1 Introduction

Antimicrobial agents are widely used pharmaceuticals in hospital and outpatient care. They are causal therapeutic agents and their rational use can decrease antibiotic resistance, and therefore, hospital stay and treatment costs. However, due to increased quality standards and cost pressure for public health services, these requirements can only be achieved if up-to-date infectious disease management strategies have been implemented. Although guidelines and recommendations from several associations and institutions were included in this chapter, it is important to note that rational empiric antibiotic therapy underlies continuous alterations. Therefore, therapeutic recommendations can only capture basic principles. Often various therapeutic options are available, and the therapeutic spectrum is not always comparable in different countries or institutions. Various treatment options help to avoid allergic reactions and allow to choose antibiotic agents according to the individual patient’s risk profile.

2 Basic Principles of Antimicrobial Therapy

Characterization of antibiotics, pharmacokinetics, efficacy, antibiotic resistance, and side effects (Table 16.1).

Table 16.1 Antimicrobial agents for parenteral application
Full size table

The antibiotic agents described were selected with specific consideration of their importance in the surgical field.

3 Penicillins

The classification of penicillins is based on their chemical structure. Different chemical constitutions imply varying effects against pathogens and their beta-­lactamases. Penicillins are bactericidal due to blockade of bacterial transpeptidases which are important for the peptidoglycan synthesis in the bacterial cell wall. Benzylpenicillins, aminopenicillins, and isoxazolylpenicillins are available in parenteral and enteral pharmaceutical forms, whereas acylaminopenicillins can only be administered intravenously. Penicillins are approved for treatment of systemic and local infections with various gram-positive and gram-negative pathogens. A wider range of pathogens can be treated via combination of penicillins with a beta-lactamase inhibitor.

3.1 Pharmacokinetics

Penicillins generally exhibit a medium to high plasma concentration while their half-life is in the low to middle range (0–10 h). They reside mostly in the extracellular space with a low relative distribution volume of 0–0.4 L/kg. The rate of metabolization is low, and penicillins are mainly eliminated via the kidneys through tubular secretion. Isoxazolylpenicillins have a high plasma protein–binding capacity and low tissue distribution compared to the other penicillins. The best time-dependent efficacy kinetics can be reached if drug concentrations at the site of infection are above the minimum inhibitory concentration and therefore short treatment intervals are necessary.

3.2 Efficacy and Indication

The efficacy of penicillins is dependent on their chemical structure. It ranges from small spectrum (Penicillin G) and extends to broad-spectrum efficacy if combined with beta-lactamase inhibitors (Piperacillin-Tazobactam).

Application of Penicillin G is limited to Strep­tococcus species (spp.), Pneumococci, Meningococci, and some anaerobic pathogens (Clostridium spp., Actinomyces spp.) and should not be given as a single agent if a serious infection is present. Nevertheless, Penicillin G is still the first choice for erysipelas and treatment of infections with Streptococcus and Pneumococcus if cultures do not reveal mixed pathogens.

Aminopenicillins have a broad-spectrum efficacy. They are very effective against Enterococcus and some gram-negative pathogens. Aminopenicillins are approved for treatment of endocarditis and meningitis. In combination with beta-lactamase inhibitors, their spectrum is extended to infections with several other gram-positive and gram-negative pathogens, including infections of the upper respiratory tract, urinary tract, abdomen, genitals, skin, and soft tissue.

Isoxazolylpenicillins have a narrow spectrum only and are useful against Staphylococcus including those strains producing penicillinase. Possible indications are endocarditis, arthritis, infection of the skin and soft tissue as long as the Staphylococcus strain is not resistant against methicillin.

Acylaminopenicillins are broad-spectrum antibiotics and include gram-positive and gram-negative aerobic and anaerobic pathogens. Piperacillin also covers infections with Pseudomonas aeruginosa. In combination with beta-lactamase inhibitors, they are also effective against various beta-lactamase-producing pathogens. Indications are infections of nearly all organ systems. Piperacillin-Tazobactum can be used as rational empiric antibiotic therapy for serious infections.

3.3 Antibiotic Resistance

Resistance of Streptococcus and Pneumococcus against penicillin is still low at approximately 2% of the isolates, but can reach up to 30% in some countries. The resistance rate of Escherichia coli against aminopenicillins increased within the last years to more than 50%. The efficacy of piperacillin-tazobactam against Pseudomonas aeruginosa is still sufficient. The fraction of oxacillin-resistant Staphylococcus aureus (MRSA) is continuously increasing. It ranges from approximately 15% of Staphylococcus aureus isolates from hospital patients in some European countries to more than 60% in the United States. The antibiotic resistance rate for Staphylococcus epidermidis and coagulase-negative Staphylococcus is commonly more than 70%.

3.4 Side Effects (Table 16.2)

Allergic reactions can be observed in 0.7–10% of all patients treated with penicillins and occur particularly after repeated applications. These hypersensitive reactions are characterized by nausea, vomitus, bronchospasm, and hypotonia. Delayed allergic reactions can appear 7–10 days after administration of penicillins with fever, urticaria, lymph node swelling, and hemolytic anemia, defined as Type III hypersensitivity reactions (Arthus type). Neurotoxicity can arise only after application of high dosage of penicillins (80–100 Mio. IU/day). Additionally, pseudo-allergic skin reactions may occur after treatment with aminopenicillins if a concomitant viral infection is present (mononucleosis). Antibiotic therapy with isoxazolylpenicillins can increase liver enzymes.

Table 16.2 Side effects of penicillin treatment and alternative treatment options
Full size table

4 Cephalosporins

Cephalosporins are grouped into basic and broad-spectrum cephalosporins. They are generally classified into five groups. Cephalosporins are bactericidal, and their pharmacokinetic characteristics are comparable to penicillins. Agents of groups 1 and 2 are effective against Staphylococci which decreases in groups 3–5. In contrast, substances of groups 2–5 have increasing efficacy against gram-negative pathogens. Additionally, cephalosporins possess a good efficacy against pathogens producing beta-lactamase based on their stability against various kinds of bacterial beta-lactamases.

4.1 Pharmacokinetics

Most cephalosporins are eliminated unmodified via the kidneys, and their mean half-life is 2 h in patients with normal renal function. Their distribution in the different body compartments is also similar to those of penicillins. Only ceftriaxone (group 3a) reveals an extended half-life of 8 h, and therefore, a single daily application is sufficient. Moreover, approximately 50% of ceftriaxone is excreted via the biliary system.

4.2 Efficacy and Indication

In general, all cephalosporins are ineffective against Enterococci and methicillin-resistant Staph­ylococci. Substances of the first generation ­(cephazolin) have a good efficacy against methicillin-sensible Staphy­lococci and Streptococci, but are weak against gram-negative pathogens. Cepha­losporins of the second generation (cefuroxime, cefotiam) have an extended spectrum against gram-negative bacteria and con­tinuing activity against gram-positive pathogens. ­Third-generation cephalosporines (cefotaxime, ceftriaxone) have a broad-spectrum with excellent activity against gram-negative bacteria but decreasing effects against Staphylococci. In addition, ceftazidime (third generation with anti-pseudomal activity) and cefepime (fourth generation) exhibit anti-pseudomonal activity. Cefepime also has good efficacy against Staphylococci, Streptococci and beta-lactamase-producing bacteria compared to ceftazidime. Furthermore, cephalosporins of the fifth generation (cefoxitine) are effective against anaerobic pathogens.

Cephalosporins are approved for treatment of various kinds of infections, including infections of the respiratory and urinary tracts, bones and joints, genitals, skin and soft tissue. Cefotiam and cephalosporins of the third to fifth generation are also approved for infections of the biliary tract and abdomen. In addition, cephalosporins of the first, second, third, and fifth generation are used as prophylactic antibiotics during the perioperative phase.

4.3 Antibiotic Resistance

High rates of antibiotic resistance for second-generation cephalosporins can be detected in Enterobacter spp., Citrobacter, and indol-positive strains of the Proteus group. Since several years, increasing antibiotic resistance rates up to 28% can be observed in Escherichia coli isolated from ICU patients. Isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum-beta-lactamases (ESBL) cause antibiotic resistance against third- and fourth-generation cephalosporins ranging from 4–8% up to 55% (South America) in hospitalized patients.

4.4 Side Effects

Possible side effects are comparable to those of penicillins, but allergic reactions are fewer. Increased liver enzymes and gastrointestinal discomfort occur in 5–10% of all treated patients. Augmented risk of bleeding may appear if anticoagulants are given simultaneously with cefoxitin. Therapeutic administration of ceftriaxone can rarely lead to shadows in the ultrasound of the gall bladder which is called transitory ­biliary pseudolithiasis.

5 Carbapenems

Carbapenems are also beta-lactam antibiotics with bactericidal efficacy due to inhibition of the bacterial cell wall synthesis. They are divided into two groups with group 1 consisting of imipenem and group 2 of meropenem and ertapenem. Carbapenems, especially those of group 1, are broad-spectrum antibiotics approved for the treatment of serious life-threatening infections and empiric therapy in patients receiving immunosuppressive medication.

5.1 Pharmacokinetics

The distribution volume of carbapenems is small and mainly extracellular. Protein-binding capacity is more than 90% for ertapenem, while imipenem and meropenem have much lower capacities with 20% and 2%, respectively. In part, carbapenems are metabolized and predominately eliminated via the kidneys. Ertapenem has a longer plasma half-life of 4 h compared to the other carbapenems.

5.2 Efficacy and Indications

Carbapenems are broad-spectrum antibiotics, and their efficacy includes almost all bacteria including anaerobic pathogens, except for Enterococcus facium, methicillin-resistant Staph­ylococci, and Stenotropho­monas maltophilia. Doripenem is very effective against Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter spp. which are resistant against other antimicrobial drugs. The efficacy of ertapenem is different with no effects against Pseudomonas aeruginosa, Acinetobacter spp., and Enterococci. Carbabenems are approved for the treatment of serious pneumonia, intra-abdominal infections, sepsis, and infections of the skin and soft ­tissue and for empiric therapy in neutropenic patients.

5.3 Antibiotic Resistance

Currently, antibiotic resistances including Entero­bacteriaceae are rare. It has been shown that some Klebsiella species are resistant against carbapenems due to release of carbapenem-hydrolyzing metallo-beta-lactamases. Although the efficacy of carbapenems is still good, infections with Pseudomonas aeruginosa, Burkholderia cepacia, or other non-­fermenting bacteria in hospitalized and/or immunosuppressed patients demonstrate increased rates of resistance.

5.4 Side Effects

Mild gastrointestinal symptoms can be observed in 5–10% of all treated patients. Allergic reactions occur rarely with less than 3%.

6 Monobactams

The only available monobactam is aztreonam. The mechanism of action is similar to beta-lactams. It is stable against some beta-lactamases. Aztreonam is bactericidal through inhibition of mucopeptide synthesis in the bacterial cell wall, and thereby blocking peptidoglycan crosslinking. It is only active against gram-negative bacteria. Aztreonam displays good efficacy against Entero­bacteri­aceae and non-lactose fermenters including Pseudomonas aeruginosa. There is limited cross-reactivity between aztreonam and other beta-lactam antibiotics, and it is generally considered safe to administer aztreonam to patients with hypersensitivity to penicillins.

6.1 Pharmacokinetics

The distribution volume of aztreonam is low, but sufficient levels can be reached in urine; bile; and pleural, pericardial, and synovial fluids. Approximately 56% is bound to plasma proteins and the plasma half-life is 2 h. Aztreonam is not metabolized and is mainly excreted via glomerular filtration and tubular secretion as unchanged drug.

6.2 Efficacy and Indication

Aztreonam has strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa. It is approved for treatment of pneumonia, skin and soft tissue infections, complicated and uncomplicated urinary tract infections, gynecologic infections, and intra-abdominal infections and septicemia caused by gram-negative bacteria in combination with anaerobic coverage.

6.3 Antibiotic Resistance

Anaerobic bacteria, Acinetobacter spp., Burkholderia cepacia-complex, Stenotrophomonas maltophilia, and gram-positive pathogens are generally resistant against aztreonam.

6.4 Side Effects

Side effects include injection site reactions, rash, ­gastrointestinal disorder, and rarely toxic epidermal necrolysis. There may be drug-induced eosinophilia.

7 Fluroquinolones

Fluoroquinolones are divided into four groups. Group one has no clinical relevance and clinical relevant agents are ciprofloxacin, ofloxacin and norfloxacin (group 2), levofloxacin (group 3), and moxifloxacin (group 4). They can be administrated parenterally as well as orally due to their excellent acid stability. Fluroquinolones are bactericidal through inhibition of bacterial DNA-gyrases which are important for the nucleotide acid synthesis.

7.1 Pharmacokinetics

The relative distribution volume of all fluoroquinolones is large with 2 up to 41 L/kg and they penetrate excellently into various tissues. Their plasma protein–binding capacities add up to <40%. The half-life varies between 3 and 4 h for ciprofloxacin and norfloxacin, 7–8 h for ofloxacin and levofloxacin, and >10 h for moxifloxacin. Therefore, their intervals of administration differ. Levofloxacin and ofloxacin are eliminated via renal secretion while ciprofloxacin and norfloxacin also are eliminated via the liver and intestines. Moxifloxacin is almost completely eliminated via ­conjugation reactions.

7.2 Efficacy and Indications

Fluoroquinolones are approved for the treatment of infections of the urinary tract, ENT and respiratory tract, abdomen, genitals, bones, skin and soft tissues as well as for serious systemic infections (i.e., sepsis). Ciprofloxacin, ofloxacin, and norfloxacin (group 2) have a good efficacy against gram-negative bacteria (Enterobacteriaciae, Hemophilus influencae, Pseudomonas aeruginosa) and a considerably lower effectiveness in the gram-positive field (Staphylococci, Pneumococci, and Enterococci). Levofloxacin (group 3) has better and moxifloxacin (group 4) much better effects against gram-positive and atypical pathogens. Moxifloxacin has a poor effectivity against Pseudomonas aeruginosa but the antibiotic spectrum of moxifloxacin also includes anaerobic bacteria.

7.3 Antibiotic Resistance

In recent years, antibiotic resistance rates against fluroquinolones are on the rise in all relevant bacterial strains. Escherichia coli has resistance rates from 7% up to 20% of all isolates, Staphylococcus aureus from 15% up to 60% (mostly MRSA isolates) and Pseudomonas aeruginosa from 10% up to 30% against ciprofloxacin.

7.4 Side Effects

Side effects after treatment with fluoroquinilones are present in 4–10% of all patients. Common symptoms are gastrointestinal irritation, affection of the CNS with sleep disturbances and obnubilation. Reactions of the skin are rare, but UV exposure should be avoided due to the phototoxic effects of all fluoroquinolones. Caution is needed in patients with tendon degeneration, since tendon ruptures have been described after administration of fluoroquinolones. Additionally, prolongation of the QTc-interval has been observed after therapy with fluroquinolones.

8 Macrolides

The most commonly used macrolides are erythromycin, clarithromycin, and azithromycin which can be applied parenterally, while roxithromycin can only be given enterally. The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic, but can be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and therefore, they become transported to the site of infection. Presently, their use in the surgical field is limited.

8.1 Pharmacokinetics

The half-life of macrolides ranges from 2.5 h for erythromycin, 2–5 h for clarithromycin, 12 h for roxithromycin, and >14 h for azithromycin. The distribution volume varies considerably from 0.7 L/kg BW for erythromycin up to 25 L/kg BW for azithromycin. Erythromycin is predominantly metabolized by demethylation in the liver. The main elimination route of macrolides is via the biliary tract, and a small fraction via the urine (<4.5%).

8.2 Efficacy and Indications

Macrolides are approved for the treatment of infections of the upper airways, ENT field and the urinary tract caused by Streptococci, Pneumococci, Chlamydia, Legionella, Mycoplasma, and Ureaplasma. Entero­bacteriaceae and Pseudomonas spp. are generally resistant against macrolides. Macrolides represent an alternative treatment option for infections with Strep­tococci (scarlet fever, erysipelas) in patients with an allergy to penicillins.

8.3 Antibiotic Resistance

Antibiotic resistance rates of Pneumococci against macrolides range at approximately 20%.

8.4 Side Effects

Macrolides, mainly erythromycin and clarithromycin, have a class effect of QT prolongation which can lead to torsade de pointes. Macrolides exhibit enterohepatic recycling which can lead to recurrence of the product in the system, causing nausea, gastrointestinal disorder, and increase in liver enzymes. Local reactions at the site of application (phlebitis) are frequent. Furthermore, treatment with macrolides can cause vertigo.

9 Glycopeptides

The glycopeptides vancomycin and teicoplanin are only available for parenteral application because they are not absorbed after oral intake. This class of drugs inhibits the synthesis of cell walls in susceptible microbes by inhibiting peptidoglycan synthesis. They bind to the amino acids within the cell wall preventing the addition of new units to the peptidoglycan. Glycopeptides are only effective against gram-positive bacteria. They are considered as reserve option for the treatment of infections with multi-resistant gram-positive pathogens, as their efficacy in beta-lactam-susceptible pathogens is worse than that of the beta-lactams.

9.1 Pharmacokinetics

Glycopeptides have a time-dependent therapeutic effect and are distributed only within the extracellular space. Therefore, their distribution volume is very small. In addition, their ability to penetrate into tissue is limited. The half-life of vancomycin ranges from 6 to 8 h and for teicoplanin from 70 to 100 h. Teicoplanin has a much higher protein-binding capacity with 90% compared to vancomycin with 55%. Glycopeptides are eliminated via renal secretion. Therapeutic drug monitoring is mandatory during treatment with glycopeptides because pharmacokinetics vary largely between individuals.

9.2 Efficacy and Indication

Glycopeptides are very effective against various infections with gram-positive pathogens (Staphylococci, Streptococci, and Enterococci), such as endocarditis, pneumonia, bone infection, infection of the kidneys, and serious systemic infections (sepsis). Importantly, glycopeptides are the first-line antimicrobial agent for infections with multi-resistant Staphylococci (MRSA and MRCNS) and Enterococci.

9.3 Antibiotic Resistance

Antibiotic resistance of methicillin-resistant Staphy­lococcus aureus and Enterococcus faecalis against glycopeptides is still very rare but can be occasionally observed for Staphylococcus epidermidis. In contrast, antibiotic resistance of Enterococcus faecium against glycopeptides can be seen frequently with varying profiles of resistance against both vancomycin and teicoplanin. The resistance rates can reach up to 30% which usually occurs in intensive care patients.

9.4 Side Effects

Glycopeptides are usually given as an infusion and can cause tissue necrosis and phlebitis at the injection site if administered too rapidly. Indeed pain at the site of injection is a common adverse event. One of the side effects is called “Red man syndrome,” an idiosyncratic reaction to bolus administration, caused by histamine release. Some other side effects of vancomycin are nephrotoxicity including renal failure and interstitial nephritis, blood disorders including neutropenia, deafness, and gastrointestinal disorder (reversible after termination of treatment).

10 Lipopeptides

Daptomycin represents the first antibiotic agent of this new antibiotics class. Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function dependant on calcium integration into cytoplasmic cell membrane. It appears to bind to the membrane and cause rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA, and RNA syntheses, which results in bacterial cell death.

10.1 Pharmacokinetics

Half-life of daptomycin is 7–9 h and more than 90% binds to plasma proteins. Elimination takes place in 78% via renal secretion and 5% are egested via feces. Adjustment of dosage in older patients and patients with mild-to-moderate liver dysfunction (Child-Pugh classes A and B) is not necessary but administration intervals extend up to 48 h in patients with renal failure (creatinine clearance <30 mL/min, hemodialysis, and peritoneal dialysis).

10.2 Efficacy and Indications

Daptomycin is active against gram-positive bacteria only. It has proven in vitro activity against Enterococci (including glycopeptide-resistant Enterococci (GRE)), Staphylococci (including methicillin-resistant Staphy­lococcus aureus), Streptococci, and corynebacteria. Daptomycin is approved for skin and skin structure infections caused by gram-positive infections, Staphy­lococcus aureus bacteremia, and right-sided S. aureus endocarditis. In lung tissue, daptomycin becomes ­rapidly inactivated by surfactant, and ­therefore, daptomycin is ineffective in pneumonia treatment.

10.3 Antibiotic Resistance

Antibiotic resistance against daptomycin has been observed only in few cases.

10.4 Side Effects

Side effects commonly seen after administration of daptomycin are elevation of creatinine kinase, gastrointestinal disorders (constipation, nausea, diarrhea, vomiting, dyspepsia, abdominal pain, decreased appetite, stomatitis, and flatulence), pain at the site of administration, headache, and insomnia.

11 Aminoglycosides

The most important substances of this antibiotic class are amikacin, gentamicin, netilmicin, and tobramycin all of which can be administrated parenterally only. Tobramycin may be given in a nebulized form as well. Aminoglycosides demonstrate rapid bactericidal effects through irreversibly binding to the bacterial 30S ribosomal subunit (amikacin works by binding to the 50S subunit), inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site, and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth. Indications are serious infections with gram-negative bacteria and also in combination with beta-lactam antibiotics therapy of endocarditis caused by gram-positive cocci (Enterococci and Streptococci) due to synergistic effects. However, the decision to use aminoglycosides must be made carefully due to their poor tissue distribution and high nephrotoxicity.

11.1 Pharmacokinetics

Aminoglycosides are almost exclusively distributed within the extracellular space. Therefore, their distribution volume is low with a short half-life of approximately 2 h in patients with normal kidney function. Since the therapeutic ratio of aminoglycosides is low, drug monitoring is mandatory particularly if renal function is impaired. A daily single application time point of the total dosage has been established for all aminoglycosides because of comparable antimicrobial activity and reduced nephrotoxicity compared to administration in three smaller dosages.

11.2 Efficacy and Indications

Aminoglycosides are primarily used for treatment of infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter as well as Staphylococci. In general, they should be given in combination with other antimicrobial substances, preferably with beta-lactam antibiotics due to synergistic effects. The therapeutic administration of aminoglycosides is approved for the treatment of serious infections (sepsis), fever in neutropenic patients, Pseudomonas infections in patients with cystic fibrosis (also for inhalation), and endocarditis. Amikacin is also effective against gram-negative pathogens with resistance against gentamicin and tobramycin.

11.3 Antibiotic Resistance

Antibiotic resistance develops fast because of decreased accumulation of the substances in bacteria and loss of binding affinity. Additionally, inactivation of aminoglycosides takes place through enzyme induction via acetylation, adenylation, and phosphorylation of the drugs.

11.4 Side Effects

Aminoglycosides have potential nephrotoxic and ­ototoxic side effects which are cumulatively and dose dependant. They also interfere with neuromuscular signaling, and therefore, they should not be given if patients suffer from Myasthenia gravis. Allergic reactions, blood disorders, and impaired liver function are side effects which can occasionally be observed after treatment with aminoglycosides.

12 Oxazolidinone

Linezolid is the only agent of this new antibiotic class and can be given orally as well as i.v. Oxazolidinones are protein synthesis inhibitors and stop growth and reproduction of bacteria by disrupting translation of messenger RNA (mRNA) into proteins in the ribosome. Linezolid is considered bacteriostatic against most organisms, but has some bactericidal activity against Streptococci.

12.1 Pharmacokinetics

Linezolid has a high bioavailability which is independent of the application route (orally or intravenously). Linezolid has low plasma protein–binding capacity (approximately 31%, but highly variable) and a volume of distribution at steady state of around 40–50 L. The tissue distribution is generally good and half-life averages around 5–7 h. Linezolid is metabolized in the liver, by oxidation of the morpholine ring, without involvement of the cytochrome P450 system, and is eliminated mainly via renal secretion (85%).

12.2 Efficacy and Indications

Linezolid is effective against all clinically important gram-positive bacteria, notably Enterococcus faecium and Enterococcus faecalis (including vancomycin-­resistant Enterococci), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus, MRSA), Streptococcus agalacticae, Streptococcus pneumoniae, Streptococcus pyogenes, the viridans group Streptococci, and Listeria monocytogenes. It is also highly active in vitro against several mycobacteriae.

12.3 Antibiotic Resistance

Resistance rates have remained stable and extremely low, less than 0.5% of isolates in general, and less than 0.1% of S. aureus samples.

12.4 Side Effects

Common side effects of linezolid include diarrhea, headache, nausea, vomiting, rashes, constipation, altered taste perception, and discoloration of the tongue. In particular, a decrease in leukocyte and platelet counts can be observed after long-term use of linezolid, and therefore, in these patients, repeated blood counts are mandatory.

13 Lincosamides

Clindamycin can be given parenterally and orally. It has a bacteriostatic effect and interferes with bacterial protein synthesis (in a similar way to erythromycin, azithromycin, and chloramphenicol), by binding preferentially to the 50S subunit of the bacterial ribosome. Clindamycin is usually used to treat infections with gram-positive anaerobic bacteria.

13.1 Pharmacokinetics

Approximately 90% of an oral dose of clindamycin is absorbed from the gastrointestinal tract and it is widely distributed throughout the body, excluding the central nervous system. Adequate therapeutic concentrations can be achieved in bone. There is also active uptake into white blood cells, most importantly neutrophils. The elimination half-life is 1–5 h. Clindamycin is ­primarily eliminated by hepatic metabolism (80%) and the metabolites are excreted via the urine.

13.2 Efficacy and Indications

Clindamycin has good efficacy against Staphylococci, Streptococci, gram-positive anaerobic bacteria, Bacter­oides spp., and Mycoplasma pneumoniae. Clindamycin is used primarily to treat infections caused by susceptible anaerobic bacteria, including infections of the respiratory tract, skin and soft tissue infections, as well as peritonitis. It is also used to treat bone and joint infections, particularly those caused by Staphylococcus aureus.

13.3 Antibiotic Resistance

Resistance rates for clindamycin range at 10% for blood isolates of Staphylococcus aureus, 30% for coagulase-negative Staphylococcus, and 10–20% for Bacteroides spp. Additionally, resistance rates of MRSA and MRSE continue to rise.

13.4 Side Effects

Common side effects associated with clindamycin therapy, which can be observed in more than 1% of patients include diarrhea, pseudomembranous colitis, nausea, vomiting, abdominal pain or cramps, increased liver enzyme, rash, and/or itch. High doses (both ­intravenous and oral) may cause a metallic taste, and topical application can cause contact dermatitis.

14 Streptogramins

Streptogramins are cyclic peptides and are available as a fixed combination of dalfopristin (70%) and quinupristin (30%). Both agents have bacteriostatic effects and have bactericidal effects in combination with a ­distinct post-antibiotic effect. The combination of quinupristin/dalfopristin is only available for parenteral application. Quinupristin binds to the 50S ribosomal subunit and prevents elongation of the polypeptide. Dalfopristin binds to a nearby site, changes the conformation of the 50S ribosomal subunit, and enhances the binding of quinupristin by a factor of about 100. Quinupristin/dalfopristin is effective against all clinically relevant gram-positive bacteria, notably multi-resistant staphylococci (MRSA) and glycopeptide-resistant Enterococcus faecium. The use of quinupristin/dalfopristin should be limited to infections with gram-positive bacteria where no other antibiotics are effective.

14.1 Pharmacokinetics

Quinupristin/dalfopristin has a medium distribution ­volume, and their half-lives range from 1 to 3 h. They are mainly metabolized in the liver and eliminated via the biliary tract. The protein-binding capacity varies from 55–78% for quinupristin to 11–26% for dalfopristin.

14.2 Efficacy and Indications

The use of Quinupristin/dalfopristin is limited to infections with gram-positive cocci, including multi-resistant Staph­ylococci (MRSA) and glycopeptide-resistant Enterococcus faecium (VRE). The drug combination should not be used against Enterococcus faecalis. Quinupristin/dalfopristin is approved for the treatment of infections of the lung, skin, and soft tissues and all infections caused by glycopeptide-resistant Enterococ­cus faecium.

14.3 Antibiotic Resistance

Enterococcus faecalis, anaerobic and aerobic gram-negative bacteria are resistant against streptogramins.

14.4 Side Effects

Allergic reaction at the application site is common and administration via a central venous catheter is recommended. Other frequent side effects include arthralgia and myalgia, gastrointestinal disorder (nausea, diarrhea, or vomiting), headache, and increased liver enzymes. Quinupristin/dalfopristin also interferes with the cytochrome P450 enzyme system in the liver.

15 Tetracyclines

Tetracyclines are a group of broad-spectrum antibiotics which have lost their general usefulness due to the development of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications. The clinically most relevant agent of this antibiotic group is doxycycline which can be administered parenterally and orally. Tetracyclines generally have bacteriostatic effects through inhibition of protein synthesis by binding to the 30S ribosomal subunit in the mRNA translation complex. The treatment spectrum covers gram-positive and gram-negative bacteria.

15.1 Pharmacokinetics

The distribution of doxycycline is mainly intracellular, and it penetrates well into all tissues. The half-life ranges from 10 to 20 h. Doxycycline is partly metabolized in the liver and eliminated via feces and urine.

15.2 Efficacy and Indications

Nowadays, the use of doxycycline is limited to few indications. It is frequently used to treat infections caused by Chlamydia (trachoma, psittacosis, salpingitis, urethritis and L. venereum infection), Mycoplasma, Rickettsia (typhus, Rocky Mountain spotted fever), brucellosis, and spirochetal infections (borreliosis, syphilis, and Lyme disease). In general, approved indications for the use of doxycycline are infections of the upper and lower respiratory tracts, the bile tract, and pelvic inflammatory disease.

15.3 Antibiotic Resistance

The local resistance rates differ significantly, and there is a lack of published data. Resistance rates range from 10% to 20% for gram-positive bacteria and are higher in the gram-negative field.

15.4 Side Effects

Treatment with doxycycline can cause stomach or bowel upsets. Of particular note is a possible photosensitive allergic reaction which increases the risk of sunburn. Allergic reactions and hepatotoxicity are rarely seen.

16 Glycylcyclines

Tigecycline is the first clinically available drug in a new class of antibiotics called the glycylcyclines and has a similar structure as the tetracyclines. Tigecycline has a bacteriostatic effect and is a protein synthesis inhibitor by binding to the 30S ribosomal subunit of bacteria.

16.1 Pharmacokinetics

Tigecycline has a long half-life of 25–42 h, and it has a large distribution volume. It is eliminated via kidneys (33%) and liver (60%) without modification. No dose adjustment is needed for patients with impaired kidney or liver function (Child-Pugh-Stadium A and B). Tigecycline does not interact with the cytochrome P450 enzyme system in the liver.

16.2 Efficacy and Indications

Tigecycline is active against many gram-positive bacteria, gram-negative bacteria, anaerobes, mycoplasma and chlamydiae. It is also active against methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant strains of Acinetobacter baumannii, and isolates of Klebsiella pneumoniae and Escherichia coli producing AmpC-beta-lactamases or extended-spectrum-beta-lactamases (ESBL). Currently, the drug is licensed for the treatment of skin and soft tissue infections as well as intra-abdominal infections.

16.3 Antibiotic Resistance

In general, tigecycline has no activity against Pseudomonas spp., Proteus spp., and Burkholderia cepacia. Antibiotic resistance against usually susceptible bacteria has been observed only in few cases so far.

16.4 Side Effects

The most common side effects of tigecycline are ­gastrointestinal disorders (diarrhea, nausea, and vomiting). Increased serum bilirubin can also be rarely observed.

17 Ansamycins

Rifampicin can be administered intravenously as well as orally. It has bacteriostatic and bactericidal effects on proliferating cells which depend on the administered dose as well as the activity of the bacteria. Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding to its beta-subunit, thus preventing transcription to RNA and subsequent translation into proteins. It has a good efficacy against tuberculosis as well as in combination with other antibiotics against multi-resistant gram-positive bacteria.

17.1 Pharmacokinetics

Rifampicin has a high distribution throughout the body, and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. About 60–90% of the drug is bound to plasma proteins. The half-life of rifampicin ranges from 6 to 7 h and depends on the duration of therapy because self-induction by the agent causes increased metabolization rate. Approximately 7% of the administered drug is excreted unchanged through the urine; urinary elimination, however, accounts for 30% while 60–65% of the administered dosage is excreted via the feces.

17.2 Efficacy and Indications

Apart from the “typical use” for the treatment of mycobacterium infections, including tuberculosis and ­leprosy, rifampicin has a role in combination with glycopeptides or other antibiotics for the treatment of infections with Staphylococci (including methicillin-resistant strains), Streptococci, and Enterococci if ­susceptibility is confirmed.

17.3 Antibiotic Resistance

Rifampicin resistance develops quickly during monotherapy. Primary resistances against Mycobacterium tuberculosis and meningococci are rare.

17.4 Side Effects

The more common unwanted effects include hepatotoxicity, gastrointestinal disorder, and altered blood counts. Rifampicin is an effective liver enzyme-inducer, promoting the upregulation of hepatic cytochrome P450 enzymes, and therefore, increasing the rate of metabolism of many other drugs that are cleared by the liver through these enzymes.

18 Nitroimidazoles

Metronidazole is the most important nitroimidazole and it is used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. Metronidazole has an excellent bioavailability and can be administered parenterally as well as orally. It has a high bactericidal activity against anaerobic bacteria because it is taken up by diffusion and then inhibits protein synthesis via binding to DNA.

18.1 Pharmacokinetics

Metronidazole has a medium distribution volume, and its half-life ranges from 6 to 8 h. The agent is partially bound to plasma proteins (10–20%), and after metabolization, it is eliminated mainly via renal excretion (60–80%).

18.2 Efficacy and Indications

Metronidazole is approved for treatment of infections caused by anaerobic bacteria (including meningitis and brain abscess). It is used in combination for perioperative prophylaxis. Metronidazole is further indicated for the treatment of protozoal infections due to Entamoeba histolytica, Giardia lamblia (Giardiasis), and Tricho­monas vaginalis. Metronidazole has also been proven to be effective for the treatment of pseudomembranous colitis caused by Clostridium difficile.

18.3 Antibiotic Resistance

Primary resistance among anaerobic bacteria is rarely seen. Some strains of Helicobacter pylori have developed resistance against metronidazole.

18.4 Side Effects

Common side effects include nausea, diarrhea, and a metallic taste in the mouth. Therapy with metronidazole can be associated with leucopenia, neutropenia, and increased risk of peripheral neuropathy. Consump­tion of alcohol should be avoided while using metronidazole because a significant alcohol intolerance can develop.

19 Fosfomycin

Fosfomycin can be given parenterally and orally, but the enteral form (Fosfomycin-Trometamol) is only approved for the treatment of urinary tract infections. Fosfomycin is an antimetabolite of phosphoenolpyruvate in the enzymatic synthesis of bacterial cell wall components and has bactericidal activity. Fosfomycin is active against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, but resistance develops rapidly under monotherapy.

19.1 Pharmacokinetics

Fosfomycin is distributed selectively in the extracellular space, and therefore, its distribution volume is small. Fosfomycin does not bind to plasma proteins and is eliminated unmodified via the urinary tract.

19.2 Efficacy and Indications

Fosfomycin is effective against Staphylococci, gram-positive and gram-negative bacteria. Its use is approved for infections in different locations (particularly bone and meninges) as long as susceptibility of the pathogen has been proven.

19.3 Antibiotic Resistance

Resistance rapidly develops under monotherapy due to spontaneous mutations.

19.4 Side Effects

Gastrointestinal disorder and pain at the application site are often seen during fosfomycin therapy. Attention must be paid to the high sodium chloride content of the solution.

20 Co-trimoxazole

Co-trimoxazole is a sulfonamide antibacterial combination of trimethoprim and sulfamethoxazole and is used for the treatment of a variety of gram-positive and gram-negative bacterial infections. Trimethoprim and sulfamethoxazole inhibit successive steps in the folate synthesis pathway. Each component alone exhibits bacteriostatic effects, but together they have bactericidal effects.

20.1 Pharmacokinetics

Co-trimoxazole is distributed in the intra- and extracellular spaces, and its tissue distribution volume is low for sulfamethoxazole and medium for trimethoprim. Seventy percent of sulfamethoxazole and 45% of trimethoprim are bound to plasma proteins, and their half-lives range from 10 to 12 h. Co-trimoxazole is partly metabolized and then excreted via the urine.

20.2 Efficacy and Indications

Co-trimoxazole is effective against gram-positive and gram-negative bacteria and is predominantly used for the treatment of infections with Stenotr­ophomonas maltophilia, Pneumocystis jiroveci (formerly Pneumocystis carinii) and in combination with other drugs for infections with methicillin-resistant Staphylococcus aureus. It can be effective in a variety of upper and lower respiratory tract infections, renal and urinary tract infections (UTI), and can be used for long-term prophylaxis of UTI in patients at risk.

20.3 Antibiotic Resistance

Escherichia coli, Salmonella, Shigella, and other Enterobacteriacae have developed increased resistance rates during recent years.

20.4 Side Effects

Administration of high dosages of co-trimoxazole can be associated with gastrointestinal disorders, crystalluria (formation of crystals and excretion in the urine), and acute renal failure. Serious adverse effects including Stevens–Johnson syndrome, myelosuppression, mydriasis, agranulocytosis, and hepatitis are rarely seen.

21 Characterization of Antifungals (Table 16.3), Pharmacokinetics, Efficacy, Resistance, and Side Effects (Table 16.4)

21.1 Introduction

Invasive fungal infections (IFI) only play a minor role in the surgical field. Microbiological detection of fungi (e.g., Candida spp.) is common but is usually due to colonization of the host. Under these circumstances, antifungal treatment is usually not indicated. Nonethe­less, differentiation between colonization and invasive fungal infection is often difficulty. Verification of fungi in primarily sterile material or histological detection of invasiveness in bioptic material may represent distinct markers of invasive fungal infections. Local and systemic fungal infections are often seen in patients with diminished immunological competence, for example after organ transplantation. Additionally, biological selection of fungi occurs after long-term antibiotic therapy, and therefore, critical ill patients are at increased risk of IFI. If fungal infections are assumed or established, in particular with molds (e.g., Asper­gillus spp.), antifungal therapy must be given for ­significantly longer periods of time compared to antibacterial therapy. Efficacies of important antifungal drugs in the clinical setting are summarized in Table 16.4.

Table 16.3 Systemic antifungal agents for parenteral and oral applications
Full size table
Table 16.4 Antifungals’ efficacy
Full size table

22 Polyenes

Amphotericin B is available for parenteral application as well as an oral preparation. It may also be given in a nebulized form and for topical application, for example intra-abdominal irrigation. A liposomal formulation of amphotericin B for injection has been developed which exhibits fewer side effects (particularly nephrotoxicity) while having similar efficacy. Nystatin is only available as oral preparation. Amphotericin B antagonizes the sterol synthesis, the main component of fungal cell membranes, forming a transmembrane channel that leads to potassium leakage and fungal cell death. Polyene antifungal agents have a broad-spectrum efficacy which covers Candida and Aspergillus spp., except Scedosporium (Pseudallescheria) spp.

22.1 Pharmacokinetics

Amphotericin B and Nystatin are not absorbed after oral intake. After parenteral application, amphotericin B binds up to 90% to plasma proteins and its half-life ranges to about 20 h. The highest tissue concentration can be reached in the liver while its concentration is lower in the lungs and kidneys, but can increase up to 65% of plasma concentration in pleural, peritoneal, and synovial fluids if infection is present. The distribution into the cerebrospinal fluid is marginal. Amphotericin B is slowly eliminated via the kidneys over several days, and it cannot be removed via dialysis.

22.2 Efficacy and Indications

Amphotericin B is approved for the treatment of serious systemic fungal infections including peritonitis, sepsis, meningitis, and endocarditis. The oral preparation can be used for intestinal decontamination and therapy of thrush or other topical forms of candidiasis.

22.3 Resistance

Development of resistance under amphotericin B therapy is uncommon, and only individual reports have been published indicating primary resistance of some Candida strains.

22.4 Side Effects

Nephrotoxicity is a frequently reported side effect, and it is much milder when the liposomal formulated amphotericin B is used. Frequently, a serious acute reaction after infusion (1–3 h later) can be noted consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea. Other possible side effects include thrombophlebitis at the application site, several forms of anemia and other hematological problems as well as backache.

23 Azoles

Systemic applicable antifungal agents of this group are fluconazole, itraconazole, voriconazole, and posaconazole, which are chemically different azole derivates with imidazole or triazole structure. Inhibition of the fungal enzyme 14α-demethylase which produces ergosterol (an important component of the fungal plasma membrane) is the common mode of action. All azole derivates also inhibit cytochrome P450 enzyme system and parts of the human steroid synthesis. Therefore, careful patient evaluation must look for possible interactions with other medications. Fluconazole, itraconazole, and voriconazole can be given parenterally and orally, while posaconazole is only available for oral administration.

The effectiveness varies significantly among the azole derivates. Fluconazole is highly effective against several Candida species, but shows poor activity against Candida glabrata and no effect against Candida krusei and molds. Itraconazole has similar efficacy across Candida spp. and is additionally active against Aspergillus spp. Voriconazole also covers Candida glabrata, Candida krusei, Fusarium spp., and Scedosporium spp. Posaconazole, the most recent azole derivate, also has good efficacy against Zygomycetes.

23.1 Pharmacokinetics

Fluconazole is well absorbed after oral intake, and its half-life reaches up to 25 h. Plasma protein–binding capacity of fluconazole is low with approximately 12%. It penetrates well into various tissues and reaches high concentrations in urine, saliva, sputum, and cerebrospinal fluids. Most of the administered fluconazole (60–80%) is eliminated unmodified via the kidneys. Itraconazole is also well absorbed after oral intake, particularly if taken together with alimentation. However, the bioavailability varies individually, and therefore, drug monitoring is necessary to modify the dosage and reach therapeutic levels. Intraconazole has a half-life of 24 h and is nearly 99% bound to plasma proteins. It does not penetrate into the cerebrospinal fluid and neither renal failure nor dialysis has an impact on intraconazole serum levels. Voriconazole is almost completely absorbed after oral intake. Its half-life ranges from 6 up to 12 h and approximately 60% is bound to plasma proteins. The cerebrospinal fluid level of this drug can reach nearly 50% of plasma levels. Most of the drug (95%) is metabolized in the liver, 80% is then excreted via the urine (2% unmodified), and 20% via the feces. Posaconazole is slowly absorbed after oral intake which depends on the fat content of the nutrition. Posaconazole has a high distribution volume and a medium half-life of 35 h. Almost 98% of the drug is bound to plasma proteins and the major proportion is eliminated via the feces, while 15% is removed via the urine.

23.2 Efficacy and Indications

Fluconazole is widely used for the treatment of fungal infections caused by Candida albicans and tropicalis while itraconazole is approved for therapy and prophylaxis of various kinds of mycosis in immunocompromised patients. Voriconazole has approval for the treatment of invasive Aspergillus infection and serious candidiasis, which are resistant to fluconazole, as well as fungal infections caused by Fusarium spp. and Scedosporium spp. Posaconazole is approved for ­therapy of refractory Aspergillus infections, Fusarium infection, and Zygomycosis.

23.3 Resistance

A fraction (5–10%) of Candida spp. develop secondary resistance under fluconazole therapy. Primary resistance exists in Candida glabrata and krusei, molds and dermatophytes. In HIV-positive patients, secondary resistant Candida spp. are rarely observed under itraconazole therapy. Resistances against voriconazole and posaconazole are rarely seen.

23.4 Side Effects

The most common side effects associated with azole antifungal agents are gastrointestinal disorders, rash, adverse effects on the central nervous system, elevated liver enzymes and bilirubin, peripheral edema, and respiratory disorders. Adrenal insufficiency can occur under itraconazole therapy, and visual disturbances (blurred vision, increased light sensitivity) are unique to voriconazole.

24 Fluorinated Pyrimidine

Flucytosine, or 5-fluorocytosine, a fluorinated pyrimidine analogue, is a synthetic antimycotic drug which is available in oral and (in some countries) also in injectable form. Flucytosine represents an antimetabolite and inhibits fungal DNA synthesis.

24.1 Pharmacokinetics

Flucytosine is well absorbed (75–90%) from the gastrointestinal tract. Small amounts are bound to plasma proteins, and its half-life ranges from 3 to 4 h. Flucytosine penetrates well into cerebrospinal and peritoneal fluids. The drug is excreted mainly unchanged via the urine (90%), and only traces are metabolized and excreted with the feces.

24.2 Efficacy and Indications

The range of efficacy includes Candida spp., Cryptococcus spp., and some Aspergillus spp. The combination of flucytosine and amphotericin B may exhibit synergistic effects in vitro, particularly for the treatment of life-threatening fungal infections (e.g., cryptococcal meningitis), but may also increase the toxicity of amphotericin B and vice versa.

24.3 Resistance

Secondary resistance is quite commonly seen under monotherapy, and therefore, flucytosine should be combined with other antifungal agents. Resistance in Candida spp. has been noted to occur in 10–50% and in 2–20% of Cryptococcus neoformans isolates.

24.4 Side Effects

Bone marrow depression (anemia, leucopenia, pancytopenia, or even rarely agranulocytosis) may reversibly occur in 10% of the patients. Elevations of liver enzymes and bilirubin, gastrointestinal disorder, and adverse central nervous system effects are rarely observed during flucytocine therapy.

25 Echinocandins

Caspofungin is an antifungal drug, the first of a new class termed the echinocandins, which was introduced in 2001. Further derivatives, anidulafungin and micafungin, were approved by the Food and Drug Administration in 2005 and 2006, as well as in Europe in 2007 and 2008. Echinocandins inhibit the enzyme β(1,3)-d-Glucan synthase and disturb the integrity of the fungal cell wall. These agents exhibit fungicidal efficacy and cover almost all Aspergillus and Candida spp.

25.1 Pharmacokinetics

All echinocandins are administered intravenously and 84–99% is bound to plasma proteins. Their half-lives range from 9 to 11 h for caspofungin, 11–17 h for micafungin, and 40–50 h for anidulafungin. All echinocandins are slowly metabolized and egested via feces and urine. Neither mild to medium hepatic nor renal dysfunction has an impact on drug serum levels. None of the echinocandines can be removed by dialysis.

25.2 Efficacy and Indications

These drugs are approved for the treatment of general invasive candidiasis (acute disseminated candidiasis, candida peritonitis, abscesses and esophageal candidiasis), invasive Aspergillus infection, and empiric therapy in neutropenic patients with fever. Micafungin is also approved for the prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplantation.

25.3 Resistance

Resistance in Candida albicans has been described for caspofungin, but is currently still rare. Cryptococcus spp. and Mucoraceae are primarily resistant against echinocandins.

25.4 Side Effects

Fever, phlebitis, gastrointestinal disorder, adverse central nervous system effects, increased liver enzymes, altered blood count, rash, proteinuria and erythrocyturia may occur under antifungal therapy with echinocandins. Hypersensitivity reaction with rash, facial edema, and pruritus can be observed rarely.

26 General and Specific Aspects of Antimicrobial Therapy (Table 16.5)

Antimicrobial therapy is defined as the monocausal use of drugs which selectively and directly affect specific pathogens. Therefore, location and kind of infection, particularly in surgical patients, has to be evaluated and adequate antimicrobial substances have to be selected before antimicrobial therapy is introduced. The option of surgical intervention must always be considered.

Table 16.5 Selection of antimicrobial agents for different indications
Full size table

The rational use of antimicrobial agents for directed therapy can only occur on the basis of sufficient microbiological diagnostics. For this purpose, a close cooperation between attending physician and the microbiologist is of importance.

Note:

Fever alone is no indication for antimicrobial therapy!

 

26.1 General Principles of Antimicrobial Therapy

  • Microbiological diagnostics should always be done prior to initiating antimicrobial therapy. Therefore, correct sampling of suitable material and transportation in the correct medium (e.g., transport medium for detection of anaerobic pathogens or specific blood culture media) must be ensured.

  • Selection of the agent for calculated antimicrobial therapy should be directed by the location of the assumed infection and by the associated microbiological spectrum, as well as the local pathogen and resistance situation. Additionally, patient-specific issues have to be considered before selecting a certain substance (length of hospitalization, prior surgical interventions, underlying disease, specific risk factors, and previous antibiotic therapy).

  • Calculated antimicrobial therapy for treatment of serious infections (e.g., pneumonia, peritonitis, ­sepsis), especially during the postoperative course, should always be given parenterally to reach effective tissue levels rapidly.

  • The antimicrobial agent should always be given at the highest recommended dosage and the treatment period should be maintained as short as possible. After receiving microbiological results, the selected antibiotic substance should be adjusted according to the antibiogram. Oral administration of the antimicrobial substances should be considered if a medium severe infection is present and uncomplicated enteral resorption of the drug is assumed. Mild infections (e.g., soft tissue or urinary tract infections) can be treated with orally available antibiotics.

  • If clinical symptoms do not improve within 3 days of antimicrobial therapy, the assumed site of infection must be reevaluated and treatment with a different antibiotic should be initiated.

26.2 Causes for Failure of Antimicrobial Treatment and Primary/Secondary Resistance

Contradicting results of microbial sensitivity testing and clinical effects of specific antimicrobial therapy can occur for a number of reasons. The following issues must always be considered:

  • Tissue concentration does not reach therapeutic drug levels due to application of an insufficient ­dosage or impaired tissue diffusion.

  • Discrepancy between in vivo and in vitro activities of the antimicrobial substance, testing of nonrelevant pathogens, change of the underlying pathogen, and/or development of secondary resistance during therapy.

  • Patient-specific causes (preexisting disease, imm­unodeficiency).

  • Incorrect application of the antimicrobial drug (inactivation due to interaction with other drugs), antagonism of antimicrobial drug combinations, absence of bactericidal activity of the used agent.

26.3 Antibiotic Resistance

Currently plays an increasing role and is due to unfocused application of antimicrobial agents. Several mechanisms contribute to the development of anti­biotic resistance of pathogens. These include pro­duction of enzymes which inactivate antimicrobial substances, altered target molecules, and impaired permeability (reduced cell penetration). The encoding genes for antibiotic resistance can be located within the bacterial chromosome or in plasmids which allows for a rapid horizontal spread. The development of antibiotic resistance in bacteria relies on genetic variability and selection of resistant mutants.

Development of antibiotic resistance can be influenced by the following measures:

  • Antibiotic therapy should be patient specific.

  • The use of treatment regimes combining different antibiotics should be preferred.

  • The same diagnosis does not always require the same antibiotic regimen.

  • Indications for antibiotic prophylaxis and topical application should always be considered critically.

  • Statistical evaluation of local pathogen environment and resistance rates should be documented continuously and critically reviewed.

  • Staff members must be continuously educated in close collaboration with the clinical microbio­logists.

Note:

We are only guests on the planet of the bacteria!

 

27 Antimicrobial Prophylaxis in Surgical Procedures

27.1 Definition

Antimicrobial prophylaxis for surgical procedures is a short-term (usually single shot) administration of antimicrobial agents, just before the start of (or latest during) surgical procedures. The prophylaxis aims to minimize the rate of surgical site infections which are caused by displaced or resident bacteria within the operating field.

27.3 Selection Criteria for Antimicrobial Agents and Antimicrobial Prophylaxis for Surgical Procedures (Table 16.7)

Antimicrobial prophylaxis must be selected based on the expected microbiological spectrum, the local ­resistance epidemiology of the institution, and ­pharmacokinetics of the substance (e.g., half-life, concentration within the target tissue). Furthermore, toxicity and compatibility of the antimicrobial agent must be taken into account. Controlled randomized studies (where available) should be the basis for selection of a certain agent. Antibiotic prophylaxis in surgical practice should adhere to the following principles:

Table 16.7 Recommendation for antimicrobial prophylaxis in surgical procedures
Full size table

  • Single-shot application of the maximum dosage.

  • Administration less than 2 h before surgery to ensure optimal plasma and tissue levels.

  • If the surgical procedure does not exceed 3 h, single-dose administration is sufficient.

  • Second shot administration should be considered if the surgical procedure takes longer than 3 h or blood loss exceeds 1 L.

  • Antimicrobial prophylaxis for more than 24 h after surgery is not reasonable.

  • Intravenous application of the antibiotic agent is beneficial.

  • Patients who will need postoperative antimicrobial therapy should receive these antibiotics also as ­prophylactic agents.