Anti-infectives (Antibacterials, Virostatics, Antimycotics, Antiparasitics, Antiseptics, Immunoglobulins)

4	Anti-infectives (Antibacterials, Virostatics, Antimycotics, Antiparasitics, Antiseptics, Immunoglobulins)

Antibacterials

Definitions

Strictly speaking, antibiotics are antimicrobial agents produced by fungi or bacteria. However, the term often includes their semisynthetic derivatives or even completely synthetic chemo-therapeutics with an antimicrobial effect (Table 4.1).

As more and more compounds are now manufactured chemically, the term anti-infectives is increasingly preferred. This term must not be confused with disinfectants (antiseptics) (Table 4.8).

Ideally, anti-infectives should only be directed at the pathogens of an infection. Their activity is essentially based on the specific inhibition of bacterial enzyme systems. It is possible to develop always new derivatives through chemical modification of the antibiotic molecules, with the derivatives getting better and better with respect to effectiveness and tolerance.

As microorganisms develop counterstrategies (e. g., mutation, selection, exchange of genomes), the search for new compounds and derivatives continues.

Unfortunately, all known anti-infectives interact also with the host organism, although usually only to a minor extent. Sulfonamides or β-lactam antibiotics can cause allergic reactions, aminoglycosides may have nephrotoxic and ototoxic effects, and erythromycin may cause gastrointestinal symptoms, depending on the dose.

In addition to undesired reactions in the host organism itself, the bacterial population changes to various extents, depending on both the antibiotic agent and its target pathogen. These changes involve primarily the local flora and the selection of resistant pathogens.

Table 4.1 Antibacterials and their sitesof action

Group of compounds	Site of action	Compounds (representative trade names)
Penicillins	Cell wall synthesis	Penicillin G, benzathine−penicillin V, amoxicillin, piperacillin
Penicillins + β-lactamase inhibitors	Cell wall synthesis	Amoxillin + clavulanate (Augmentin), ampicillin + sulbactam (Unasyn), piperacillin + tazobactam (Zosyn)
Cephalosporins (i. v. or p. o.)	Cell wall synthesis	Cefuroxime (Zinacef), cefotiam (Spizef), ceftriaxone (Rocephin), ceftazidime (Fortum)
Carbapenems	Cell wall synthesis	Imipenem + cilastatin (Primaxim), meropenem (Merrem)
Tetracyclines	Protein synthesis	Doxycycline (Vibracin)
Aminoglycosides	Protein synthesis	Gentamycin (Garamycin), amicacin (Amikin), tobramycin (Tobrex)
Macrolides	Protein synthesis	Erythromycin (Erythrocin, Staticin), roxithromycin (Xoxin), azithromycin (Zithromax)
Lincosamides	Protein synthesis	Clindamycin (Cleocin)
Glycopeptides	Cell wall synthesis	Vancomycin (Vancocin)
Fluoroquinolones	DNA gyrase activity	Ciprofloxacin (Cipro, Ciloxan), moxifloxacin (Avelox), ofloxacin (Floxin, Ocuflox), levofloxacin (Levaquin)
5-Nitroimidazoles	Nucleic acid synthesis	Metronidazol (Flagyl)
Sulfonamides	Folic acid synthesis	Trimethoprim + sulfamethoxazole (Co-Trimoxazol, Bactrim)

Hence, anti-infective therapy should always be well thought out, and it requires a clear diagnosis.

At the start of the treatment, the clinical condition of the patient is crucial; the severity of the disease and the pathogens that might be involved will determine which compound should be chosen. Any material for microbiological diagnosis must be collected prior to administering the first dose. Pathogens found after one to three days should be taken into account when deciding on further treatment.

Determination of Antibiotic Effectiveness In Vitro

The in-vitro effectiveness of an antibiotic is established by determining the minimal inhibitory concentration (MIC) using the serial dilution test. The MIC is defined as the concentration resulting in complete growth inhibition within 24 hours; it depends on the seeding density of the pathogen, the culture medium, and the incubation time.

In the normal routine, however, the disc diffusion test is used; it is less expensive. Agar plates are inoculated with the pathogen isolated from the patient, and individual filter discs soaked with different antibiotics are placed on the culture. The effectiveness of the antibiotic is then deduced from the size of the field of inhibition around the disc. This test is only moderately accurate and depends on many parameters, e. g., bacterial seeding density, culture medium used, thickness of the agar layer, stability of the antibiotic, and the antibiotic’s ability to diffuse in agar.

Although the determination of resistance in vitro will provide a rough idea about the activity of anti-infectives, the process is much more complex in vivo and does not always agree with the testing in vitro.

Resistance

We distinguish different types of resistance. In the case of natural or intrinsic resistance, a bacterial species is not at all sensitive to a certain antibiotic agent; for example, penicillin is completely ineffective against Pseudomonas aeruginosa. In addition, there is acquired resistance, which includes mutational resistance and secondary resistance. The latter is due to the selection of resistant variants during antibiotic therapy.

Bacteria may acquire resistance by means of chromosomal mutation or by the uptake of plasmids from other bacteria. In the latter case, we talk about transferred resistance.

Mutations causing resistance to antibiotics may occur spontaneously, although they are promoted by the presence of antibiotics. In hospitals, resistance acquired through plasmids plays a larger role than chromosomal resistance. Transferred resistance frequently occurs particularly in gram-negative rod-shaped bacteria. For example, the multiple resistances of Salmonella can be transmitted to originally sensitive Escherichia coli strains, and this may take place in the intestinal tract, on the mucosae, or on the skin. Conversely, the loss of acquired transferred resistance is also possible.

β-Lactam Antibiotics

These all contain one β-lactam ring. We distinguish four subgroups: penicillins, cephalosporins, carbapenems, and monobactams.

Mechanisms of Resistance to β-Lactam Antibiotics

The two essential mechanisms of resistance are the production of β-lactamases, which hydrolyze the β-lactam ring, and the production of alternative enzymes, which have a reduced affinity to penicillins and take on the function of carboxy-peptidases.

Of special importance among the (3-lac-tamases of gram-positive bacteria is the penicillinase of staphylococci. The β-lactamases of gram-negative bacteria include classes A to D, with the chromosomal class A and the plasmid-coded class C being the most important ones clinically.

There is also production of penicillin-binding proteins in gram-positive bacteria.

Penicillins

Properties and Spectrum of Activities

Penicillins represent a well-tolerated group of compounds that may be administered without reservations during pregnancy. They have a bactericidal effect on the multiplication of bacteria by inhibiting cell wall synthesis. The initially narrow spectrum of penicillins has been expanded by altering the side chains. Due to the skeletal structure of 5-aminopenicillanic acid, however, they are not resistant to penicillinase or β-lactamases. By combining them with β-lactamase inhibitors, the spectrum has been expanded for certain pathogens. The half-lives of penicillins are short (apart from a few exceptions) and found to be approximately one hour. For this reason, they must be administered at least three times daily.

The most important penicillins are:

Penicillin G. Parenteral administration only (i. v. or i.m.). Depot formulations have a prolonged activity. Very effective against streptococci of group A, gonococci, treponemes, sensitive staphylococci (only 20–60%), clostridiae, and other anaerobes (but not all of them).

Phenoxymethyl penicillin (penicillin V). This is an acid-resistant penicillin and can therefore be administered orally. It has the same mode of action as penicillin G, but is less potent.

Penicillinase-resistant penicillins. They have only one indication—namely, penicillinase-producing staphylococci—because their activity in sensitive strains is only one-tenth of the activity of penicillin G.

Three compounds are important: dicloxacillin, flucloxacillin, and oxacillin.

Aminopenicillins (ampicillin, bacampicillin, amoxicillin). The spectrum corresponds to that of penicillin G, and there is an increased activity against streptococci, in particular enterococci, and also listeriae. Gonococci and many Enter-obacteriaceae are affected as well.

Ampicillin was the first broad-spectrum penicillin to be developed. It is preferred during pregnancy because of its broad spectrum, good tissue permeability, and the long-time experience with this compound.

Amoxicillin is better resorbed than ampicillin. It is effective also against species of Chlamydia and Borrelia.

A major disadvantage of this group of antibiotics is the lack of β-lactamase stability; many staphylococci, enteric bacteria, or other opportunistic pathogens are therefore not affected. Here, an anti-biogram provides valuable information.

Another disadvantage is the high rate of exanthemas, ranging from 5–20%. Only very few exanthemas are caused by allergies, whereas exanthemas are very common when mononucleosis is present simultaneously.

Combinations of aminopenicillins with β-lactamase inhibitors. β-lactamases are enzymes that open the β-lactam ring of β-lactam antibiotics (penicillins and cephalosporins) and thus destroy their activity.

The preferred location of β-lactamases is the periplasmic space of many gram-negative bacteria. Here, the enzymes serve as part of the bacterial defense system.

The genes coding for β-lactamases may be located on the chromosome or on an episome, i. e., they occur naturally in certain bacteria and can be transferred to other bacteria.

In order to expand the effectiveness of (β-lactam antibiotics, β-lactamase inhibitors have been developed. These usually represent rudimentary β-lactam rings that irreversibly bind to (β-lactamases and thus inactivate the β-lactamases of the bacterial cell.

The spectrum of penicillins, and also that of cephalosporins, can be considerably expanded in this way.

Common β-lactamase producers include opportunistic pathogens, such as Staphylococcus aureus, many enteric bacteria, and certain anaerobes from the Bacteroides group.

Three different β-lactamase inhibitors are available today:

clavulanic acid

sulbactam

tazobactam.

They can be administered either as a supplement to the antibiotic or in a fixed combination with the antibiotic, for example:

amoxicillin + clavulanate

ampicillin + sulbactam

piperacillin + tazobactam.

Ureidopenicillins. They are available for parenteral administration only. Their activities are slightly broader than that of ampicillin. Some opportunistic pathogens, such as species of Pseudomonas, Klebsiella, and Serratia, should therefore be more affected; however, studies have not clearly confirmed this. In addition, these antibiotics are not β-lactamase stable.

Examples: azlocillin, mezlocillin, and piperacillin.

Cephalosporins

They are among the most frequently prescribed antibiotics due to their broad spectrum and good tolerance.

Bacteria resistant to cephalosporins include enterococci, listeriae, chlamydiae, and methicillin-resistant Staphylococcus aureus strains (MRSA).

Initially, cephalosporins were only available for parenteral administration. Meanwhile, there are also several effective preparations that can be taken orally.

They are subdivided into four groups (first to fourth generation cephalosporins) (Table 4.2), and their spectrum of activity has shifted more and more from gram-positive to gram-negative pathogens and also to opportunistic pathogens.

Properties and Spectrum of Activities

Like the penicillins, cephalosporins belong to the β-lactam antibiotics and inhibit the synthesis of the cell wall (peptidoglycan synthesis).

They differ in their mode of action from the penicillins. They have a different affinity for the bacterial binding proteins, they can penetrate through the bacterial cell membrane, and they are β-lactamase stable.

Through alterations of the side chains, the spectrum of cephalosporins has been increasingly expanded, in particular with respect to gram-negative bacteria. However, this has resulted in some loss of activity with respect to gram-positive bacteria, and the effectiveness against staphylococci has decreased.

Cephalosporins play an important role in gynecology because they are very effective and well tolerated. They may be administered during pregnancy.

One disadvantage of cephalosporins in gynecology is their ineffectiveness against Chlamydia and Listeria. Enterococci commonly found as colonizing pathogens are also resistant to cephalosporins; they are therefore more often detected in association with this therapy, but this plays only a minor role clinically.

First Generation: Cephalothin Group

These are very effective against gram-positive bacteria, such as streptococci, staphylococci, and also gonococci, whereas their effectiveness against gram-negative bacteria varies.

Second Generation: Cefuroxime Group

These preparations are largely stabile against β-lactamases. They are highly effective against gram-positive bacteria (e.g., staphylococci), but they also show an increased activity against many gram-negative rod-shaped bacteria. They are effective against gonococci, in particular against β-lactamase-producing gonococci. Klebsiella pneumoniae is highly sensitive as well. By contrast, pseudomonads, enterococci, mycoplasma, and chlamydiae are resistant.

Today, the most commonly used compounds are cefuroxime and cefotiam.

Table 4.2 Cephalosporins

Group	Generic name	Representative trade name
First generation	Cefazolin	Ancef
Second generation	Cefamandole Cefoxitin Cefuroxime Cefotiam	Mandol Mefoxin Zinacef Spizef
Third generation	Cefotaxime Ceftriaxone Cefadizime	Claforan Rocephin Opticef
Fourth generation	Ceftazidime Cefepime Cefpirome	Fortaz Maxipime Cefrom

Cefamandole, cefoperazone, cefotetan, and moxalactam are hardly used anymore because of their adverse effects on coagulation and other problems. Cefoxitin is very effective against isolated strains of the Bacteroides fragilis group, but less effective against E. coli and Klebsiella. It has been used in gynecology for a long time.

Third Generation: Cefotaxime Group

This group has an even broader spectrum, especially with respect to gram-negative bacteria. Some preparations are also fairly effective against the opportunistic pathogen Pseudomonas. The half-lives of these compounds vary, ranging from one hour for cefotaxime to eight hours for ceftriaxone, depending on their binding to proteins, among other things

Ceftriaxone is the preferred antibiotic for meningitis because of its pharmacokinetic properties.

Fourth Generation

This group has the broadest spectrum of activity. Ceftazidime and cefepime are effective also against pseudomonads. They are less effective against gram-positive bacteria and anaerobes.

Oral Cephalosporins

Their main indications are infections of the skin and soft-tissue infections when it is suspected that streptococci and staphylococci may be involved. These compounds belong to the most commonly prescribed oral antibiotics (Table 4.3).

For example, cefuroxime axetil is very effective against streptococci of groups A and B, gonococci, Staphylococcus aureus, and many other gram-negative bacteria. Two doses of this drug are sufficient for gonococci infection; for other infections twice daily for five days or more.

Table 4.3 Oral cephalosporins

Generic name	Representative trade name
Cefalexine (cephalexin)	Keflex
Cefaclor	Ceclor
Cefadroxil	Duricef
Cefuroxime axetil	Ceftin
Cefixime	Suprax
Cefpodoxime proxetil	Vantin
Ceftibuten	Cedax

Carbapenems

Of all β-lactam antibiotics, carbapenems have the broadest antibacterial activity, even against opportunistic pathogens and anaerobes. Only mycobacteria, Enterococcus faecium, and MRSA strains are resistant. Carbapenems are well suited for monotherapy in the case of severe, unclear infections. Although well tolerated, they do have a noteworthy side effect: if taken for a long period, they promote the selection of multiresistant pathogens and of fungi, in particular.

Carbapenems include:

imipenem + cilastatin, a fixed combination of antibiotic and inhibitor

meropenem

ertapenem.

Monobactams

Particularly effective against Enterobacteriaceae (with exception of Citrobacter and Enterobacter) combination with other drugs or in case of allergy to penicillin.

Other Antibiotics

Tetracyclines

Their bacteriostatic effect is based on the inhibition of protein synthesis, and their activity depends on the medium and its pH. They have long half-lives (approximately 12 hours) and are therefore administered only once a day; moreover, they are effective orally. They diffuse passively through the plasma membrane and cannot diffuse back. The resulting intracellular concentration of the drug is advantageous in cases of intracellular infections (e.g., with Chlamydia).

Because these drugs are incorporated into teeth and bones, they must not be administered during pregnancy and breast-feeding. They also interact with oral contraceptives, and security is impaired by bacterial hydrolysis of conjugated estrogens in the intestine. Anticonvulsives affect the activity of tetracyclines.

Tetracyclines have a relatively broad spectrum of activity. Because of their extensive use, resistances have increased especially with respect to gram-negative bacteria. They are therefore unsuitable for monotherapy of severe infections. However, they are effective against many gynecologically important pathogens, such as gonococci (although not all of them), Treponema pallidum, listeriae, mycoplasma, and chlamydiae.

Antibiotics of this group include:

tetracycline

oxitetracycline

doxycycline

minocycline.

Doxycycline is preferred because it can be administered orally, is well resorbed independently of food, and is well tolerated due to its low metabolism.

Aminoglycosides

They, too, inhibit protein synthesis, and they are bactericidal against a wide range of gram-negative bacteria, in particular.

The bactericidal effect is due to the production of nonfunctional proteins that become incorporated into the bacterial cell membrane and thus change permeability. Recently, aminoglycosides have been used less often because of their limited therapeutic range and because new, less toxic compounds with a comparable spectrum have become available.

Aminoglycosides are very effective against staphylococci, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, and other enteric bacteria. They are less effective against streptococci and anaerobes. As combination antibiotics, they play a major role in severe infections. They must be administered parenterally. Because of their nephrotoxicity, they have to be individually adjusted for patients with renal insufficiency.

They should be avoided during pregnancy because of their nephrotoxic and ototoxic potential.

The trend today is to use a single dose, whereas it has been recommended in the past that the daily dose be divided into three doses while the patient is under therapeutic drug monitoring. The single dose reduces the risk of nephrotoxicity, and the postantibiotic effect (PAE) of the higher initial concentration raises the drug’s effectiveness.

The most important examples, for parenteral administration only, are:

gentamicin

tobramycin

netilmicin

amicacin.

Other compounds include:

neomycin, a topical antibiotic for skin infections or, in cases of liver coma, for suppression of the intestinal flora

spectinomycin, an aminocyclitol antibiotic, has a broad spectrum but relatively low activity. It is used only for single treatment (intramuscular injection) in the case of gonorrhea.