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This specific immunosuppressive pro- cedure is an empirical application of immunological knowledge buy generic nitrofurantoin 50mg online antimicrobial wall panels, although the precise mechanism involved is not yet been completely understood buy nitrofurantoin 50 mg fast delivery antibiotics zithromax. There are other additional blood group systems against which antibodies may be produced buy nitrofurantoin now antibiotics for uti cefdinir, and which can present a risk dur- ing transfusions. Thus, the crossmatch test represents an important measure in the avoidance of transfusion problems. Immediately prior to a planned transfusion, serum from the prospective recipient is mixed with erythrocytes from the prospective donor, and serum from the prospective donor is mixed Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license The Pathological Immune Response 113 with erythrocytes from the prospective recipient. To ensure no reaction following transfusion, there should be no agglutination present in either mixture. Some potentially dangerous serum antibodies may bind to the er- ythrocytes causing opsonization, but not necessarily inducing agglutination. To check for the presence of such antibodies, anti-human immunoglobulin 2 serum is added and should it crosslink such antibodies agglutination will result. The main hall- mark of such reactions is inflammation with the involvement of comple- ment. Normally, large antigen-antibody complexes (that is, those produced in equivalence) are readily removed by the phagocytes of the reticuloendo- thelial system. Occasionally, however—especially in the presence of persistent bacterial, viral, or environmental, antigens (e. Such processes are mainly observed within infected organs, but can also occur within kidneys, joints, arteries, skin and lung, or within the brain’s plexus choroideus. Most importantly, activation of complement by such complexes results in production of inflammatory C components (C3a and C5a). Some of these anaphylatoxins cause the release of vasoactive amines which increase vascular permeability (see also p. Additional chemotactic activities attracts granulocytes which attempt to phagocytize the complexes. When these phagocytes die, their lysosomal hydrolytic en- zymes are released and cause further tissue damage. There are two basic patterns of immune complex pathogenesis: & Immune complexes in the presence of antigen excess. The acute form of this disease results in serum sickness, the chronic form leads to the de- velopment of arthritis or glomerulonephritis. Serum sickness often resulted from serum therapy used during the pre-antibiotic era, but now only occurs rarely. Inoculationwith equine antibodies directed against humanpathogens, or bacterial toxins, often induced the production of host (human) antibodies against the equine serum. Because relatively large amounts of equine serum were administered for such therapeutic purposes, such therapy would result Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license 114 2 Basic Principles of Immunology in the induction of antigen-antibody complexes—some of which were formed in the presence of antigen excess—and occasionally induced a state of shock. The so-called Arthus reaction is observed when an individual is exposed to repeated small 2 doses of an antigen over a long period of time, resulting in the induction of complexes and an antibody excess. Further exposure to the antigen, particu- larly dermal exposure, induces a typical reaction of edema and erythema which peaks after three to eight hours and disappears within 48 hours, but which sometimes leads to necrosis. Arthus-type reactions often represent occupational diseases in people exposed to repeated doses of environmental antigens: farmer’s lung (thermophilic Actinomyces in moldy hay), pigeon breeder’s lung (protein in the dust of dried feces of birds), cheese worker’s lung (spores of Penicillium casei), furrier’s lung (proteins from pelt hairs), malt-worker’s lung (spores of Aspergillus clavatus and A. This delayed skin reaction can serve as a test to confirm immunity against intracellular bacteria or parasites. Autoimmune T cells are usually directed against autoantigens that would otherwise be ignored (since they are only expressed in the extralymphatic periphery). Usage subject to terms and conditions of license Transplantation Immunity 115 basic protein in multiple sclerosis, against collagen determinants in poly- arthritis, and against islet cell components in diabetes. Interspecies re- jection is additionally contributed to by antibodies, and intolerance between complement activation mechanisms. Methods for reducing, or preventing, rejection include general immunosuppression, tolerance induction by means of cell chimerism, and sequestering of the transplanted cells or organ. This type of reaction results when immunologically respon- sive donor T cells are transferred to an allogeneic recipient who is unable to reject them (e. Usage subject to terms and conditions of license 116 2 Basic Principles of Immunology secondary lymphatic organs. Indeed the same foreign transplantation anti- gens are hardly immunogenic when expressed on fibroblasts or on epithelial or neuroendocrine cells, unless these cells are able to reach local lymphoid tissue. This can be achieved by using anti-T-cell antibo- dies, anti-lymphocyte antisera, and complement or magnetic bead cell-se- paration techniques. However, it is noteworthy that complete elimination of mature T cells leads to a reduction in the acceptance rate for bone marrow transplants, and that it may also weaken the anti-tumor effect of the trans- plant (desirable in leukemia). Bone Marrow Transplants Today & Reconstitution of immune defects involving B and T cells & Reconstitution of other lymphohematopoietic defects & Gene therapy via insertion of genes into lymphohematopoietic stem cells & Leukemia therapy with lethal elimination of tumor cells and reconstitution with histocompatible, purified stem cells, either autologous or allogenic. This also applies to transplants between monozygotic twins or genetically identical animals (syngeneic transplants). However, transplants between non-related or non-inbred animals of the same species (allogeneic transplants), and transplants between individuals of different species (xeno- geneic transplants) are immunologically rejected. These include the occurrence of natural cross-reactive antibodies, and a lack of complement in- activation by anti-complement factors (which are often species-incompatible and therefore absent in xenogeneic transplants), which together often results in hyperacute rejection within minutes, hours, or a few days—that is before any specific immune responses can even be induced. Three types of transplant rejection have been characterized: & Hyperacute rejection of vascularized transplants, occurring within min- utes to hours and resulting from preformed recipient antibodies reacting Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license Immune Defects and Immune Response Modulation 117 against antigens present on the donor endothelium, resulting in coagulation, thromboses, and infarctions with extensive necrosis. This is accompanied bya perivascular and prominent occurrence of T lymphocyte infiltrates. This is caused by low-level chronic T-cell responses, and can be mediated by cellular and hu- moral mechanisms. This can include obliterative vascular intima prolifera- tion, vasculitis, toxic, and immune complex glomerulonephritis. Methods of implanting foreign tissue cells or small organs strictly extralymphatically, without inducing immune responses, are currently undergoing clinical trials (i. Immune Defects and Immune Response Modulation & Immune defects are frequently acquired by therapy or viral infections, or as a consequence of advanced age. Immunomodulation can be attempted using interleukins or monoclonal antibodies directed against lymphocyte surface molecules or antigenic peptides. Immunostimulation is achieved using adjuvants or Kayser, Medical Microbiology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license 118 2 Basic Principles of Immunology the genetically engineered insertion of costimulatory molecules into tumor cells. Immunosuppression can be induced globally using drugs, or specifi- cally using antibodies, interleukins or soluble interleukin receptors; this can also be achieved by means of tolerance induction with proteins, peptides, or cell chimerism.
Streptodornase: Streptococcal deoxyribonuclease 184 Mixtures of streptokinase and streptodornase are used in “enzymatic debridement” 3 best buy nitrofurantoin antibiotics for acne short term. Hyaluronidase: Spreading factor It degrades the ground substance of connective tissue (hyaluronic acid) and aids in spreading infectious micro- organoism 5 order 50 mg nitrofurantoin with visa antibiotics for sinus infection not penicillin. Hemolysins: Two types Streptolysin O and Streptolysin S Antistreptolysin O antibody titer > 1:200 todd: Supportive evidence for Acute reheumatic fever 2 cheap 50 mg nitrofurantoin visa antibiotics for uti not helped. Erythrogenic toxin: Pyrogenic exotoxins It is responsible for the erythematous rash in scarlet fever. Acute rheumatic fever 185 Immunological damage to the heart valves and muscle following Streptococcal upper respiratory tract infection It clinically presents with fever, malaise, migratory non- sppurative polyarthritis, carditis, erythema marginatum and subcutaneous nodules 2. Post streptococcal acute glomerulonephritis Immunological damage to the kidney following infection of skin with streptococci It clinically manifests with generalized body edema, elevated bloood pressure, protein and blood in the urine, bloood urea nitrogen retention and low complement level. Necrotizing fascitis(Streptococcal gangrene): Extensive and rapidly spreading necrosis of skin and subcutaneous tissue S. Streptococcus mitis Streptococcus mutans Streptococcus salivarius Streptococcus sanguis Clinical features. Grow in ordinary media with shiny or dry colonies with grey-white or colorless appearance. Penicillin + Gentamicin 188 Streptococcus pneumoniae • Fastidious, lancet-shaped gram positive diplococci. Septic arthritis Laboratory Diagnosis: Specimen: Sputum, blood, cerebrospinal fluid, ear discharge and sinus drainage. Look for the appearance of capsule swelling under the 100X objective microscope Treatment: Amoxicillin Chloramphenicol Thid generation Cephalosporins Prevention and control: Pneumococcal conjugate vaccine: Immunization of individuals with type specific polysaccharide vaccine Biochemical reaction to diagnose streptococci. Cutaneous anthrax (Malignant pustule): 95 % of anthrax presentation Characterized by a black necrotic lesion with a definite edematous margin onhands, arms, face or neck with regional lymphadenitis associated systemic symptoms. Intestinal anthrax: Presents with abdominal pain, vomiting, and bloody diarrhea Bacteremic and intestinal anthrax are rare to occur Laboratory diagnosis: Specimen: Fluid or pus from skin lesion, Blood, sputum Smear: Non-capsulated gram-positive rods with centrally located spores from culture Large capsulated gram-positive rods with out spores from primary specimen. Non-hemolytic,large, dense, grey-white irregular colonies with colony margin of “Medussa Head” or “curled-hair lock” appearance due to composition of parallel chaining of cells. Biochemical reaction: Gelatin-stab culture: Gelatin liquefaction Growth along the track of the wire with lateral spikes longest near the surface Providing “inverted fur tree” appearance. Ocular infection Ocular disease following trauma from non-sugical penetrating objects 196 Manifests with keratitis, endophthalmitis, and panophthalmitis Treatment: Clindamycin + Aminoglycosides 2. Genus: Clostridium Characteristics: • Clostridia are anaerobic, spore-forming motile, gram-positive rods. PhospholipaseC (α toxin) It has lethal, necrotizing and hemolytic effect on tissue. It causes cell lysis due to lecithinase action on the lecithin which is found in mammalian cell membrane. Clostridial food poisoning It causes secretory diarrhea due to release of enterotoxin in the intestine Self-limiting diarrhea similar to that produced by B. Saccharolytic property showing reddening of the meat with a rancid smell due to carbohydrate decomposition. Proteolytic property showing blackening of the meat with unpleasant smell due to protein decomposition. Nagler reaction: Lecithinase C activity- Opacity in the egg-yolk medium due to lecithin break down 199 Procedure: 1. Treatment: Penicillin Prompt and extensive wound debridement Polyvalent antitoxin Prevention and control Early adequate contaminated wound cleansing and debridement 200 Closridium difficile General characteristics:. Not frequently found in the healthy adult, but is found often in the hospital environment. Human feces are the expected source of the organism Pathogenesis and clinical features: Administration of antibiotics like ampicillin, clindamycin and cephalosporins results in killing of colonic normal flora and proliferation of drug resistant C. Dignosis: Identification of toxin A and B in feces by latex agglutination test Treatment: Dicontinuation of offending drugs Administration of metronidazole or vancomycin 201 Clostridium tetani General characteristics: • World wide in distribution in the soil and in animal feces • Longer and thinner gram-positive rods with round terminal spores giving characteristic “drum-stick” appearance. Tetanolysin: Hemolytic property Pathogenesis and Clinical manifestation: Infection of devitalized tissue (wound, burn, injury, umblical stamp, surgical suture) by spores of C. Muscle spasm and rigidity Laboratory diagnosis: The bacteria can be cultured in a media with anaerobic atmosphere. The toxin is absorbed from the gut and acts by blocking the release of acetylcholine at synapses and neuromuscular junction and manifests with flaccid paralysis and visual disturbance, inability to swallow, and speech difficulty Death is secondary to respiratory failure or cardiac arrest 2. Treatment: Administration of intravenous trivalent antitoxin ( A,B,E) Mechanical ventilator for respiratory support Prevention and control:. Diphteria toxin causes respiratory tract epithelial destruction tesulting in formation of necrotic epithelium with pseudomembrane formation over the tonsils, pharynx, and larynx. Distant toxic damage includes parenchymal degeneration and necrosis in heart muscle, liver, kidney, adrenal glands and peripheral and cranial nerves. Wound/skin diphteria occurs chiefly in the tropics and forms membrane-covered wound that fails to heal. Laboratory diagnosis: Specimen: Swabs from the nose, throat, or suspected lesion Smears: Beaded rods in typical arrangement when stained with alkaline methylene blue or gram’s stain Culture: Small, granular,and gray, with irregular edges with small zone of hemolysis on blood agar Selective media are necessary for isolation from cilincal specimens Selective media 1. Blood tellurite agar: Produce characteristic grey-black colonies due to their ability to reduce potassium tellurite to tellurium Characteristics of C. Gel-precipitation (Elek) test: a filter paper strip previously immersed in diphteria antitoxin is incorporated into serum agar; the strain of C. Incubate at 37 c for 1-2 days, and observe for lines of precipitation in the agar indicating toxin-antitoxin interaction. Schick test: a skin test to demonstrate immunitydue to immunization or natural infection Method: Intradermal injection of toxin into the anterior aspect of one forearm and heat-inactivated toxin into the other. Reactions due to the toxin are slower and longer lasting than those resulting from hypersensitivity. Listreriolysin( hemolysin) Pathogenesis and clinical features: Transmitted to humans through ingestion of poorly coooked meat and unpasteurized milk and milk products 1. Swine is major reservoir Pathogenicity and clinical features: Most human cases of disease are related to occupational exposure, i. Diagnosis: Specimen: Blood Culture: Shows α-hemolysis on Blood agar Biochemical reaction:. Neisseria gonorrhoea Antigenic structure: antigenically heterogeneous and capable of changing its surface structures. Pili: Hair-like appendages extending from bacterial surface and enhance attachment to host cells and evade human defense. Fbp(Iron binding protein):Expressed when there is limited available iron supply 8. IgA1 protease:Splits and inactivates major mucosal IgA(IgA1) Clinical manifestation: Route of infection: Sexual contact Male:. Gonococcal urethritis If complicated: Urethral stricture Gonococcal epididymitis Gonococcal epididymo-orchitis Infertility. Gonococcal salpingitis If compicated: Gonococcal tubo-ovarian abscess 215 Pelvic peritonitis Infertility Infant (When delivered through the infected birth canal).
Lung Neoplasms Lung cancer is the leading cause of cancer deaths in the United States among both men and women buy nitrofurantoin 50mg overnight delivery antibiotics for acne philippines. Approximately 180 generic nitrofurantoin 50 mg mastercard infection 2 months after surgery,000 patients are diagnosed with lung cancer per year in the United States trusted nitrofurantoin 50mg topical antibiotics for acne list. The long-term survival for lung cancer remains poor, with only a 14% overall 5-year survival. High cure rates following resection can be expected with patients who present with early disease. It is imperative for physicians treating lung cancer to properly evaluate their patients to determine which patients may beneﬁt from surgical resection and which may beneﬁt from multi- modality therapy. Epidemiology Studies have conﬁrmed that 80% to 90% of lung cancers are caused by tobacco use. Risk factors include the age at which smoking is started, the frequency, and the duration. Studies have demonstrated an increased risk of lung cancer in people exposed to secondhand smoke. Several studies also have demonstrated an increased risk of lung cancer in uranium miners. Occupational exposure linked to lung cancer includes inhala- tion of asbestos and polycyclic aromatic hydrocarbons, and exposure to arsenic, chromates, and bis(chloromethyl)ether. Cancer Prevention Studies have linked diets high in fruits and vegetables to lower inci- dence of lung cancer, suggesting that vitamin A may help prevent lung cancer. However, the vitamin A derivative beta-carotene did not show an improvement in survival or in the prevention of lung cancer in prospective randomized studies. Ongoing studies are evaluating other agents that may reduce the risks of lung cancers. Malignant Tumors The majority of lung tumors that are malignant consist of adenocarci- noma, squamous cell carcinoma, large-cell carcinoma, or small-cell lung carcinoma (Table 13. Squamous cell carcinoma Variant: Papillary Clear cell Small cell Basaloid Small-cell carcinoma Variant: Combined small-cell carcinoma Adenocarcinoma Acinar Papillary Bronchioloalveolar carcinoma Solid adenocarcinoma with mucin Large cell carcinoma Source: Reprinted from World Health Organization. Adenocarcinoma is the most common cause of lung cancer, accounting for 46% of the cases. Adenocarcinoma most frequently presents as a peripheral lung nodule and has the tendency to spread via the lymphatics and hematogenously. Bronchoalveolar carcinoma, an adenocarcinoma subtype, may present as a discrete nodule, as mul- tifocal nodules, or as a diffuse inﬁltrating tumor. Squamous cell carcinoma typically presents as a central tumor, which can occlude a proximal bronchus. Immunohisto- chemical staining should allow for proper identiﬁcation of these tumors. Small-cell lung carcinomas have a propensity for early spread and are typically treated by chemotherapy. However, patients with small-cell lung carcinomas can present with a small tumor (less than 3-cm) without metastasis and have 5-year survivals of 50% following surgical resection. Hamartoma repre- sents 75% of all benign tumors of the lung and accounts for 8% of pulmonary neoplasm. Langenfeld Bronchial Gland Tumors Five tumors comprise bronchial gland tumors: bronchial carcinoid, adenoid cystic carcinoma, mucoepidermoid carcinoma, bronchial mucous gland adenoma, and pleomorphic mixed tumors. Ninety percent of carcinoid tumors present in the main stem or lobar bronchi, with less than 10% presenting as a solitary nodule. Because carcinoid tumors fre- quently present in major bronchi, patients may present with symptoms secondary to an obstructed airway. The more common typical carcinoid tumor only metastasizes in 5% to 6% of patients. Carci- noid tumors are a common cause of lung tumors presenting in young patients. Ninety percent of patients with typical carcinoids are cured with a surgical resection. Atypical carcinoids occur in 15% of patients and have a higher incidence of metastasis when compared to typical carcinoids. Metastatic Tumors Sarcomas and carcinomas arising from the breast, kidney, and colon have a propensity to metastasize to the lung. Although never studied in a prospective randomized trial, several studies have suggested a survival advantage in patients whose lung metastases are surgically resected. The rec- ommendation for surgical resection results from the following criteria: the lung is the only site of metastatic spread, the primary tumor is controlled, there is no effective medical treatment available, and the metastatic tumor can be resected completely. Survival appears to be dependent on the tumor type, number of metastasis, and the latency between the diagnosis of the primary tumor and the development of metastatic spread to the lung. The best survival has been in patients with solitary tumors and a latency over 1 year. However, 5-year survivals up to 20% are reported with multiple pulmonary metastasis presenting as synchronous disease. Tumors of the Mediastinum Tumors presenting in the chest cavity that are not originating from the lung or pleural surface are classiﬁed according to their location within the mediastinum (Table 13. The mediastinum anatomic alley is divided into the anterior, middle, and posterior compartments. The anterior compartment extends from the undersurface of the sternum to the anterior borders of the heart and great vessels. The posterior com- partment extends from the anterior border of the vertebral bodies to the ribs posteriorly. The middle mediastinum includes all structures between the anterior and posterior mediastinum. These anatomic boundaries serve as an excellent means to develop an accurate differ- 13. Anterior Thymus Thymoma Thymic carcinoma Carcinoid Lymphoma Germ cell tumor Thyroid Most commonly a benign goiter Parathyroid adenoma Posterior mediastinum Neurogenic tumors Benign Schwannoma (neurilemmoma) Neuroﬁbroma Ganglioneuroma Pheochromocytoma Paraganglioma Malignant Malignant schwannoma Neuroblastoma Malignant paraganglioma ential diagnosis. The anterior mediastinum consists mainly of tumors of the thymus (predominantly thymomas), lymphomas, and germ cell tumors. The majority of posterior mediastinal tumors are neuroen- docrine in origin and usually are benign in adults. Clinical Presentations Primary Tumor Patients with lung cancer typically present with symptoms (Table 13. Symptoms at presentation are from the primary tumor in 27% of patients and are dependent on the location of the tumor. Peripheral tumors are more likely to present with chest pain, dyspnea, or pleural effusion. The primary tumor may cause symptoms by direct extension into mediastinal structures. Patients may present with pain from direct rib involvement, or a tumor in the superior sulcus (Pancoast) can cause radicular arm pain and weakness from invasion of the brachial plexus. Invasion of the superior vena cava (superior vena cava syndrome) may cause facial and upper torso venous engorgement.
They differ by carrying different chlorine and ﬂuorine substitutions in the side chain which have been introduced for pharmacokinetic reasons cheap nitrofurantoin 50mg otc antibiotics for sinus infection in babies. The antibacterial effect of this betalactam is too weak for clinical use as an antibacterial drug buy nitrofurantoin 50mg antibiotic resistance keflex. It has generic nitrofurantoin 50mg fast delivery antimicrobial resistance statistics, however, another property that makes it useful in the context of treating bacterial infec- tions with penicillins. When attacked by a betalactamase, its betalactam bond is hydrolyzed as with other betalactams, but this reaction leads to an irreversible inactivation of the enzyme. That is, the betalactamase commits suicide by exposing its active center to a covalent binding with the hydrolysis product of clavulanic acid. There are two other such suicide inhibitors, sulbactam and tazobactam, which are more similar to peni- cillin in that they have ﬁve-membered sulfur-containing rings attached to the betalactam structure. This inhibition phenomenon has been turned to advantage by combining clavulanic acid with a penicillin such as amoxycillin. The betalactamase inactivation by clavulanic acid protects the penicillin from enzymic degradation. The destructive effect of clavulanic acid on the betalactamase cannot take place, and in turn its protecting effect on the penicillin is abolished (Fig. These mutationally changed betalactamases retain their betalactam-cleaving ability but have become refractory to clavulanic acid. In example 1, penicillin is degraded by betalactamase to destroy its antibacterial effect; in example 2, the presence of clavulanic acid pro- tects penicillin by inactivating the betalactamase present in the infecting bacterium, and the antibacterial effect is intact; in example 3, the infect- ing bacterium possesses a betalactamase that has mutated to exclude clavulanic acid from its substrate spectrum to make it resistant against its inhibiting effect, and the betalactamase present will then destroy the antibacterial effect of penicillin. The ﬁrst cephalosporin isolated from Cephfalosporium was cephalosporin C (4-15), of which many semisynthetic derivatives were later produced, showing differences in antibacterial spectra and in susceptibilities to different betalactamases. In analogy with penicillin G, the side chain of cephalosporin C can be removed enzymically to give 7-aminocephalosporanic acid, which can be acylated chemically to give new derivatives. Most are effective only when given parenterally, but cephalexin and ceﬁxime can be given per os. Cefuroxime is not degraded by many common betalactamases and can then be used against pathogens that are resistant to many other betalactams. Like all betalactams, cephalosporins work by interfering with the cell wall synthesis of growing bacteria. As indicated, there have been both medical and commercial incentives for medicinal chemists to synthesize cephalosporin modiﬁcations. One has been to obtain new betalactams with wide antibacterial spectra embracing different pathogens. Another reason has been to ﬁnd betalactams with an increased ability to resist betalactamases, which have been observed to increase in frequency among pathogenic bacteria. The latter goal has turned out to be very difﬁcult to achieve, at least for more than a short time, since betalactamase evolution seems to have been able to keep pace with the ability of medicinal chemists to produce new derivatives. It is also effective against penicillin-resistant Streptococcus pneumoniae strains and against penicillin-resistant Pseudomonas strains. One ﬁnding along these lines was that of monobactams occurring in soil bacteria (Fig. In these, the four-membered antibacte- rial betalactam structure is alone and not fused to another hetero- cyclic ring as in penicillins and cephalosporins. One semisyn- thetic monobactam preparation is aztreonam (4-18;tradename, Azactam). It was announced as being stable to betalactamases but has been shown to be hydrolyzed by betalactamases with an extended spectrum. This hap- pens because penicillin binds covalently to a blood protein, which the immune system then recognizes as a foreign protein. The immune system responds to it in the future by mounting an attack on penicillin and many other betalactams, whether or not they are linked to a protein. People allergic to penicillin as described can be treated safely with monobactams, which do not trigger an allergic response in the way that other betalactams would do. Thienamycins Another group of betalactams found in soil bacteria are the thienamycins, the ﬁrst member of which, thienamycin (4-19), was found in Streptomyces cattleya. Thienamycins are structurally similar to penicillins but without sulfur in the ﬁve-membered ring attached to the betalactam ring; instead, the side chain con- tains sulfur. Thienamycins are efﬁcient antibacteri- als and show a broad antibacterial spectrum. Thienamycin itself is very labile and decomposes in water solution, so is there- fore impractical for clinical use. Meropenem is a fur- ther developed semisynthetic derivative of thienamycin, which resists the renal dihydropeptidase and can therefore be admin- istered without the peptidase inhibitor cilastin. Still another thienamycin derivative is ertapenem, which is structurally simi- lar to meropenem. Betalactams have never been of much use in the treatment of tuberculosis, and one reason for the lack of efﬁciency of betalactams in this context was found inthegenom esequenceofM. The deﬁned daily dose of one of the new thien- amycin derivatives is more than 300 times more expensive than the corresponding dose of penicillin V. As mentioned earlier, these enzymes have the ability to hydrolyze the betalactam bond of betalactams to destroy their antibacterial activity completely. The cleavage product of this enzymic reaction with penicillin is penicilloic acid, which lacks antibacterial activity. They dif- fer from each other by having different substrate proﬁles toward penicillins, cephalosporins and monobactams, and carbapenems. They can be classiﬁed after their substrate proﬁle, which can include clavulanic acid. Some of the betalactamases do not attack clavulanic acid, since it is not included in their substrate proﬁle; clavulanic acid is simply not recognized by the active center of these enzymes. The oxacillinases also include the isoxazolyl derivatives cloxacillin, dicloxacillin, and ﬂucloxacillin among their substrates, mediating resistance to these penicillin deriva- tives, originally marketed as penicillinase-stable penicillins. In later years two groups of betalactamases also hydrolyzing thien- amycins (imipenem, meropenem, ertapenem) have been identi- ﬁed in pathogenic bacteria (carbapenemases). This illustrates the statement that for any clinically used betalactam, a betalactamase has also been found. The ﬁrst horizontal transfer of betalac- tamase activity discovered between bacteria was described in 1963 by Naomi Datta in London and Polyxeni Kontomichalou in Athens. This means that ampicillin is a good substrate for this betalactamase, which could not at all degrade the cephalosporins cefotaxim, ceftazidim, or cefuroxime and also not the monobac- tam aztreonam or the carbapenem imipenem. This has changed the substrate proﬁle of the enzyme to include in its substrate spectrum the cephalosporins cefotaxim and ceftazidim and the monobactam aztreonam. These amino acid changes dra- matically affect the resistance pattern of the host bacterium, which now retains only its susceptibility to imipenem. Those simple mutational changes have widened the substrate spec- trum of the betalactamase and in consequence also widened the pattern of resistance that it can mediate. The work of medicinal chemists to ﬁnd new betalactams and to modify existing ones has aimed primarily at ﬁghting resistance by ﬁnding derivatives outside the substrate spectra of clinically known betalactamases. This is a pathogen resistant to practically all betalac- tams, and thus very difﬁcult to treat.
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