Antibiotics for pyelonephritis

Antibiotics for pyelonephritis should have high bactericidal properties, a broad spectrum of action, minimal nephrotoxicity and excreted in urine in high concentrations.

The following medicines are used:

• antibiotics;
• nitrofurans;
• non-fluorinated quinolones (derivatives of nalidix and pipemidic acid);
• derivatives of 8-hydroxyquinoline;
• sulfonamides;
• plant uroantiseptics.

[1], [2], [3], [4], [5], [6]

Antibiotics used in the treatment of pyelonephritis

The basis of antibacterial treatment is antibiotics, and among them the beta-lactam group: aminopenicillins (ampicillin, amoxicillin) are characterized by very high natural activity against E. Coli, protea, enterococci. Their main disadvantage is exposure to enzymes - beta-lactamases, produced by many clinically significant pathogens. Currently, aminopenicillins are not recommended for the treatment of pyelonephritis (with the exception of pyelonephritis in pregnant women) because of the high level of resistant strains of E. Coli (over 30%) to these antibiotics, therefore, the drugs of choice for empirical therapy are protected penicillins (amoxicillin + clavulanate, ampicillin + sulbactam), highly active against both gram-negative bacteria, producing beta-lactamases, and against gram-positive microorganisms, including penicillin-resistant golden and coagulase-negative staphylococci. The level of resistance of strains of Escherichia coli to protected penicillins is not high. Assign amoxicillin + clavulanate inside 625 mg 3 times a day or parenterally for 1.2 g 3 times a day for 7-10 days.

"Flemoklav Solutab"  is an innovative dosage form of amoxicillin with clavulanic acid. The drug belongs to the group of inhibitor-protected aminopsninillinone and has proven effectiveness in infections of the kidneys and lower urinary tract. It is allowed to use in children from 3 months and pregnant women.

The tablet "Solutab" is formed from microspheres, the protective shell of which protects the contents from the action of gastric juice and dissolves only at alkaline pH. Those. In the upper parts of the small intestine. This provides the most effective absorption of active components to the preparation "Flemoclav Solutab" in comparison with analogues. In this case, the effect of clavulanic acid on the intestinal microflora remains minimal. A significant reduction in the incidence of adverse drug reactions (especially diarrhea) with the use of Flemoklava Solutab in children and adults is confirmed by clinical studies.

The form of the preparation "Flemoclav Solutab" (dispersible tablets) ensures the convenience of taking: the tablet can be taken as a whole or dissolved in water, a syrup or a suspension with a pleasant fruit taste.

With complicated forms of pyelonephritis and suspected infection  with  Pseudomonas aeruginosa (Pseudomonas aeruginosa), carboxypenicillins  (carbenicillin, ticarcillin) and ureidopenicillins (piperacillin, azlocillin) can be used  . However, a high level of secondary resistance of this pathogen to these drugs should be taken into account. Antisignagic penicillins are not recommended for use as a monotherapy because the rapid development of the resistance of microorganisms during treatment is possible, therefore combinations of these drugs with beta-lactamase inhibitors (ticarcillin + clavulanic acid, piperacillin + tazobactam) or in combination with aminoglycosides or fluoroquinolones are used. The drugs are prescribed for complicated forms of pyelonephritis, severe hospital infections of the urinary system.

Along with penicillins, other beta-lactams are widely used, primarily  cephalosporins, which accumulate in the kidney and urine parenchyma in high concentrations and have moderate nephrotoxicity. Cephalosporins currently occupy the first place among all antimicrobial agents for the frequency of use in hospital patients.

Depending on the spectrum of antimicrobial action and the degree of resistance to beta-lactamases, cephalosporins are divided into four generations. Cephalosporins of the 1st generation (cefazolin, etc.) in view of the limited activity spectrum (predominantly Gram-positive cocci, including penicillin-resistant Staphylococcus aureus) in acute pyelonephritis are not used. A wider spectrum of activity, including E. Coli and a number of other enterobacteria, is characterized by cephalosporins of the second generation (cefuroxime, etc.). They are used in outpatient practice to treat uncomplicated forms of pyelonephritis. More often, the effect of these drugs is broader than that of the 1st generation (cefazolin, cephalexin, cefradine, etc.). For complicated infections, third-generation cephalosporins are used for both ingestion (cefixime, ceftibutene, etc.), and for parenteral administration (cefotaxime, ceftriaxone, etc.). The latter is characterized by a longer half-life and the presence of two pathways - with urine and bile. Among the third generation cephalosporins, some drugs (ceftazidime, cefoperazone and inhibitor-protected cephalosporin cefoperazone + sulbactam) are active against Pseudomonas aeruginosa. Cephalosporins of the 4th generation (cefepime), preserving the properties of 3rd generation drugs against gram-negative enterobacteria and Pseudomonas aeruginosa, are more active against gram-positive cocci.

In the treatment of complicated forms of pyelonephritis, aminoglycosides  (gentamycin, netilmicin, tobramycin, amikacin), which have a powerful bactericidal effect on the plant-negative bacteria, including the Pseudomonas aeruginosa, are used for serious nosocomial infections  , being their means of choice. In severe cases, they are combined with penicillins, cephalosporins. The peculiarity of pharmacokinetics of aminoglycosides is their poor absorption in the gastrointestinal tract, therefore they are administered parenterally. The drugs are excreted by the kidneys in an unchanged form, with renal failure, dose correction is necessary. The main disadvantages of all aminoglycosides are pronounced ototoxicity and nephrotoxicity. The frequency of hearing loss reaches 8%, kidney damage (neoliguric renal failure, usually reversible) - 17%, which dictates the need to monitor the level of potassium, urea, serum creatinine during treatment. In connection with the proven dependence of the severity of unwanted reactions on the concentration level of drugs in the blood, it was suggested to administer a full daily dose of drugs once; with the same dosage regimen, the risk of nephrotoxic action is reduced.

The risk factors for developing nephrotoxicity in the use of aminoglycosides are:

• old age;
• repeated use of the drug with an interval of less than a year;
• chronic therapy with diuretics;
• combined use with cephalosporins in high doses.

In recent years, the fluoroquinolones of the 1st generation  (ofloxacin, pefloxacin, ciprofloxacin) are considered to be the drugs of choice in the treatment of pyelonephritis both on an outpatient and inpatient basis  , which are active against most pathogens of the urinary tract infection and have low toxicity, a long half-life, that gives an opportunity of reception 1-2 times a day; well tolerated by patients, create high concentrations in urine, blood and kidney tissue, can be administered orally and parenterally (except norfloxacin: only applied orally).

Preparations of the  new (2nd) generation of fluoroquinolones  (proposed for use after 1990): levofloxacin, lomefloxacin, sparfloxacin, moxifloxacin - show significantly higher activity against gram-positive bacteria (primarily pneumococci), while in the activity against gram-negative bacteria not inferior to the early ones (the exception is the Pseudomonas aeruginosa).

[7], [8], [9], [10], [11]

Ciprofloxacin for pyelonephritis

The highest activity against P. Aeruginosa is ciprofloxacin.

Ciprofloxacin ("Cyprinol") is a systemic fluoroquinolone with a broad spectrum of antimicrobial activity. It has a bactericidal effect on most gram-negative and on some phamp-positive microorganisms. To ciprofloxacin in vitro, some intracellular pathogens are moderately sensitive.

[12], [13], [14], [15],

Dosage

Tablets are taken whole with a small amount of liquid. For intravenous administration, it is best to use a short infusion (60 min).

In severe complicated infections and depending on the pathogen (for example, with P. Aeruginosa infection ), the daily dose can be increased to 750 mg 3 times when ingested or up to 400 mg 3 times intravenously.

[16], [17], [18], [19], [20], [21]

Indications

• Bacterial infections of the urinary and lower respiratory tract, ear, throat and nose, bones and joints, skin, soft tissues, genital organs.
• Prevention of infections during surgical interventions, in particular, in urology, gastroenterology (in combination with metronidazole) and orthopedic surgery.
• Bacterial diarrhea.
• Abdominal and hepatobiliary infections.
• Heavy systemic infections.

Contraindications

• Hypersensitivity to the drug or other quinolones.
• Pregnancy and lactation.
• It is not recommended the use of ciprofloxacin in children and adolescents during the period of growth.

[22], [23], [24], [25], [26], [27]

Packaging

10 tablets of 250 mg, 500 mg or 750 mg; solution for infusions (conc.) 100 mg in 10 ml No. 5 (amp.); solution for infusions of 200 mg in 100 ml of No. 1 (fl.).

In most cases, with pyelonephritis, fluoroquinolones are administered orally, in severe forms, general infection is parenteral ("stepwise" therapy is possible).

Empirical antibiotic therapy for pyelonephritis

Pyelonephritis acute or exacerbation of chronic (mild and moderate severity) - outside the hospital (outpatients)

Drugs of choice	Alternative drugs
Amoxicillin + clavulanic acid inside by 375 -625 mg 3 times a day Levofloxacin inside 250 mg once a day Lomefloxacin inside 400 mg once a day Norfloxacin inside 400 mg twice a day Ofloxacin inside 200 mg twice a day Pefloxacin inside 400 mg twice a day Ciprofloxacin administered 250 mg twice daily	Co-trimoxazole orally 480 mg twice a day after meals Cefixime by 400 mg once a day Ceftibutin by 400 mg once a day Cefuroxime inside by 250 mg twice a day

Pyelonephritis (severe and complicated forms) - hospital

Amoxicillin + clavulanic acid intravenously on 1,2 g 3 times a day, inside by 625 mg 3 times a day Levofloxacin intravenously 500 mg once a day, inside 500 mg once a day Ofloxacin intravenously 200 mg twice a day, inside 200 mg twice a day or Pefloxacin intravenously on 400 mg 2 times a day, inside 400 mg twice a day or Ciprofloxacin intravenously on 200 mg 2 times a day, inside 250 mg twice a day

Gentamicin intravenously or intramuscularly at 80 mg 3 times a day [3-4 mg / (kilogram)), or Ticarcillin + clavulanic acid intravenously by 3.2 g 3-4 times a day or Imipenem + cilastine intramuscularly at 500 mg 2 times a day or Cefotaxime intravenously or intramuscularly 1-2 g 2-3 times a day or Ceftazidime intravenously or intramuscularly 1-2 g 2-3 times per day or Ceftriaxone intravenously or intramuscularly 1-2 g once a day Cefoperazone intravenously 2 g 2-3 times a day

The half-life of various fluoroquinolones ranges from 3-4 hours (norfloxacin) to 18 hours (pefloxacin).

When the renal function is disturbed, the half-life of ofloxacin and lomefloxacin is much longer. With severe renal failure, correction of the doses of all fluoroquinolones is necessary, with a violation of the liver - pefloxacin.

When hemodialysis, fluoroquinolones are removed in small amounts (ofloxacin - 10-30%, the rest - less than 10%).

In the appointment of ciprofloxacin, norfloxacin and pefloxacin together with drugs alkalinizing urine (inhibitors of carbonic anhydrase, citrates, sodium bicarbonate), the risk of crystalluria and nephrotoxic effects increases.

To the possible, but very rare (0.01-0.001%) undesirable reactions can be attributed inflammatory reactions from the tendons (associated with a violation of the synthesis of peptidoglycan in the structure of tendons), tendinitis and tendovaginitis (more often Achilles tendon, less often the shoulder joint), due to than it is recommended to be used with caution in elderly patients on hormone therapy. Patients with diabetes mellitus may develop hypo- or hyperglycemia.

Fluoroquinolones are not allowed in pregnant women and children under 16 due to the risk of chondro toxicity. It is possible to prescribe fluoroquinolones to children for vital signs (severe infections caused by multiresistant strains of bacteria).

In the treatment of particularly severe complicated forms of pyelonephritis, reserve preparations with an extra-wide spectrum of action and resistance to the action of most beta-lactamases are carbapenems (imipenem + cilastatin, meropenem). Indications for the use of carbapenems are:

• generalization of infection;
• bacteremia;
• sepsis;
• polymicrobial infection (combination of gram-negative aerobic and anaerobic microorganisms);
• presence of atypical flora;
• ineffectiveness of previously used antibiotics, including beta-lactam.

The clinical efficacy of carbapenems is 98-100%. Carbapenems are a means of choice for the treatment of infections caused by resistant strains of microorganisms, especially Klebsiella spp. Or E. Coli producing broad spectrum beta-lactamases, as well as Class C chromosomal beta-lactamases (Enterobacter spp., etc.), which are most common in intensive care units and organ transplantation. It is possible to use protected beta-lactams (ticarcillin + clavulanic acid, piperacillin + tazobactam) or cefepime (optimal with the sensitivity set to them) as an alternative for the eradication of enterobacteria producing beta-lactamases of the extended spectrum. It should be remembered that carbapenems are not active against methicillin-resistant staphylococci, as well as atypical pathogens - chlamydia and mycoplasmas.

Along with antibiotics, other antimicrobial agents are used in the treatment of pyelonephritis, which are introduced into long-term therapy after the abolition of antibiotics, sometimes prescribed in combination with them, more often to prevent exacerbations of chronic pyelonephritis. They include:

• Nitrofurans (nitrofurantoin, furazidine);
• 8-hydroxyquinolines (nitroxoline);
• nalidix and pipemidic acid;
• combined antimicrobials (co-trimoxazole).

The pH of urine may have a significant effect on the antimicrobial activity of some drugs. Increase of activity in acidic medium (pH <5,5) was noted in aminopenicillins, nitrofurans, oxyquinolines, nalidixic acid, in alkaline medium - in aminoglycosides, cephalosporins, semisynthetic penicillins (carbenicillin), sulfonamides, macrolides (erythromycin, clindamycin).

In the presence of chronic renal failure in the usual dose, antibiotics can be prescribed that are metabolized in the liver: azithromycin, doxycycline, pefloxacin, chloramphenicol, cefaclor, cefoperazone, erythromycin. Do not recommend the appointment of aminoglycosides, tetracyclines, nitrofurans, co-trimoxazole. It should be borne in mind that the nephrotoxicity of various drugs increases in conditions of using diuretics and with renal failure.

[28], [29]

Criteria for the efficacy of antibiotics for pyelonephritis

[30], [31], [32], [33]

Early criteria (48-72 hours)

Positive clinical dynamics:

• decreased fever;
• decrease in intoxication;
• improvement of general well-being;
• normalization of the functional state of the kidneys;
• sterility of urine after 3-4 days of treatment.

[34], [35], [36], [37], [38]

Late criteria (14-30 days)

Persistent positive clinical dynamics:

• no recurrence of fever;
• absence of chills within 2 weeks after the end of antibiotic therapy;
• negative results of bacteriological examination of urine on the 3-7th day after the end of antibiotic therapy.

Final criteria (1-3 months)

Absence of repeated infections of the urinary tract for 12 weeks after the end of antibacterial treatment of pyelonephritis.

[39], [40], [41], [42], [43], [44]