 g intravenously every 6 or 8 hours
Meropenem	Cystitis: 1 g intravenously every 8 hours; Pyelonephritis or complicated infections: 2 g intravenously every 8 hours
Imipenem	Cystitis: 500 mg intravenously every 6 hours; Pyelonephritis or complicated infections: 500 mg to 1 g every 6 or 8 hours
Gentamicin	Cystitis: 5 mg/kg intravenously qd
Amikacin	Cystitis: 15 mg/kg intravenously qd

Table 2.

First-line antibiotics used in the treatment of MDR A. baumannii.

5.2 Second-line agents

When it is diagnosed as a resistant infection to all the first-line agents, one of the options below must be considered (Table 3) [33, 34, 35, 36].

Antibiotic	Dosage
Colistin (polymyxin E)	Loading dosage of 9 million units of colistimethate sodium. Daily maintenance dosage of 9 to 11 million units, divided into three or three infusions.
Cefiderocol	2 g every 8 hours - this medication was approved by the Food and Drug Administration (FDA) for complicated UTIs in 2019. It is only available in some countries.

Table 3.

Second-line antibiotics used in the treatment of MDR A. baumannii.

5.3 Combined therapy

Some antibiotics, even with adequate sensitivity on antibiogram, could be ineffective as monotherapy. Although aminoglycosides are a good option for treating mild cases of UTI, their isolated administration is not recommended for moderate and severe infections (Table 4) [32, 37, 38].

Antibiotic	Dosage
Polymyxin B	Zavascki et al. demonstrated in a study that only 1% of the unaltered drug was found in the urine. Therefore, colistin is preferred for the treatment of UTIs. When colistin is unavailable, the recommended loading dose of polymyxin B is 20.000 units/kg, followed by a maintenance dose of 15.000 units/kg bid.
Gentamicin	Pyelonephritis or complicated infections: 7 mg/kg intravenously for the first dose, followed by 2–3 mg/kg/day divided into two or three doses.
Amikacin	Pyelonephritis or complicated infections: 20 mg/kg intravenously for the first dose, followed by 15 mg/kg/day, in a single dose or divided into two doses.

Table 4.

Antibiotics used as part of combined therapy in the treatment of MDR A. baumannii.

5.4 Other considerations

1. To treat cystitis without systemic manifestations, some experts recommend the oral administration of fosfomycin. However, its effectiveness could be better. A. baumannii is intrinsically resistant in vitro studies. No protocols define the duration of treatment, and there is no standardized methodology to determine susceptibility [39, 40].

2. Doxycycline, minocycline, and tigecycline usually do not present enough serum or urinary concentrations to treat UTI properly [41, 42, 43].

3. Novel antibiotics should not be used because they have limited in vitro activity against Acinetobacter strains [44, 45].

6. Conclusion

The incidence of MDR Acinetobacter has increased in recent decades with higher resistance to carbapenems and colistin. To treat these infections became a challenge and a public health problem. When analyzing the management of UTI-caused MDR A. baumannii, the options become scarce because of the low urinary concentration of some drugs. Novel agents until now are ineffective, owing to an observed in vitro intrinsic resistance. Therefore, developing new antibiotics, and even vaccines, is necessary and is in the sights of scholars as part of the WHO’s goals for the near future.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

bid	two times a day;
qd	once time a day;
ICU	intensive care unit
MDR	multidrug-resistant
MRSA	methicillin-resistant Staphylococcus aureus
UTI	urinary tract infection
WHO	world health organization